Review Article

Specialized Proresolving Mediators in Innate and Adaptive Immune Responses in Airway Diseases

Published Online:https://doi.org/10.1152/physrev.00026.2017

Abstract

Airborne pathogens and environmental stimuli evoke immune responses in the lung. It is critical to health that these responses be controlled to prevent tissue damage and the compromise of organ function. Resolution of inflammation is a dynamic process that is coordinated by biochemical and cellular mechanisms. Recently, specialized proresolving mediators (SPMs) have been identified in resolution exudates. These molecules orchestrate anti-inflammatory and proresolving actions that are cell type specific. In this review, we highlight SPM biosynthesis, the influence of SPMs on the innate and adaptive immune responses in the lung, as well as recent insights from SPMs on inflammatory disease pathophysiology. Uncovering these mediators and cellular mechanisms for resolution is providing new windows into physiology and disease pathogenesis.

I. INTRODUCTION

The lung is subjected to constant provocation by airborne particles, potential pathogens, allergens, and other environmental stimuli. In the face of these irritants, it is imperative to health to maintain mucosal integrity and lung function. Inflammation integrates innate and adaptive immune responses for lung host defense and homeostasis. If unrestrained, the inflammatory response can lead to “bystander” tissue injury and organ dysfunction (166). In health, defense and controller systems exist to temper inflammation and prevent tissue damage (165). There are several processes for resolution that work in concert to returned injured, infected, or inflamed lung back to homeostasis in a process termed catabasis (165). These fundamental processes include the following: cessation of granulocyte recruitment in conjunction with induction of macrophage recruitment and differentiation; clearance of pathogens, inflammatory cells, and tissue debris; restoration of vascular integrity; regeneration and/or repair of injured tissues; remission of fever; and relief of inflammatory pain (22).

Mucosal inflammation encompasses multicellular host responses, including epithelial cell activation, an increase in vascular permeability, infiltration of polymorphonuclear leukocytes, secretion of cellular mediators, and engagement of cellular immunity. The resolution of tissue inflammation (i.e., catabasis) is an active process that is orchestrated in part by specialized proresolving mediators (SPMs). These resolution mediators transduce anti-inflammatory and proresolving actions to stop inflammation and promote catabasis. SPM actions include epithelial cell restitution to restore barrier integrity, cessation of neutrophil trafficking, efferocytosis of apoptotic neutrophils by specialized macrophages, and lymphocyte differentiation to effector cells that secrete tissue suppressive and healing cytokines like transforming growth factor (TGF)-β and amphiregulin, respectively (34).

SPMs are produced by enzymatic conversion of essential dietary fatty acids. Of interest, several epidemiological studies indicate that diets rich in omega-3 fatty acids are inversely related to the prevalence of inflammatory diseases (5, 102). In addition, omega-3 fatty acid consumption during pregnancy can protect children from asthmatic symptoms and respiratory infections (26, 214). The beneficial effects of these essential omega-3 fatty acids have been attributed in part to their enzymatic conversion to SPMs (101, 102, 253). SPMs exhibit spatial and temporal regulation of inflammatory responses in the lung and elsewhere in the body. Structurally distinct families of SPMs are classified by parent fatty acids, including lipoxins from arachidonic acid (AA, C20:4n-6); E-series resolvins from eicosapentaenoic acid (EPA, C20:n-3); and D-series resolvins, protectins, and maresins from docosahexaenoic acid (DHA, C22:n-3). Most recently, SPM-sulfido conjugates (SPM-SC) have been identified with protective roles in tissue regeneration. In several inflammatory diseases, defective SPM generation has been documented (22, 97, 155).

Significant advances have been made over the last decade in identifying these novel mediators, outlining the biochemical pathways involved in SPM biosynthesis, structural elucidation, their cellular targets, and receptors actions for resolution. In this review, we specifically focus on SPM production and their influence on innate and adaptive immune responses in the lung during sterile and infectious inflammation. We will also highlight the potential translational impact of SPMs for improving our understanding of physiology, and in forming novel research questions for bench-to-bedside insights into pathophysiology of lung diseases and potential new resolution pharmacology.

II. SPM PRODUCTION

In response to tissue injury, phospholipase A2 enzymes catalyze the release of polyunsaturated fatty acids (PUFA) from membrane phospholipids for subsequent enzymatic conversion to bioactive specialized mediators. These biosynthetic circuits are under spatiotemporal regulation (138, 157, 185). At the onset of inflammation, AA (C20:4n-6)-derived prostaglandins and leukotrienes increase blood flow and vascular permeability, facilitating leukocyte entry to the site of injury. Local leukotriene B4 biosynthesis results in a chemotactic gradient promoting neutrophil transmigration and swarming for a rapid host inflammatory response (150). Release of thrombin, collagen, and platelet-activating factor activates circulating platelets, leading to formation of heterotypic neutrophil-platelet aggregates and amplification of thromboxane A2 production (181). In turn, thromboxane A2-mediated endothelial activation leads to neutrophil-endothelial interactions and subsequent neutrophil secondary capture and transmigration into injured lung (292).

These early initiating events plant the seeds for SPM production and later resolution of inflammation. For example, the proinflammatory mediators prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2) can increase 15-lipoxygenase (15-LOX) mRNA levels (157), a key biosynthetic enzyme involved in SPM biosynthesis, and in the presence of 15-LOX, leukotriene A4 (LTA4) can be converted to lipoxins (163). Neutrophil-platelet interactions can facilitate transfer of lipid mediator precursors from one cell type to another, resulting in transcellular biosynthesis of lipoxins and other SPMs (92, 245). As part of an endogenous resolution program, lipid mediator class switching changes AA metabolism from the production of proinflammatory mediators to the production of SPMs (157).

A systems biology approach combining liquid chromatography-mass spectrometry-based lipid mediator metabololipidomics, total organic synthesis, matching studies with determination of structure-activity relationships, and quantifiable resolution indexes have uncovered several families of fatty acid-derived lipid mediators in resolving exudates. Specific proresolving bioactions define candidate lipid mediators as SPMs; namely, 1) inhibition of granulocyte recruitment and activation, 2) nonphlogistic recruitment of macrophages, 3) clearance of leukocytes from mucosal surfaces, and 4) enhanced antimicrobial actions. Lipidomic profiling products of omega-3 essential fatty acid metabolism demonstrates enzymatic conversion of DHA to D-series resolvins (235), maresins (246), and protectins (195), whereas EPA is enzymatically converted to E-series resolvins (236). Docosapentaenoic acid (DPA; C22:n-3), the intermediate between EPA conversion to DHA, can also serve as a substrate for SPM biosynthesis to n-3-DPA-resolvins, n-3-DPA-maresins, and n-3-DPA protectins (68) as well as the 13-series resolvins (69). Glutathione transferases catalyze conversion of SPM epoxide intermediates to families of SPM-SC, such as the maresin conjugates for tissue regeneration (MCTRs) (66), resolvin conjugates for tissue regeneration (RCTRs), and protectin conjugates for tissue regeneration (PCTRs) (69). Of note, metabololipidomics has enabled precise identification and sensitive detection of SPMs in various tissues and inflammatory responses, including whole blood, isolated cells, lungs and solid tissue samples, breast milk, tears, and others (14, 43, 58, 238).

Of interest, epimers of select SPMs are produced in vivo and in some cases exhibit increased potency and longer half-lives in tissues relative to their respective lipoxygenation products (55). Epimer SPM biosynthetic pathways include cytochrome P-450 (CYP450) enzymes, many of which are abundant in the lung (54, 73). For example, AA can be converted by CYP450 enzymes to 15R-hydroxyeicosatetraenoic acid, which can serve as a substrate for 5-lipoxygenase for production of epimer lipoxins (55), including 15R-epi-lipoxin A4 (15-epi-LXA4) and 15R-epi-lipoxin B4 (15-epi-LXB4). In addition, aspirin, the lead nonsteroidal anti-inflammatory drug, can also induce biosynthesis of epimer lipoxins via 15R-hydroxyeicosatetraenoic acid production by aspirin acetylated COX-2. Irreversible acetylation of the COX-2 catalytic site blocks prostaglandin synthesis, yet the acetylated enzyme is not completely inactivated and can convert AA to this biosynthetic intermediates for 15-epi-LXA4 that has also been termed aspirin-triggered LXA4. The aspirin acetylated COX-2 can also convert omega-3 fatty acids to biosynthetic intermediates for aspirin-triggered resolvins and other aspirin-triggered SPMs. In addition to aspirin, other commonly used medicines can influence epimer SPM generation. For example, pioglitazone and atorvastatin increased cardiac myocyte-specific 15-epi-LXA4 production (24), and lovastatin increases lung-specific 15-epi-LXA4 generation via a pathway that includes 14,15-epoxyeicosatrienoic acid (14,15-EET) production (213).

Lipidomic profiling of self-limited inflammatory exudates during resolution has identified SPM and epimer-SPM biosynthetic pathways, and physical chemistry experiments have elucidated the structure and stereochemistry of each member of the major SPM families (244). The biosynthesis of each of these families of endogenous proresolving autacoids is briefly reviewed here, and a list of SPMs, chemical names, and trivial names can be found in TABLE 1.

Table 1. SPM names and chemical structure

Name Abbreviation Chemical Structure
Arachidonic acid SPM metabolome
Lipoxins
    Lipoxin A4 LXA4 5S,6R,15S-trihydroxy-7E,9E,11Z,13E-eicosatetraenoic acid
    Lipoxin B4 LXB4 5S,14R,15S-trihydroxy-6E,8Z,10E,12E-eicosatetraenoic acid
    15-Epimer-lipoxin A4 15-epi-LXA4 5S,6R,15R-trihydroxy-7E,9E,11Z,13E-eicosatetraenoic acid
    15-Epimer-lipoxin B4 15-epi-LXB4 5S,14R,15R-trihydroxy-6E,8Z,10E,12E-eicosatetraenoic acid
Eicosapentaenoic acid SPM metabolome
E-series resolvins
    Resolvin E1 RvE1 5S,12R,18R-trihydoxy-6Z,8E,10E,14Z,16E-eicosapentaneoic acid
    Resolvin E2 RvE2 5S,18R-dihydroxy-6E,8Z,11Z,14Z,16E-eicosapentaneoic acid
    Resolvin E3 RvE3 17R,18S-dihydroxy-5Z,8Z,11Z,13E,15E-eicosapentaneoic acid
Docosahexaenoic acid SPM metabolome
D-series resolvins
    Resolvin D1 RvD1 7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid
    Resolvin D2 RvD2 7S,16R,17S-trihydroxy-4Z,8E,10Z,12E,14E,19Z-docosahexaenoic acid
    Resolvin D3 RvD3 4S,11R,17S-trihydroxy-5Z,7E,9E,13Z,15E,19Z-docosahexaenoic acid
    Resolvin D4 RvD4 4S,5R,17S-trihydroxy-6E,8E,10Z,13Z,15E,19Z-docosahexaenoic acid
    Resolvin D5* RvD5 7S,17S-dihydroxy-4,8,10,13,15,19-docosahexaenoic acid
    Resolvin D6* RvD6 4S,17S-dihydroxy-5,7,10,13,15,19-docosahexaenoic acid
    17-Epimer-resolvin D1 17-epi-RvD1 7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid
    17-Epimer-resolvin D2 17-epi-RvD2 7S,16R,17R-trihydroxy-4Z,8E,10Z,12E,14E,19Z-docosahexaenoic acid
    17-Epimer-resolvin D3 17-epi-RvD3 4S,11R,17R-trihydroxy-5Z,7E,9E,13Z,15E,19Z-docosahexaenoic acid
    17-Epimer-resolvin D4 17-epi-RvD4 4S,5R,17R-trihydroxy-6E,8E,10Z,13Z,15E,19Z-docosahexaenoic acid
    17-Epimer-resolvin D5* 17-epi-RvD5 7S,17R-dihydroxy-4, 8,10,13,15,19-docosahexaenoic acid
    17-Epimer-resolvin D6* 17-epi-RvD6 4S,17R-dihydroxy-5,7,10,13,15,19-docosahexaenoic acid
    Resolvin conjugate for tissue regeneration 1 RCTR1 8-glutathionyl-7,17-dihydroxy-4Z,9,11,13Z,15E,19Z-docosahexaenoic acid
    Resolvin conjugate for tissue regeneration 2 RCTR2 8-cysteinylglycinyl-7,17-dihydroxy-4Z,9,11,13Z,15E,19Z-docosahexaenoic acid
    Resolvin conjugate for tissue regeneration 3 RCTR3 8-cysteinyl-7,17-dihydroxy-4Z,9,11,13Z,15E,19Z-docosahexaenoic acid
Protectins
    Protectin D1 PD1 10R,17S-dihydroxy-4Z,7Z,11E,13E,15Z,19Z- docosahexaenoic acid
    17-Epimer-protectin D1 17-epi-PD1 10R,17R-dihydroxy-4Z,7Z,11E,13E,15Z,19Z- docosahexaenoic acid
    Protectin conjugate for tissue regeneration 1 PCTR1 16-glutathionyl-17-hydroxy-4Z,7Z,10,12,14,19Z-docosahexaenoic acid
    Protectin conjugate for tissue regeneration 2 PCTR2 16-cysteinylglycinyl-17-hydroxy-4Z,7Z,10,12,14,19Z-docosahexaenoic acid
    Protectin conjugate for tissue regeneration 3 PCTR3 16-cysteinyl-17-hydroxy-4Z,7Z,10,12,14,19Z-docosahexaenoic acid
Maresins
    Maresin 1 MaR1 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-DHA
    Maresin 2 MaR2 13R,14S-dihydroxy-4Z,7Z,9E,11E,16Z,19Z-DHA
    Maresin conjugate for tissue regeneration 1 MCTR1 13R-glutathionyl-14S-hydroxy-4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid
    Maresin conjugate for tissue regeneration 2 MCTR2 13R-cysteinylglycinyl-14S-hydroxy-4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid
    Maresin conjugate for tissue regeneration 3 MCTR3 13R-cysteinyl-14S-hydroxy-4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid
Docosapentaenoic acid SPM metabolome
Resolvin T1* RvT1 7,13,20-trihydroxy-8,10,15,17,19-docosapentaenoic acid
Resolvin T2* RvT2 7,12,13-trihydroxy-8,10,14,16,19-docosapentaenoic acid
Resolvin T3* RvT3 7,8,13-trihydroxy-9,11,14,16,19-docosapentaenoic acid
Resolvin T4* RvT4 7,13-dihydroxy-8,10,14,16,19-docosapentaenoic acid
Resolvin 1 n-3 DPA* RvD1n-3 DPA 7,8,17-trihydroxy-9,11,13,15E,19Z-docosapentaenoic acid
Resolvin 2 n-3 DPA* RvD2n-3 DPA 7,16,17-trihydroxy-8,10,12,14E,19Z-docosapentaenoic acid
Resolvin 5 n-3 DPA* RvD5n-3 DPA 7,17-trihydroxy-8E,10,13,15E,19Z-docosapentaenoic acid
Protectin 1 n-3 DPA* PD1n-3 DPA 10,17-dihydroxy-7Z,11,13,15,19Z-docosapentaenoic acid
Protectin 2 n-3 DPA* PD2n-3 DPA 16,17-dihydroxy-7Z,10,13,14,19Z- docosapentaenoic acid
Maresin 1 n-3 DPA* MaR1n-3 DPA 7,14-dihydroxy-8,10,12,16Z,19Z-docosapentaenoic acid
Maresin 2 n-3 DPA* MaR2n-3 DPA 13,14-dihydroxy-7Z,9,11,16Z,19Z-docosapentaenoic acid
Maresin 3 n-3 DPA* MaR3n-3 DPA 4,21-dihydroxy-7Z,10Z,12E,16Z,19Z-docosapentaenoic acid

*Complete stereochemistry is being determined.

A. Lipoxins

Lipoxins are lipoxygenase interaction products, and the first family of SPMs to be discovered (241). LXA4 (5S,6R,15S-trihydroxy-7E,9E,11Z,13E-eicosatetraenoic acid) and LXB4 (5S,14R,15S-trihydroxy-6E,8Z,10E,12E-eicosatetraenoic acid) are generated from AA by the sequential actions of 5-LOX and 15-LOX (240). As lipoxygenase activity is predominantly compartmentalized into different cell types, lipoxins are generally produced by bidirectional transcellular biosynthesis during multicellular host responses, such as inflammation (92). The inflammatory milieu brings leukocytes in close proximity to tissue stromal cells, allowing for exchange of AA-derived biosynthetic precursors and generation of lipoxins that neither cell type alone can produce in significant amounts. In response to lung inflammation, transcellular biosynthesis in the lung occurs under spatial and temporal regulation. In upper and lower airways, epithelial 15-LOX can convert AA to 15S-hydroxyeicosatetraenoic acid (15S-HETE), which can be transformed by neutrophil 5-LOX to LXA4 and LXB4 (78, 153, 163). At sites of vascular inflammation, lipoxins can be generated during platelet-neutrophil interactions; platelet 12-LOX acts as an lipoxin synthase to convert neutrophil 5-LOX-derived LTA4 to LXA4 and LXB4 (92, 245).

Distinct from insertion of molecular oxygen by lipoxygenases that give rise to the (S) enantiomer (244), CYP450 enzymes and aspirin-acetylated COX-2 utilize water to hydroxylate the AA backbone, resulting in epimer-lipoxin enantiomers (54, 73, 141). Acetylation by aspirin of a serine in the catalytic center of COX-2 inhibits prostaglandin production and allows conversion of AA to 15R-HETE, which can serve as a substrate for subsequent conversion by 5-LOX to 15-epi-LXA4 (55). In addition, 15R-HETE can also be produced by statin-nitrosylated COX-2 (24, 213). Lovastatin triggers transcellular biosynthesis of 15-epi-LXA4 during neutrophil-airway epithelial cell interactions (213). Furthermore, lovastatin increases levels of the CYP450-derived 14,15-EET, which indirectly alters AA metabolism to favor 15-epi-LXA4 biosynthesis. This aspirin-independent pathway for 15-epi-LXA4 generation can be amplified by inhibitors of soluble epoxide hydrolase (213) and is subject to sabotage by Pseudomonas aeruginosa and related bacteria that can harbor the virulence factor Cif with epoxide hydrolase activity (96).

Furthermore, peroxisome proliferator-activated receptor-γ agonists, such as rosiglitazone (254), and pioglitazone (24), can increase 15-epi-lipoxin biosynthesis via pathways that remain to be determined. Lipoxin and 15-epi-lipoxin biosynthetic routes are illustrated in FIGURE 1, and drugs impacting their production are noted in TABLE 2.

FIGURE 1.

FIGURE 1.Biosynthesis of lipoxin family. Lipoxin biosynthesis requires insertion of molecular oxygen at C15 on arachidonic acid (AA; C20:4n-6). This can occur via 15S-HETE generation by 15-LO or conversion of LTA4 by 15-LO or 12-LO. Aspirin-triggered lipoxin biosynthesis requires 15R-HETE generation by acetylated COX2 or CYP450 enzymes. The aspirin-triggered mediators are in a dashed box.


Table 2. Action of drugs on SPM generation

Drug Action on SPM and Function Dose and Route Reference Nos.
Statins
Lovastatin Promotes lung-specific generation of 15-epi-LXA4 and decreases acute lung injury 0.2 or 2 mg/kg (iv) 213
Atorvastatin Increases cardiac myocyte-specific generation of 15-epi-LXA4 10 mg/kg (oral) 24
Aspirin
Aspirin Aspirin-triggered lipoxins inibit allergic airway hyperresponsiveness and inflammation 10 μg·mouse−1·day−1 (iv) 158
Aspirin-triggered lipoxins decrease neutrophilic inflammation and bacterial burden in cystic fibrosis ling 10 μg/ml (oral) plus 1 μg (iv) 136
Aspirin-triggered lipoxins attenuate LPS-induced acute lung injury 0.7 mg/kg (iv) 133
Aspirin-triggered lipoxins protect from acid-induced acute lung injury 0.125 g/kg (ip) 99
Aspirin-triggered resolvin D1 attenuates bacterial pneumonia 100 ng/mouse (iv) 2
Aspirin-triggered resolvin D3 reduces acid-induced lung injury 10 ng/mouse (iv) 59
Steroids
Dexamethasone Upregulates ALX receptor in neutrophils and monocytes 10−5 M in vitro cell culture concentration 109, 115, 230
Budesonide Blunts LPS-induced ALX/FPR2 expression 10 μg/mouse (in) 30

B. Resolvins

In addition to AA, the essential n-3 PUFAs are also available at sites of inflammation for enzymatic transformation to bioactive lipid mediators. In health, the total fatty acid pool in whole blood contains EPA (∼0.5–2.8% of total fatty acids) and DHA (∼1.3–5.0%) (5, 274). During resolution of a self-limited experimental model of acute inflammation, liquid chromatography-tandem mass spectrometry-based profiling of resolving exudates reveals that EPA and DHA are enzymatically converted in vivo into specific bioactive products with protective anti-inflammatory and proresolving actions. E-series resolvins (resolution phase interaction products) from EPA and D-series resolvins from DHA were the first n-3 PUFA-derived families to be discovered.

C. E-Series Resolvins

As with AA, EPA can be converted into 18R-hydroxy-EPA (18R-HEPE) by CYP450 enzymes and aspirin-acetylated COX-2 (236). This intermediate can be subsequently transformed by 5-LOX in activated leukocytes to 5S (6)-epoxy-18R-HEPE. This epoxy intermediate can next be converted by hydrolases to RvE1 (5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-EPA) (12). RvE1 biosynthesis can also be initiated via CYP450-mediated oxygenation of EPA to 18R-HEPE in the absence of aspirin (237). RvE2 (5S,18R-dihydroxy-6E,8Z,11Z,14Z,16E-EPA) can be generated from the RvE1 precursor, 5S-hydroperoxy-18-hydroxy-EPA, via 5-LOX in a parallel stereospecific pathway (268). RvE1 and RvE2 are present in resolving exudates and human whole blood (205, 268). 18S-HEPE is also a substrate for conversion by 5-LOX and LTA4 hydrolase to epimeric RvE1 and RvE2 (199). A third member of the E-series resolvins is RvE3 (17R,18S-dihydroxy-5Z,8Z,11Z,13E,15E-EPA) with a natural C-18 stereoisomer of RvE3 (131). This molecule is generated via the actions of 12/15-LOX, which is distinct from RvE1 and RvE2 (130) (FIGURE 2).

FIGURE 2.

FIGURE 2.Biosynthesis of E-series resolvins. Eicosapentaenoic acid (EPA; C20:5n-3; blue box) is converted via aspirin acetylated COX-2 to the intermediate 18R-HEPE. The intermediate 18R-HEPE is transformed via neutrophil 5-LOX to RvE1 or RvE2. RvE3 is generated directly from 18R-HEPE via 15-LOX or 12-LOX.


D. D-Series Resolvins

A distinct family of resolvins can also be derived from DHA. The biosynthetic conversion of DHA to D-series resolvins (RvD1–RvD6) involves insertion of molecular oxygen at the C-17 position catalyzed by 15-LOX to produce 17S-hydroxy-DHA, followed by a second lipoxygenation via 5-LOX at the C-7 or C-4 position, giving two possible peroxide intermediates (242, 244). The 7-peroxy intermediate can be converted to a 7S,8S-epoxide, followed by enzymatic hydrolysis to RvD1 and RvD2 or enzymatic reduction to RvD5, whereas the 4-peroxy intermediate can be similarly enzymatically converted to RvD3, RvD4, and RvD6. In addition, epimeric D-series resolvins can be synthesized via the actions of CYP450 enzymes or aspirin-acetylated COX-2 that converts DHA (C22:6) to 17R-hydroxy-DHA (125, 242). The latter can then follow a similar biosynthetic pathway and lead to formation of 17R-epi-RvD1, 17R-epi-RvD2, 17R-epi-RvD3, 17R-epi-RvD4, 17R-epi-RvD5, and 17R-epi-RvD6. Each of these resolvins has a distinct chemical structure (TABLE 1), and the precise stereochemistry of RvD1, RvD2, RvD3, and RvD4 has been established experimentally (70, 246, 261, 280).

E. Protectins

In addition to D-series resolvins, DHA can be converted to protectins (or neuroprotectins when generated in neural tissues) (125, 175, 195). Biosynthesis involves 15-LOX-dependent formation of a C16,17-epoxide intermediate followed by enzymatic hydrolysis to protectin D1 (PD1) with the following stereochemistry: 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid (125, 239). As with lipoxins and resolvins, CYP450 enzymes or aspirin acetylated COX-2 can convert DHA to epimeric PD1 with the complete stereochemistry of 10R,17R-dihydroxy-4Z,7Z,11E,13E,15Z,19Z-DHA (17-epi-PD1) (175). In keeping with the definition of SPM, protectins carry stereoselective anti-inflammatory and proresolving actions in vivo (175, 239).

F. Maresins

Maresins (macrophage mediators in resolving inflammation) are another family of DHA-derived SPM first identified in macrophages (246). Maresin biosynthesis begins with 12-LOX conversion of DHA to 13S,14S-epoxy-DHA followed by hydrolysis to MaR1 (7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-DHA) (238), or MaR2 (13R,14S-dihydroxy-4Z,7Z,9E,11E,16Z,19Z-DHA) (72). MaR1 is also produced during cell-cell interactions. Transcellular biosynthesis of MaR1 can occur with neutrophil-platelet aggregates via interactions between platelet 12-LOX and neutrophil hydrolases (1). MaR1 is lung protective in murine models of lung injury (1, 108, 278). In addition, MaR1 acts directly to promote tissue regeneration in planaria, emphasizing preservation of ancient evolutionary bioactions for this family of SPMs (238). The biosynthetic pathways of D-series resolvins, protectins, and maresins are illustrated in FIGURE 3.

FIGURE 3.

FIGURE 3.Biosynthesis of D-series resolvins, protectins, and maresins. Docosahexaenoic acid (DHA; C22:6n-3; blue box) is converted by 15-LO to the intermediate 17S-hydroperoxy-DHA. The hydroperoxy molecule is further catalyzed by 5-LOX (present in neutrophils) to the D-series resolvins, RvD1–RvD6 (RvD6 not shown here). Aspirin-triggered resolvin biosynthesis requires acetylated COX-2 or CYP450 enzymes. DHA can also be converted via 15-LOX to a 16,17-epoxy-protectin intermediate and then on to protectin D1. The conversion to the aspirin-triggered form requires the presence of COX-2 and hydrolase enzymes. DHA is metabolized via 12-LOX in macrophages to a 13S,14S-epoxy-maresin and then through enzymatic hydrolysis to MaR1. The aspirin-triggered mediators are in dashed boxes.


G. SPM-Sulfido Conjugates for Tissue Regeneration

Recently, systematic metabololipidomic profiling of resolving infectious exudates and human tissues identified peptide-lipid conjugate molecules that accelerate resolution of infection and stimulate phagocytic functions, tissue regeneration, and repair, thereby fulfilling criteria as immunoresolvents, namely agents that stimulate resolution of inflammation (66). Biosynthesis of these sulfido-conjugates begins with DHA lipoxygenation and conversion to a 13S,14S-epoxy-maresin intermediate, followed by insertion of glutathione by LTC4 synthase and glutathione-S-transferase M4 to produce MCTR1 (13R-glutathionyl, 14S-hydroxy-4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid) (66, 280). Conversion of MCTR1 to MCTR2 (13R-cysteinylglycinyl, 14S-hydroxy-4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid) proceeds via γ-glutamyl transferase (280). Dipeptidases then cleave cysteinyl-glycinyl bond of MCTR2 to give MCTR3 (13R-cysteinyl, 14S-hydroxy-4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid) (280). Further metabololipidomic profiling uncovered sulfido-conjugation of the DHA-derived resolvin and protectin epoxide intermediates, giving RCTRs and PCTRs (69) (TABLE 1). Biosynthesis and actions of MCTRs, RCTRs, and PCTRs in lung tissues are currently under investigation (66).

H. DPA-Derived SPM

In mammals, α-linolenic acid (9Z,12Z,15Z-octadecatrienoic acid; ALA) is converted via elongation and desaturation to EPA and subsequently to DHA. An intermediate in the conversion of EPA to DHA is n-3 docosapentaenoic acid (7Z,10Z,13Z,16Z,19Z-docosapentaenoic acid; n-3 DPA) (71). Using targeted lipid mediator metabololipidomics, n-3 DPA products were identified and found to have biological actions, namely reduced neutrophil chemotaxis and adhesion, and enhanced macrophage phagocytosis (68). The new n-3 DPA structures include 7,8,17-trihydroxy-9,11,13,15E,19Z-docosapentaenoic acid (RvD1n-3 DPA), 7,14-dihydroxy-8,10,12,16Z,19Z-docosapentaenoic acid (MaR1n-3 DPA), and related bioactive products (68) (TABLE 1). Additional n-3 DPA hydroxylation products identified by liquid chromatography-tandem mass spectrometry were found to have a C13 alcohol (69). These 13-series resolvins (RvT1, RvT2, RvT3, RvT4) were found to promote survival in a mouse model of bacterial sepsis (69, 151).

I. SPM Biosynthesis in Lung Tissue

Targeted metabololipidomics of healthy murine lung tissue identified baseline levels of several SPMs, including epimer SPMs (1, 2, 59, 146). In preclinical animal models of injury, infection, and inflammation, lung SPM production increases selectively. For example, MaR1 is upregulated in sterile lung injury (1) and allergic airway inflammation (146), but follows different kinetics in lungs infected with E.coli (2). 17-epi-RvD3 is also increased in sterile lung injury, but its levels peak much later than MaR1 (59). MaR1 biosynthesis demonstrates spatial regulation; intravascular neutrophil-platelet aggregates produce the lion’s share of MaR1 during the first 2 h after experimental acute lung injury, whereas later production is neutrophil independent (1). In addition to leukocytes and platelets, the cellular sources of SPMs include lung structural cells from the airways and alveoli, such as bronchial epithelial cells (28) and alveolar epithelial type II cells (88), as well as alveolar macrophages (163), all of which possess at least part of the enzymatic machinery to synthesize SPMs. SPM biosynthesis principally occurs during cell-cell interactions in vivo, such as during neutrophil-epithelial cell interactions (213), neutrophil-platelet interactions (1), and interactions between epithelial cells and mesenchymal stem cells (88). Aspirin-triggered SPM biosynthesis depends on increased COX-2 expression and subsequent acetylation, which can result in a different time course for aspirin-triggered SPM biosynthesis compared with SPM and endogenous epimer SPMs (98). Aspirin treatment results in increased aspirin-triggered-LXA4 during resolution of inflammation after hydrochloric acid-induced acute lung injury (99). Individual SPM and epimer SPM tissue levels have kinetics that are context and organ specific, differing even between murine sterile lung injury and bacterial pneumonia (2). In summary, spatial and temporal regulation of SPM production in the lung emphasizes unique and nonredundant bioactive properties of individual SPMs for lung biology.

J. SPM Metabolism

SPMs are autacoids that are rapidly produced, locally active, and rapidly inactivated via local enzymatic catabolism in target tissues. Several enzymatic pathways are involved in SPM metabolism, including ω-oxidation, dehydrogenation, and/or reduction. LXA4 is converted to inactive oxo and hydroxylated metabolites by sequential dehydrogenation and reduction involving 15-hydroxyprostaglandin dehydrogenase (PGDH) (56). In the lung, RvE1 is further metabolized by PGDH to 18-oxo-RvE1, which lacks the protective actions of its precursor (98), and alveolar macrophages enzymatically convert RvD1 to the inactive 17-oxo-RVD1 (225). Of note, 17-epi-RvD1 partially resists metabolism by PGDH (225). In some instances, SPM further metabolism gives products that retain the proresolving actions of the parent SPM. PD1 is enzymatically converted by CYP1 monooxygenases to 22-OH-protectin D1 that also potently regulates leukocytes (271). Whereas macrophages convert MaR1 to the inactive 14-oxo-MaR1, neutrophils convert MaR1 to 22-OH-MaR1, which carries similarly potent bioactions on leukocyte responses (2). Identification of these inactivation pathways has enabled the design and development of SPM analogs that resist further metabolism (49).

III. RECEPTORS FOR SPMs

The finding that SPMs regulate select bioactions by specific cell types at nanomolar concentrations suggested receptor-mediated signaling. Subsequent investigations led to the identification of the LXA4 receptor ALX/FPR2 (90), a 7-transmembrane G protein-coupled receptor (GPCR). The identification of multiple additional receptors followed, all of which specifically bind SPMs and regulate select immune and nonimmune cell types (FIGURE 4). In addition, specific SPMs can antagonize select proinflammatory receptors.

FIGURE 4.

FIGURE 4.SPM receptors and their cell targets. SPMs signal are via specific G protein-coupled receptors. Many of these receptors have been identified. Lipoxin A4 (LXA4) and some D-series resolvins, including RvD1, are agonists for the ALX/FPR2 receptor. Select D-series resolvins are also agonists at the DRV1 and DRV2 receptors. RvE1 and RvE2 signal via CMKLR1/ERV receptor and have antagonistic effects on the BLT1 receptor. The receptors for protectins and maresins have not been identified. SPMs evoke different immune responses based on the receptor expression on the cell type.


A. ALX/FPR2

Of the proresolving receptors, the most detailed information is available for the ALX/FPR2 receptor. The ALX/FPR2 receptor is a 7-transmembrane GPCR that can interact with and transmit intracellular signals from LXA4, 15-epi-LXA4, RvD1, and 17-epi-RvD1 (50, 90, 147, 148). The receptor displays specific binding of radiolabeled [11,12-3H]LXA4 (91). LXA4 binding at ALX/FPR2 is reversible, stereoselective, and specific relative to LXB4, LTB4, LTD4, and PGE2 (50, 91). In addition to LXA4 and 15-epi-LXA4, RvD1 and 17-epi-RvD1 are high-affinity ligands of ALX/FPR2 with a Kd of ~0.17 nM (148). The glucocorticoid-induced protein annexin A1 (ANXA1) and its associated NH2-terminal peptides also bind specifically with ALX/FPR2 receptors with proresolving effects (211). There are several other peptide ligands for ALX/FPR2 receptors, including bacterial-derived peptides, host-derived peptides [e.g., serum amyloid A (SAA), PrP106–126, amyloid β peptide Aβ42], HIV 1 envelope peptides (e.g., T21, N36, F peptide), mitochondria-derived peptides (e.g., MT-ND1), and other neurotoxic and synthetic peptides (50). While peptide ligands can bind at all seven transmembrane domains, the seventh transmembrane domain is specific for lipid ligands (50).

First identified in human neutrophils, ALX/FPR2 receptors are also expressed on human eosinophils, monocytes, macrophages, T cells, synovial fibroblasts, airway and intestinal epithelium, natural killer (NK) cells, and innate lymphoid cells (ILCs) (21, 28, 50, 90, 171). LXA4 binding to ALX/FPR2 receptor evokes cell-specific responses. For instance, LXA4-ALX/FPR2 interactions inhibit neutrophils yet stimulate monocytes in a nonphlogistic manner (171). Receptor orthologs with conserved structure and function are present in mice (263) and rats (51). ALX/FPR2-deficient mice have increased inflammation with delayed resolution in response to an arthritic inflammatory challenge (76), indicating that ALX/FPR2 signaling can control the amplitude and duration of acute inflammation (165, 194). Allergic lung inflammation is decreased by transgenic human ALX receptor expression in murine leukocytes (158). At the cellular level, ALX/FPR2 expression is controlled by local factors, such as inflammatory mediators, epigenetic mechanisms, and transcription factors (165, 251). Of interest, ALX/FPR2 expression is increased by the activation of its promoter by LXA4 in a positive feedback manner (251). This pathway is relevant to the chronic inflammation of severe asthma, as diminished LXA4 generation and ALX/FPR2 expression on granulocytes are evident (166). In mucosal epithelium, the lymphocyte-derived cytokines IL-13 and IFN-γ increase transcription of ALX receptors that, in the presence of LXA4, can counterregulate IL-8- and TNF-α-driven inflammation (110).

B. DRV1/GPR32

In addition to LXA4, RvD1 also binds ALX/FPR2 to initiate anti-inflammatory and proresolving actions. RvD1 can also serve as a high-affinity ligand for GPR32 in human leukocytes (148). Since RvD1 acts directly on GPR32, the name resolvin D1 receptor, or DRV1, was adopted per nomenclature committee recommendations (32). DRV1/GPR32 is expressed on human neutrophils, lymphocytes, macrophages, monocytes, and vascular tissues (148). 17-Epi-RvD1 binds to DRV1/GPR32 with similar affinity as RvD1 (147, 261), and other D-series resolvins, namely RvD3, 17-epi-RvD3, RvD4, and RvD5, can also transmit signals through interactions with DRV1/GPR32 (47, 70, 242, 261).

Human neutrophils express both ALX/FPR2 and DRV1/GPR32. RvD1-receptor binding is associated with the relative abundance of ligand. RvD1 binds with high affinity to DRV1 at low concentrations (~0.1–10 nM), and can engage ALX/FPR2 at higher concentrations (10–100 nM) (204). With preferential upregulation of cell surface ALX/FPR2 via granules associated with neutrophil activation, RvD1 can bind to ALX/FPR2 for control of neutrophil responses (47, 204). This suggests a physiological role of RvD1-DRV1/GPR32 interactions in homeostatic actions (47).

C. DRV2/GPR18

The resolvin D2 receptor, DRV2, has been identified as a GPCR previously labeled GPR18 (44). DRV2/GPR18 is expressed on human and murine neutrophils, monocytes, and macrophages and signals for antibacterial phagocytic functions and organ protection (44). RvD2 protective actions are disrupted in DRV2/GPR18-deficient mice. In DRV2/GPR18-deficient mice, exudates from a murine infection model contain a higher amounts of proinflammatory lipid mediators and lower amounts of SPMs (45). The decreased abundance of SPMs in the DRV2/GPR18-deficient mice highlights the impact of the RvD2-receptor binding and suggests a similar role in human infection (45).

D. ERV1/CMKLR1

The resolvin E1 receptor (ERV1) was originally characterized as the chemokine receptor-like 1 (CMKLR1) and was also referred to as the ChemR23 receptor, based on its binding to the peptide chemokine chemerin (281). RvE1 is a high-affinity (Kd ~11.3 nM) and stereoselective ligand for ERV1/CMKLR1 (12, 13). Binding both peptide and lipid ligands is a property shared with ALX/FPR2 (12), and these receptors have 36% homology in the proposed lipid-binding domains (12, 50). In addition to RvE1, RvE2 binds to ERV1/CMKLR1 with a Kd of ~25 nM as a partial agonist (205).

In humans, ERV1/CMKLR1 is expressed on NK cells, ILC2s, macrophages, monocytes, dendritic cells, and epithelial cells (21, 35, 38, 74, 228). ERV1/CMKLR1 is more abundantly expressed on M1 murine peritoneal macrophages than M2 macrophages, suggesting a role for RvE1 in polarizing macrophage function (121). Of interest, an important role of ERV1/CMKLR1 in anti-viral immunity was identified by recognition of impaired lung responses to viral pneumonia in receptor-deficient mice (27).

E. Antagonism of Proinflammatory Receptors

In addition to binding to the proresolving receptor ERV1/CMKLR1, RvE1 and RvE2 can bind to the LTB4 receptor BLT1 (13). LTB4 mediates leukocyte chemotaxis (291) and swarming via interactions with BLT1 (150). While human neutrophils do not express ERV1/CMKLR1, RvE1 and RvE2 can serve as BLT1 receptor antagonists for inhibition of LTB4-mediated chemotaxis, intracellular calcium release, and NF-κB activation (13). Additionally, LXA4 and 15-epi-LXA4 bind the leukotriene D4 receptor (CysLT1) to antagonize leukotriene D4-mediated events (111). SPMs may also function as partial agonists of proinflammatory receptors. RvE1 enhances phagocytosis-induced neutrophil apoptosis via BLT1 signaling (82, 83) FIGURE 5. These examples of receptor antagonism and partial agonism provide important additional mechanisms for SPM control of proinflammatory signaling (13).

F. Multiple Ligands

Of interest, several of the proresolving receptors bind multiple ligands, including peptide and lipid mediators with ligand-specific signal transduction. The diverse ligands that activate the ALX/FPR2 receptor exemplify this concept. A myosin heavy chain binding peptide derived from mitochondrial NADH hydrogenase interacts with ALX/FPR2 receptors to trigger neutrophil chemotaxis and increase macrophage phagocytosis of neutrophils (46, 187). A naturally cleaved urokinase plasminogen activator receptor fragment primarily functions in fibrinolysis, but this fragment can also bind to ALX/FPR2 to serves as an endogenous chemotactic agonist (221). SAA is produced as an acute phase reactant during inflammation and binds to ALX/FPR2 as a leukocyte chemoattractant that, during resolution, is allosterically inhibited by LXA4 and 15-epi-LXA4 (30).

The peptide ANXA1 binds with ALX/FPR2 to trigger proresolving effects. Glucocorticoids can induce the production of ANXA1 and ALX/FPR2 in monocytes and neutrophils (109, 115, 230). In a murine model of chronic obstructive pulmonary disease (COPD) exacerbation, budesonide inhibited LPS-initiated increase in lung ALX/FPR2 expression (30). ANXA1 and 15-epi-LXA4 transduce significant reduction of neutrophil migration via ALX/FPR2, and the combination of ANXA1 and 15-epi-LXA4 displays synergistic inhibition of neutrophil migration (211). The protective actions mediated by ANXA1 can be lost in disease states, such as cystic fibrosis (CF), as ANXA1 can be cleaved rapidly by neutrophil elastase in the lung, limiting its proresolving actions (270). Multiple and diverse proresolving mediators for ALX/FPR2 suggest a redundancy developed to ensure that inflammation is controlled and ultimately resolved (211). Proresolving receptors, and their cellular expression, are illustrated in FIGURE 4.

IV. SPM RECEPTOR SIGNALING

SPMs signal for the resolution of inflammation via specific receptors expressed on multiple cell types. The cognate receptors for SPMs identified to date belong to the GPCR superfamily of receptors, albeit in some cases SPMs can interact with receptors outside the GPCR family, such as LXA4 signaling via the aryl hydrocarbon receptor to regulate CYP450 genes, including CYP1A1 (231). This section focuses on GPCR-mediated SPM signaling.

A. ALX/FPR2: Examples in Downstream Signaling

The ALX/FPR2 receptor is currently the most extensively studied SPM receptor and provides the most granular example of SPM receptor signaling. ALX/FPR2 receptors are members of the GPCR family (93). The use of chimeric receptors has established that ALX/FPR2 binds lipid and protein ligands at distinct sites: lipoxins bind primarily at the seventh transmembrane domain and third extracellular loop, whereas peptide ligands such as ANXA1 and SAA bind at the NH2-terminal domain or first two extracellular loops, respectively (23, 46, 93). Despite their distinct binding sites, peptide ligands such as SAA can serve as allosteric inhibitors for ALX/FPR receptor binding to lipoxins (46).

Just as the distinct binding sites on the ALX/FPR2 receptor allow it to bind to various types of ligands, the diversity of intracellular signaling cascades from GPCR activation enables ALX/FPR2 receptors to transduce both proinflammatory and proresolving actions. For example, SAA and LXA4 serve as agonists for ALX/FPR2 receptors, but each can antagonize the signaling properties of the other ligand, signaling for opposite functional responses. SAA is an acute-phase protein that triggers proinflammatory cytokine production (including TNFα, IL-1β, and IL-8), leukocyte chemotaxis, and neutrophil survival (83, 119). In contrast, LXA4 inhibits proinflammatory cytokine production, induces anti-inflammatory cytokine production (including IL-10), and inhibits neutrophil chemotaxis and activation (30, 51, 119, 216). Postreceptor signaling pathways downstream of the ALX/FPR2 receptor best explain how engagement of this receptor can mediate such contrasting cellular responses for inflammation and its resolution. SAA binding and intracellular calcium mobilization increase the expression of the NF-κB family of transcription factors (119). In contrast, LXA4 suppresses NF-κB activity in isolated human neutrophils, mononuclear leukocytes, and reporter assays in vitro (51, 134). RvD1 and 17-epi-RvD1, additional lipid mediator agonists at ALX/FPR2, also decrease NF-κB activity in lung macrophages and airway epithelial cells after lung injury, as does RvD1 in human small airway epithelial cells and in a murine sepsis model (40, 80, 128).

On binding to ALX/FPR2 on neutrophils, SAA triggers the phosphorylation of extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K), leading to subsequent downstream activation of the p38 mitogen-activated protein kinase (MAPK), and protein kinase B (PKB/Akt). The net result is that SAA promotes neutrophil survival (83, 119). This prosurvival action of SAA can also occur independently of p38 MAPK, by preserving the expression of Mcl-1 (89). The ERK/MAPK and PI3K/PKB/Akt pathways, illustrated in FIGURE 5, regulate cell growth, survival, differentiation, motility, metabolism, and immune responses (85, 226). In contrast to SAA, LXA4 binding to ALX/FPR2 reduces SAA-mediated phosphorylation of ERK and myeloperoxidase (MPO)-induced phosphorylation of ERK and PKB/Akt in neutrophils, and decreases ERK phosphorylation and subsequent TNF-α secretion from stimulated T cells (9, 84, 119). This suppression of ERK phosphorylation is also seen with RvD1-treated human airway epithelial cells exposed to viral-like peptides (128).

FIGURE 5.

FIGURE 5.Signaling via the ALX/FPR2 receptor. The ALX/FPR2 receptor is the most extensively studied of the SPM receptors and is known to bind lipid and protein ligands. Lipid agonists include lipoxins and resolvins, whereas peptide ligands include serum amyloid A (SAA), annexin A1 (ANXA1), and ANXA1-derived peptide Ac2-26. SAA and LXA4 each serves as an agonist for the ALX/FPR2 receptor, but each can antagonize the signaling of the other through allosteric inhibition, promoting opposite intracellular effects, as shown above. Binding of monomers, homodimers, and heterodimers evokes different downstream signaling cascades (89). Red lines represent inhibition, and black arrows represent activation of a pathway. Signaling schematic was adapted from Filep et al. (89).


In addition to the ERK/MAPK and PI3K/PKB/Akt intracellular pathways, ALX/FPR2 receptors also regulate intracellular polyisoprenyl phosphate signaling, a critical pathway for the control of neutrophil activation and function. Presqualene diphosphate (PSDP) is a polyisoprenyl phosphate, which is present in neutrophil cell membranes and inhibits superoxide ( O 2 ) production during neutrophil stimulation (162). PSDP is rapidly inactivated via dephosphorylation by phospholipid phosphatase 6 (PLPP6; previously identified as polyisoprenyl diphosphate phosphatase 1), which converts PSDP to its monophosphate form, presqualene monophosphate (37, 98). Neutrophil exposure to soluble stimuli results in the rapid decrease of PSDP levels and subsequent activation of phospholipase D and O 2 production. When LXA4 is present, the activation of ALX/FPR2 disrupts polyisoprenyl phosphate signaling by increasing intracellular PSDP levels to inhibit phospholipase D and suppress O 2 production (159, 164). The maintenance of intracellular PSDP levels by ALX/FPR2 signaling is due to inhibition of PLPP6 activation: LXA4 agonism at ALX/FPR2 inhibits PLPP6 phospho-regulation by preventing PLPP6 interaction with specific protein kinase C isoforms (36). Thus neutrophil ALX/FPR2 activation by agonists such as LXA4 results in suppression of neutrophil superoxide production by preventing PLPP6-mediated polyisoprenyl phosphate remodeling.

Of note, these effects of signal transduction pathways are cell-type dependent. For example, recent studies indicate that stimulation with proresolving 15-epi-LXA4 and ANXA1 promotes ERK2 and MAPK phosphorylation, respectively, in primary human monocytes (62, 252). As another example, RvD1 also suppresses the phosphorylation of PKB/Akt and ERK2, but not ERK1, in primary rat lung fibroblasts (284).

Like many GPCRs, ALX/FPR2 can undergo posttranscriptional modification to affect receptor activity, including glycosylation, phosphorylation, cell surface receptor expression and subsequent receptor internalization, and receptor dimerization. For example, impaired glycosylation of the amino terminus of ALX/FPR2, seen frequently in viral and bacterial infection, inhibits receptor recognition of select peptides but not of LXA4 (46). Phosphorylation of ALX/FPR2 receptors at either the third intracellular loop or the COOH-terminal domain can inactivate the receptor (135). Cell surface expression of ALX/FPR2 can be increased by agonists such as LXA4, or decreased by receptor phosphorylation and subsequent internalization, which in some cases appear necessary for ligand-induced actions, such as LXA4-triggered macrophage phagocytosis (19, 173).

B. Receptor Dimerization

Unlike many types of cellular receptors, most GPCRs do not appear to require dimerization for fully effective intracellular signaling (86, 170). Recent evidence suggests that some GPCRs do form homodimers or heterodimers, thereby altering intracellular signaling by allowing colocalization of effector domains, enhancing intracellular activation, or creating new ligand specificity (170). Emerging evidence suggests that the ALX/FPR2 receptor dimerizes in response to specific ligands, and that this dimerization alters the activation of intracellular signaling pathways. ALX/FPR2 homodimers decrease in response to binding by the proinflammatory agonist SAA, but increase in response to binding by the proresolving ligands LXA4 and ANXA1; LXA4 and ANXA1 also increase heterodimers of ALX/FPR2 with FPR1, whereas SAA does not (62). Of interest, phosphorylation of the Jun amino-terminal kinase-caspase-3 pathway is not altered in cells transfected with either ALX/FPR2 or FPR1, but is upregulated in cotransfected cells, suggesting that heterodimers of ALX/FPR2 and FPR1 propagate proapoptotic signaling pathways that are unique to the heterodimer (62). These findings are supported by the neutrophil proapoptotic effects of LXA4 and ANXA1, which enhance heterodimerization, compared with prosurvival effects of SAA, which do not (62, 89). These different signaling pathways triggered by the specific dimerization state are illustrated in FIGURE 5.

C. Patterns in SPM Receptor Signaling

As more SPM receptors are identified, patterns across receptor signaling will likely become more evident. For example, ERV1/CMKLR1 receptors share many similarities to ALX/FPR2 signaling, including “dual ligand” capacity to propagate signals from competing agonists. Signaling through ERV1/CMKLR1, RvE1 and a chemerin-derived peptide trigger differential effects on ERK and NF-κB phosphorylation (12). ERV1/CMKLR1 binding to RvE1 at physiological concentrations (≤10 nM) deactivates NF-κB, ERK, and PKB/Akt signaling, thereby inhibiting leukocyte trafficking and promoting neutrophil apoptosis (12, 82). In vivo, RvE1 inhibits lung NF-κB activity and cytokine production in a murine aspiration pneumonia model (234). Additionally, 17-epi-RvD1, a cognate ligand for both ALX/FPR2 and DRV1/GPR32, reduces TNF-α expression and NF-κB translocation to the nucleus in a murine acid-induced acute lung injury model (80), and similar findings are reported with RvD5 signaling through DRV1/GPR32 in a murine sepsis model (47). Similar to signaling via ALX/FPR2 and DRV1/GPR32, RvD2 signals through DRV2/GPR18 to increase cAMP, ERK, and other signaling activity at physiological concentrations (10 nM), subsequently enhancing phagocyte clearance of bacteria and reducing neutrophil infiltration in murine sepsis and peritonitis models (44, 45). Of interest, SPM signaling can promote expression of agonists for other SPM receptors, exemplified by RvE1 signaling, promoting increased biosynthesis of LXA4 in murine allergic lung inflammation (118).

Overall, the relative abundance of several SPMs, proresolving protein mediators, and proinflammatory proteins can influence cell fate by interacting with pivotal GPCRs that propagate signals in a ligand-specific manner. Distinct ligand binding, dimerization, and intracellular signal coupling evoke specific phosphorylation and activation patterns. These distinct signaling pathways enable SPM receptors to serve as critical checkpoints for inflammation and its resolution.

V. INNATE RESPONSES TO SPMs AT THE CELLULAR AND TISSUE LEVELS

The restoration of homeostasis following acute inflammatory responses is an active process governed by several proresolving mechanisms, including the interaction of SPMs with specific cellular effectors of the innate immune system. In addition to leukocytes, SPMs interact with receptors on structural cells, including epithelial and endothelial cells (2, 191). In this section, we review SPM actions on cells of the innate immune system, listed in TABLE 3 and illustrated in FIGURES 6 AND 7.

Table 3. SPM cell-specific bioactions

Target Cell SPM Actions Human (H) or Murine (M) Reference Nos.
Neutrophil LXA4 Inhibits chemotaxis H 154, 243
Inhibits transepithelial and transendothelial migration H 61
Inhibits neutrophil-epithelial cell interactions H 28, 209
Inhibits superoxide anion generation and degranulation H 159
Upregulates CCR5 expression for efferocytosis H 10
LXB4 Inhibits chemotaxis H 154
Inhibits transepithelial and transendothelial migration H 61
Inhibits neutrophil-endothelial interactions H 209
RvE1 Inhibits transepithelial and transendothelial migration H 35
Inhibits superoxide anion generation H 116
Upregulates CCR5 expression for efferocytosis H 10
RvE3 Inhibits infiltration H 131
RvD1 Inhibits transmigration H/M 261
RvD2 Inhibits transendothelial migration H/M 258
MaR1 Released by PMN-platelet aggregates to stop PMN infiltration M 1
PD1 Inhibits transmigration M 20
Inhibits TNF and IFN-γ release H 11
Upregulates CCR5 expression for efferocytosis H 10
Monocyte LXA4 Stimulates chemotaxis and adhesion H 172
Reduces IL-8 and peroxynitrite release in asthmatic subjects H 134
LXB4 Stimulates chemotaxis and adhesion H 172
Macrophage LXA4 Increases efferocytosis of apoptotic neutrophils H 106
RvE1 Stimulates nonphlogistic efferocytosis of apoptotic neutrophils H/M 233
Stimulates repolarization to M2 phenotype H 121
RvD1 Inhibits LPS-induced TNF release M 75
Increased phagocytosis of allergen and apoptotic cells M 225
RvD2 Stimulates nonphlogistic efferocytosis of apoptotic neutrophils M 258
Increases presence of M2 phenotype M 258
MaR1 Stimulates nonphlogistic efferocytosis of apoptotic neutrophils M 246
PD1 Stimulates nonphlogistic efferocytosis of apoptotic neutrophils M 233
NK cell LXA4 Increases NK cell cytotoxicity H 219
Increases NK cell-mediated granulocyte apoptosis H 21, 266
RvE1 Stimulates CMKLR1 receptor expression M 117
ILC2 LXA4 Inhibits IL-13 release H 21
MaR1 Inhibits IL-13 production, stimulates amphiregulin production M 146
Dendritic cells RvD1 Inhibits IL production, surface expression of MHC class II M 185
Mast cells LXB4 Inhibits degranulation H 137
Eosinophils LXA4 Inhibits chemotaxis M 18, 158, 257
LXB4 Inhibits chemotaxis M 137
PD1 Decreases expression of CD11b and CD62L H 160, 188
Epithelial cell LXA4 Increases proliferation after injury H 28
Inhibits IL-6 and IL-8 release H 28
Regulates ion channels for enhanced repair H 33
Inhibits neutrophil infiltration in CF M 136
RvD3 Counterregulates NF-κB and stimulates re-epithelialization H/M 59
Restores barrier function H/M 59
MaR1 Inhibits organic dust-induced cytokine production H/M 203
Endothelial cell LXA4 Stimulates prostacyclin formation to promote vasodilation H 31
Blocks generation of reactive oxygen species H 200
Inhibits growth factor-induced endothelial-cell migration H 39
Attenuates LPS-induced vascular stiffening H/M 183
RvD2 Inhibits ability of neutrophil migration through nitric oxide production H/M 258
FIGURE 6.

FIGURE 6.Cellular mechanisms for both anti-inflammatory (left) and proresolving (right) actions of SPMs in the alveolar space. SPMs act to stop the inflammatory cascade (red) and to facilitate the resolution of lung inflammation (green). Left: neutrophil recruitment from capillaries follows a chemotactic gradient into the alveolar space, where they remove microbes and debris through phagocytosis and reactive oxygen species. SPMs halt infiltration of neutrophils to prevent damage done by neutrophil degranulation. Right: in contrast, the catabasis of inflammation is depicted as macrophages perform efferocytosis of apoptotic neutrophils to clear the alveolus of dead granulocytes. Here, SPMs promote neutrophil apoptosis, CCR5 expression on apoptotic cells, and macrophage clearance of apoptotic neutrophils to allow for the restoration of homeostasis.


FIGURE 7.

FIGURE 7.SPMs stimulate the resolution of the allergic response in the airway. The allergic airway responses in asthma (left) are characterized by eosinophil infiltration, edema, damage to airway epithelium, and goblet cell hyperplasia. These cellular actions result in airway swelling and mucus overproduction, such that normal respiration is impaired. SPMs (shown in green) work to counter these pathologies by restoring epithelial and endothelial barrier function, decreasing bronchial mucus metaplasia, inhibiting leukocyte infiltration, and removing allergen via phagocytosis.


A. Neutrophils

Neutrophils are the first leukocytes to be recruited to a site of inflammation and are a critical element of the innate immune response to tissue injury and infection (144). Dysregulated neutrophil responses are central to the pathophysiology of many inflammatory airway diseases. In health, a critical component of resolving tissue inflammation and a defining criterion for a SPM is the modulation of further neutrophil influx and activation. Of paramount importance to the control of acute inflammation, there is SPM redundancy for limiting neutrophil recruitment and activation. Lipoxins, resolvins, maresins, and protectins all can inhibit neutrophil chemotaxis and diapedesis in vitro and block tissue neutrophil accumulation in vivo (TABLE 3). LXA4 and 15-epi-LXA4 inhibit N-formyl-methionyl-leucyl-phenylalanine-mediated neutrophil chemotaxis and neutrophil-epithelial cell interactions through integrin regulation (61, 154, 209, 243). Additionally, LXA4 and 15-epi-LXA4 limit degranulation of azurophilic granules and NADPH oxidase assembly for superoxide anion generation (159). LXB4 has similar actions as LXA4, inhibiting neutrophil chemotaxis, migration, and epithelial interactions (61, 154, 209). LXA4 inhibits neutrophil transepithelial migration in a physiological direction from the basolateral to the apical side (28) and enhances reverse transmigration in an apical-to-basolateral direction to promote luminal neutrophil clearance (61). Indeed, LXA4 enhanced reverse migration of neutrophils as quantified using a microfluidic channel model (114). Resolvins can regulate neutrophil trafficking and activation with RvE3 inhibiting neutrophil tissue infiltration and RvE1 inhibiting transmigration and superoxide anion generation (35, 116, 130). RvD1, 17-epi-RvD1, and RvD2 limit neutrophil transmigration (258, 261). PD1 decreases neutrophil release of proinflammatory cytokines TNF and IFN-γ, while also promoting the upregulation of CC-chemokine receptor 5 (CCR5), an important chemokine scavenger expressed on apoptotic neutrophils (10, 11). Of special note, LXA4 and MaR1 are produced via bidirectional, transcellular biosynthesis by neutrophil-platelet aggregates to serve as autacoid regulators. By decreasing these heterotypic aggregates, LXA4 and MaR1 limit secondary capture of neutrophils at sites of activated endothelium to convey a braking mechanism for acute inflammation by limiting further neutrophil tissue infiltration (1).

Apoptosis is a form of programmed cell death that limits the release of granule contents and other intracellular molecules that are potentially injurious to innocent bystander neighboring healthy tissues. Apoptotic cells are cleared by phagocytes to provide tissue level mechanisms for efficient resolution. ALX/FPR2 ligands can have opposing actions on neutrophil apoptosis. For example, SAA can delay neutrophil apoptosis by concurrent activation of the ERK and PI3K/Akt signaling pathways, leading to phosphorylation of BAD and decreased caspase-3 activation (83), whereas 15-epi-LXA4 counterregulates these SAA-mediated prosurvival signals and promotes neutrophil apoptosis (83) (FIGURE 5). Of note, ANXA1, a peptide agonist of ALX/FPR2, induces neutrophil apoptosis and also counterregulates SAA-induced neutrophil survival (255). Myeloperoxidase is abundantly expressed in neutrophils, generates cytotoxic oxidants and signals through the β-integrin (2) Mac-1 to rescue neutrophils and prolong inflammation (84). 15-epi-LXA4 attenuates MPO-induced activation of ERK and Akt-mediated phosphorylation of BAD through downregulation of Mac-1 expression (84). RvE1 counterregulates MPO-activated prosurvival neutrophil signaling (82), and MaR1 directly activates proapoptotic signaling pathways (107).

Microbial clearance is a defining feature for resolution of inflammation. While SPMs decrease neutrophil activation, they also display anti-microbial properties, in part by promoting neutrophil phagocytosis of bacteria. These SPM properties to facilitate clearance of infection represent a bioaction that differentiates this class of mediators from immunosuppressive molecules (reviewed in Ref. 22). In a murine model of bacterial pneumonia, RvE1 increased phagocytosis of E.coli by neutrophils, decreased neutrophil activation, and induced apoptosis of neutrophils (82). In E.coli-mediated sepsis, RvD2 increases neutrophil phagocytosis of bacteria (258).

B. Monocytes and Macrophages

Macrophages, both tissue dependent and monocyte derived, play pivotal roles in health and disease, ensuring homeostasis, and orchestrating the timely resolution of inflammatory responses (201). LXA4 and LXB4 promote monocyte chemotaxis and adhesion, increasing their presence and differentiation into macrophages at sites of inflammation (172). In keeping with their proresolving properties, select SPMs increase phagocytosis of microbial particles by macrophages (69, 70, 246). For example, RvD1, RvD2, and RvD5 increase bacterial phagocytosis by macrophages in vitro (47, 258), and 17-epi-RvD1 increases phagocytosis of E.coli particles in live precision-cut murine lung sections (2). Once activated by SPMs, macrophages transition from a proinflammatory phenotype (M1) to a proresolution phenotype (M2), engaging in efferocytosis to limit the release of proinflammatory molecules, and produce additional SPMs and counterregulatory molecules, such as IL-10 and IL-1Ra (4). RvE1 promotes this polarization of peritoneal macrophages from the M1 to the M2 phenotype (121, 204), and RvD2 increases the number of M2 macrophages in cigarette smokers (64). The SPMs LXA4, RvD1, 17-epi-RvD1, RvE1, PD1, and MaR1 all stimulate efferocytosis with the added triggering of further SPM release to amplify catabasis (106, 225, 233, 244, 246). In response to injury, several subtypes of lung macrophages appear and catalyze the resolution of acute inflammation (2, 120, 132). Specifically, inflammatory macrophages (iMacs) that exhibit M1 phenotype markers are particularly efficient at conducting efferocytosis (2), and exudative macrophages (ExMacs) that exhibit M2 phenotype markers produce proresolving cytokines, including IL1-Ra (120). Such processes can be regulated directly by SPMs, as efferocytosis of apoptotic neutrophils by macrophage subsets sorted after experimental lung injury is increased after ex vivo treatment with 17-epi-RvD1 (2). In a murine model of peritonitis, efferocytosis of apoptotic neutrophils by macrophages results in release of proresolving cytokines locally. Emigration of these satiated macrophages to lymphoid organs from the peritoneum promotes accelerated resolution (232).

C. Natural Killer Cells

NK cells have pivotal roles in host inflammatory responses. In addition to promoting inflammation and host defense by the release of cytokines and cytotoxic granules in response to pathogens, NK cells can participate in resolution by inducing granulocyte apoptosis and clearance of activated leukocytes (21, 266). NK cells accelerate granulocyte apoptosis after which the apoptotic cells can be engulfed by macrophages, limiting further release of potentially harmful granule contents (21, 266). NK cells from peripheral venous blood and bronchoalveolar lavage fluid express the ALX/FPR2 receptor, and LXA4 triggers NK cell-mediated apoptosis of granulocytes (21, 77). This proresolving action of LXA4 is distinct from NK cell suppression by glucocorticoids (77). Of interest, LXA4 can partially reverse the dexamethasone-induced suppression of healthy NK cells, but not of cells from patients with severe asthma (77). NK cells also express ERV1/CMKLR1 and respond to RvE1 to enhance clearance of eosinophils and antigen-specific CD4+ T cells in vivo after allergen challenge (21, 117). In a murine model of allergic lung inflammation, depletion of NK cells at the peak of the inflammatory response resulted in the delayed clearance of airway eosinophils and antigen-specific CD4+ T lymphocytes.

D. Innate Lymphoid Cells

The three classes of ILCs serve important yet distinct roles in protective immunity. These cells rapidly respond to alarm stimuli and secrete copious amounts of cytokines without the need for antigen recognition. The unrestrained cytokine production by ILCs is documented in several pathologies, including asthma, so endogenous counterregulatory mechanisms for ILCs are critical for a controlled host response. LXA4 inhibits type 2 cytokine release from group 2 ILCs (ILC2s) via signaling through ALX/FPR2 receptors (21, 117, 259). In addition to ALX/FPR2, both NK cells and ILC2s express ERV1/CMKLR1 receptors (21). MaR1 inhibits ILC2 release of type 2 proinflammatory cytokines IL-5 and IL-13 and increases ILC2 amphiregulin production, highlighting the selective nature of SPM actions on ILC2s for resolving inflammation and restoring epithelial barrier function (21, 146). Group 3 ILCs (ILC3s) also respond to SPMs and can serve protective roles in infection resolution. Recently, an important role in host protection against E.coli was established for ILC3s (67). The PCTR biosynthetic pathway in ILC3 is increased by acetylcholine, and conversely vagotomy results in decreased levels of acetylcholine and impaired PCTR1 generation (67). Of note, vagotomy or antibody-mediated deletion of ILC3 results in greater susceptibility to infection. The important regulatory actions of SPM on ILCs are illustrated in FIGURES 7 and 8.

FIGURE 8.

FIGURE 8.SPMs action on T, B, and innate lymphoid cells. Naive CD4 T cells are skewed via different lineages, both in vitro and in vivo. Recent evidence highlights how SPMs target specific lineages and impact the pathophysiology of diseases like asthma. Innate lymphoid cells of different groups are mirror images of their adaptive CD4 T-cell lineages. These cells do not require antigen engagement for cytokine production. NK cells and ILC2 express SPM receptors and are responsive to SPM regulation. CD8 T-cell effector and cytotoxic function was recently shown to be modulated by SPMs. B cells produce an array of antibodies tailored to the adaptive immune response. The production of these antibodies is also influenced by SPMs. SPMs in red are inhibitory, and SPMs in green promote the specific immune response.


E. Dendritic Cells

Dendritic cells (DCs) prime and instruct naive T cells to differentiate to a specific lineage by the secretion of cytokines and expression of costimulatory and activation molecules (184). In an ovalbumin model of allergic inflammation, RvE1 suppresses DC cytokine production, namely IL-6 and IL-23 (118). Given the critical role played by cytokines in promoting and maintaining T helper subtype 17 (TH17) responses, it is evident that RvE1 utilizes a multipronged approach in modulating allergic immune responses (118).

SPM regulation of DCs occurs in extrapulmonary allergic inflammatory disorders that are often associated with allergic airway inflammation. Phospholipase A2 group IID (PLA2G2D), an enzyme involved in SPM biosynthesis, is preferentially expressed in tissue resident dendritic cells, and a deficiency of PLA2G2D decreases SPM levels such as RvD1 and compromises the resolution of inflammation in a model of hapten-induced contact dermatitis (185). In addition, in this model DCs from PLA2G2D knockout mice are hyperactivated with increased expression of CD40 and trigger skin inflammation (185). SPMs display direct actions on DCs. RvD1 reduces IL-12 secretion and surface expression of myosin heavy chain class II in LPS-stimulated bone marrow-derived DCs (185). RvE1 also regulates dendritic cell migration in contact dermatitis (229).

F. Mast Cells

Mast cells are found in the skin and in mucosal tissues during homeostasis, and mast cell numbers are increased in lungs from patients with asthma and in nasal polyps associated with rhinitis (149, 247, 260). Environmental, immunological, and soluble stimuli cause mast cells to degranulate and release preformed peptide mediators, like histamine, cytokines, and chemokines, and rapidly synthesized prophlogistic lipid mediators, like prostaglandins and leukotrienes, and these mediators are elevated in inflammatory disorders (103). In a murine model of allergic inflammation and rhinitis, SPMs regulated the intensity of the inflammatory response to allergen. In this model, mast cell degranulation and cytokine release following immunoglobulin E (IgE)-mediated activation was decreased by LXB4 (137), highlighting the potential therapeutic impact of an SPM directed approach to limit mast cell activation.

G. Eosinophils

Eosinophils are granulocytes of the innate immune system that mature in bone marrow, travel to sites of inflammation, and can signal to other innate and adaptive immune cells. When activated, eosinophils discharge granules to release a collection of enzymes, chemokines, and cytokines. These include eosinophil peroxidase, eosinophil-associated ribonucleases, major basic protein-1, and granulocyte macrophage colony-stimulating factor (reviewed in Ref. 197). Eosinophils play a critical role in parasite host defense and allergic inflammation, including asthma pathogenesis.

Eosinophils functionally respond to SPM signaling. The migration of eosinophils toward proinflammatory chemokines is inhibited by LXA4 in vitro (257), and recruitment of eosinophils to sites of inflammation is inhibited by LXA4 in murine models of allergic inflammation in vivo (18, 158). LXB4 also inhibits murine bone marrow-derived eosinophils (137). This inhibition of eosinophil migration by LXA4 is mediated by the ALX/FPR2 receptor on eosinophils (158), and reduced ALX/FPR2 signaling correlates with prolonged eosinophilia in murine models (60). In addition to ALX/FPR2 ligands, PD1 decreases eosinophil expression of integrins and selectins (CD11b and CD62L) and inhibits eosinophil infiltration into airways during allergic inflammation (160, 188).

Of interest, eosinophils can also produce SPMs and possess proresolving properties. In human peripheral blood and in murine models of sterile inflammation, eosinophils can synthesize LXA4, RvD1, RvD2, RvE3, and PD1, via 12-LOX and 15-LOX (131, 188, 265, 287). Eosinophil-derived SPMs inhibit neutrophil chemotaxis and enhance clearance of neutrophils in murine models of sterile inflammation (131, 287). Eosinophil biosynthesis of PD1 is preserved in healthy subjects but impaired in patients with asthma exacerbation (188), suggesting that impaired SPM synthesis by eosinophils is a key factor in asthma pathogenesis.

Eosinophils can further influence adaptive immune responses by signaling for the recruitment of TH2 effector T lymphocytes, the resolution of tissue neutrophilia, the migration and maturation of dendritic cells, and macrophage polarization toward a M2 phenotype (3, 131, 283, 287, 288). For example, eosinophils regulate macrophage expression of CXCL13 in a 12/15-LOX-dependent manner; CXCL13 then regulates the migration of phagocytes to draining lymph nodes to promote resolution of inflammation (265). Overall, eosinophils can serve as important effectors of SPM signaling in both inflammation and resolution, by their direct actions and influence on other immune effector cells.

H. Epithelial Cells

The restitution of epithelial cell barrier function is integral to resolution after airway injury, infection, and exposure to noxious stimuli (28, 59, 203). In vitro ALX/FPR2 receptor expression in human bronchial epithelial cells is upregulated after transient acid injury in a COX-2 and PGE2-dependent manner. LXA4 induces basal epithelial cell proliferation and inhibits both neutrophil transepithelial migration and epithelial production of IL-6 and IL-8 (28). Epithelial NF-κB is also regulated by SPMs, including RvD3 and 17-epi-RvD3, and in vivo these SPMs promote a more rapid restitution of barrier integrity and edema clearance via lymphatics (59). Of note, MaR1 also reduces epithelial cytokine production and regulates inflammatory responses to organic dust in a non-NF-κB-dependent manner (203). Inflammatory cytokine exposure induces primary epithelial cells to stimulate neutrophils to produce LXA4/15-epi-LXA4 by releasing 14,15-EET (213). For patients with CF, this axis is critical to regulating neutrophil transmigration and cytokine production as P. aeruginosa can harbor a virulence factor Cif that hydrolyzes 14,15-EET to the inactive 14,15-DHET, which disrupts SPM production (96). In addition, DHA and RvD1 can control human bronchial epithelial cell expression of MUC5AC and proinflammatory mediators, including IL-6 and IL-8, when exposed to P. aeruginosa (190).

I. Endothelial Cells

The lung is a fragile organ that is susceptible to breaches of the vascular integrity. Disruption of endothelial cell barrier function by vascular injury or inflammation can lead to edema, which can threaten alveolar ventilation and oxygenation. SPMs display several protective actions for endothelial cells. SPMs decrease neutrophil adherence and diapedesis (35, 61, 258) and can regulate GTPases on the endothelial surface to decrease both leukocyte adhesiveness and transmigration during lung injury (25). SPMs regulate reactive oxygen species generation by endothelial cells and VEGF-stimulated endothelial cell chemotaxis (39, 200). While this migration is useful in angiogenesis, endothelial cell migration weakens the integrity of the extracellular matrix around the endothelial barrier, which further increases the negative effects of inflammation or vascular leak (39). Lipoxins stimulate vasodilation in an endothelial-dependent manner via prostacyclin formation and can attenuate LPS-induced vascular stiffening (31, 183).

J. Mesenchymal Stem Cells

Bone marrow-derived mesenchymal stem (stromal) cells (MSCs) possess anti-inflammatory and lung protective properties (179). In preclinical studies, MSCs reduce the severity of lung inflammation induced by endotoxin (113) and live bacteria (152). These protective actions are in part mediated by SPMs (88). Indeed, culture of human MSCs with alveolar epithelial type II cells increases the production of LXA4, which can mediate MSC proresolving actions after endotoxin-induced lung injury (88).

K. Isolated Bronchial and Vascular Tissue

SPMs also play an important role in counterregulating bronchial and vascular smooth muscle contraction and airway hyperresponsiveness. In the presence of spasmogenic agents, such as methacholine, histamine, and thromboxane, proinflammatory cytokines (e.g., TNF-α and NF-κB) induce hyperresponsiveness in bronchi (192). Treatment with 15-epi-LXA4 markedly reduces TNF-α-induced airway hyperreactivity in human bronchi (206). In addition, RvD2 can also reverse TNF-α- and LTD4-induced airway hyperreactivity (140). Furthermore, RvD1 and RvE1 reverse vascular hyperresponsiveness and Ca2+ sensitivity in cultured human pulmonary arteries caused by TNF-α and IL-6 (123, 124). The effects of SPMs on different innate immune cells in the bronchial airways are shown in FIGURE 6.

VI. ADAPTIVE RESPONSES TO SPMs AT THE CELLULAR AND TISSUE LEVELS

Adaptive immune cells and their secreted products play a central role in amplifying inflammatory responses in the airways. Adaptive immune responses are tailored to a specific pathogen or noxious insult; however, these adaptive responses can become overly exuberant or chronic and lead to pathologies, such as chronic airway inflammation in asthma. The actions of SPMs on adaptive immune cells have adjuvant properties in host defense and can control sterile lung inflammation. This section reviews the literature on the impact of SPMs on T and B lymphocytes in health and disease.

A. CD4+ T Cells

Naive CD4+ T lymphocytes can differentiate into specific lineages of CD4 TH1, TH2, TH17, and regulatory T cells (Tregs), depending on the instructing signals they encounter from DCs (184, 220). Recent studies document that SPMs can either promote or inhibit the skewing of CD4+ T cells toward a specific lineage, underscoring their immunomodulatory role (52, 146). In vitro studies focusing on CD4+ T cell differentiation show that RvD1 and RvD2 prevent naive human CD4+ T-cell differentiation into TH1 and TH17 phenotypes (52). DRV1/GPR32 and ALX/FPR2 receptors are expressed on naive CD4+ T cells, and incubation of RvD1 and RvD2 along with cytokine cocktails responsible for TH1 and TH17 differentiation result in the decreased production of lineage-specific cytokines IFN-γ (TH1) and IL-17 (TH17) with a concomitant decrease in their respective transcription factors, T-bet and RORc (52). Additionally, these SPMs also curtailed the production of IL-2 from CD4 and CD8 T cells following their activation by anti-CD3/CD28 (52). Interestingly, the SPM MaR1 promotes de novo generation of FoxP3-expressing Tregs from naive CD4 T cells isolated from both mice and humans (52, 146). MaR1 augments the production of the suppressive cytokine TGF-β and tissue-restorative growth factor amphiregulin, highlighting the proresolving property of MaR1 in the context of the adaptive immune responses (146). RvD1 and RvD2 also promote the generation of FoxP3-expressing Tregs from naive human CD4+ T cells, albeit to a lower extent than MaR1. Neutrophil-derived LXA4 also promotes Treg generation and inhibits TH1 and TH17 differentiation in a murine model of dry eye disease (105).

B. CD8+ T Cells

CD8+ T cells exert their effector function via the production of cytotoxic molecules, perforin and granzymes, and inflammatory cytokines, IFN-γ, and TNF-α, to combat intracellular pathogens, particularly viruses. The in vitro activation of CD8+ T cells in the presence of RvD1 and RvD2 inhibits production of IFN-γ and TNF-α and impairs production of IL-2. RvD1 and RvD2 did not impact the viability of these cells, although there was impaired IL-2 production (52).

C. B Cells

The effect of SPMs on B cells and antibody production highlights the importance of these mediators in altering the sequence of events during late stages of inflammation and pathogen clearance. RvD1 increases IgM and IgG production from activated human B cells in vitro. Furthermore, this increased antibody production is attributed to augmented B-cell differentiation toward a CD27+CD38+ antibody-secreting cell phenotype (217). Interestingly, RvD1 inhibits IgE production by human B cells and suppresses the differentiation of naive B cells into IgE-secreting cells (142). This inhibitory action of SPMs is achieved by selectively targeting the epsilon germline transcription. Importantly, this effect is specific to human IgE and does not impair production of IgM and IgG or IgA (142). RvD1 dampens IgE production in B cells from asthma patients (143). Interestingly, this protective effect of RvD1 on B cells was lost from a subset of patients taking oral corticosteroids (143). Together, these findings support the concept that SPMs can inhibit the differentiation of IgE-producing B cells without being broadly immune suppressive. The impact of SPMs on T and B cells along with ILC1, ILC2, ILC3, and NK cells are illustrated in FIGURE 8.

D. Relationship Between SPMs and Immunosuppressive Cytokines

In several experimental settings, SPMs induce anti-inflammatory cytokine production, including IL-10 and TGF-β. When LPS-stimulated primary human monocytes are exposed to RVD1, RVD2, and MaR1, the release of proinflammatory cytokines TNF-α, IL-1β, IL-8, and IL-12 p40 is suppressed, and production of the anti-inflammatory cytokine IL-10 is increased (112). These counterregulatory actions are accompanied by increased phosphorylation of glycogen synthase kinase 3β along with increased phosphorylation of Akt, SGK1, and CREB. Interestingly, the MAPK pathway was not involved in the SPM-directed change in monocyte responses. In contrast to MAPK, silencing of CREB diminishes MaR1-mediated IL-10 production in response to LPS (112). In adipose tissue explants, RvD1 limits excessive activation of inflammatory cytokines following LPS stimulation by reducing phosphorylation of the STAT proteins STAT1 and STAT3. Additionally, proresolving actions of RvD1 are increased by enhancing expression of the IL-10 target gene heme oxygenase-1 via p38 MAPK activity (267). Cell-specific responses by SPMs can regulate the anti-inflammatory cytokine IL-10 and suggest a role for Toll-like receptor-4 (TLR-4) signaling in transducing SPM actions.

In addition to IL-10, SPMs can regulate TGF-β in a context-specific manner. In murine allergic lung inflammation triggered by ovalbumin, the administration of MaR1 at the peak of inflammation blunts lung eosinophil infiltration, serum ova-specific IgE levels, and promotes Treg generation. In this model, MaR1 administration increases TGF-β levels in the BAL fluid and numbers of TGF-β producing FoxP3-expressing Tregs in the BAL (146). Conversely, MaR1 treatment in a model of bleomycin-induced lung fibrosis prolongs survival and reduces collagen deposition. In this setting, MaR1 blunted TGF-β1 levels in BAL fluid (293). In vitro experiments on epithelial mesenchymal transition (EMT), 17-epi-RvD1 inhibits TGF-β1-induced EMT by specifically targeting the mammalian target of rapamycin pathway (293). Together, these data suggest that SPMs can engage TGF-β signaling for resolution in physiological responses while restraining TGF-β-mediated pathological responses. More research is needed to define these interesting mechanisms.

VII. RESPONSES TO SPMs IN PRECLINICAL MODELS AND HUMAN DATA

Lung inflammation integrates innate and adaptive cellular immune responses to injury and infection with the ultimate goal of restoring organ function. In health, innate immune cells are actively involved in resolution of lung inflammation to control and ultimately clear adaptive immune effector cells and tissue debris to restore homeostasis. In health, SPMs signal specific cell types to orchestrate lung catabasis (see above). Harnessing these protective and proresolving cellular actions position SPMs as pivotal regulators of inflammatory responses with the potential to serve as the basis for new therapeutic strategies when the endogenous mechanisms are deficient or disabled. In this section, we review SPM bioactivity in preclinical models of lung disease and human translational research.

A. ARDS

Excess lung inflammation with resulting bystander tissue injury and life-threatening respiratory failure are the hallmarks of the acute respiratory distress syndrome (ARDS), a devastating illness with limited therapeutic options (156). It is characterized by leukocyte and platelet activation and increased permeability of alveolar endothelial and epithelial barriers in response to sterile injury (e.g., burns, pancreatitis) or pathogen-mediated injury (e.g., pneumonia, sepsis). Alveoli fill with edema and exudative fluid, resulting in life-threatening respiratory failure from impaired gas exchange. When microbial products or cell injury-associated endogenous molecules (i.e., danger-associated molecular patterns) are detected by host pattern recognition receptors, such as the TLRs (207), innate immune responses are activated, and at times overly robust neutrophil infiltration and activation in the lung (174) can lead to bystander tissue injury of previously uninvolved lung, sometimes termed the “enemy from within” (179). Endogenous control mechanisms are overwhelmed in this situation, leading to ARDS.

SPMs play important roles in resolution of inflammation in self-limited preclinical models of acute lung injury. In a murine model of lung injury induced by gastric acid aspiration, an important clinical risk factor for human ARDS (227), SPM production proceeds in a spatially and temporally regulated manner (1, 59). For example, intratracheal hydrochloric acid results in an early increase in MaR1 biosynthesis by circulating neutrophil-platelet aggregates, which later becomes neutrophil independent (1). Whereas MaR1 is the predominant SPM in injured lung early after injury, RvD1, RvD3, and LXA4 lung levels increase at later time points (1, 59). Treatment after injury with several individual SPMs, including 15-epi-LXA4 (133, 213), RvE1 (234), RvD1 (80), 17-epi-RvD1 (80), RvD3 (59), 17-epi-RvD3 (59), and MaR1 (1), promote a more rapid resolution of acute lung injury and restoration of organ function. In a hyperoxia-induced lung injury model of particular relevance to pediatric ARDS, treatment with RvD1 or LXA4 improved alveolarization (177), and decreased ROS and NF-κB-mediated lung inflammation (63, 177). MaR1 mitigates LPS-induced acute lung injury (107), counterregulating TLR-4 signaling for acute lung injury, a mechanism common to several etiologies of ARDS (180). SPMs can protect lung function through several cellular and organ-level mechanisms, including decreased neutrophil recruitment [MaR1 (108), 17-epi-RvD1 (80), 15-epi-LXA4 (208)], restoration of epithelial barrier function [MaR1 (41), 17-epi-RvD3 (59), LXA4 (42)], and acceleration of alveolar fluid clearance [17-epi-RvD3 (59), RvD1 (277), LXA4 (276)].

SPMs also protect lung function in murine models of indirect lung injury. RvD1 decreases inflammatory responses and lung injury in a mouse model of drug-induced acute pancreatitis (169). Arterial vessel occlusion can lead to ischemia-reperfusion upon reflow with secondary organ injury to the lung by activated neutrophils and, in extreme cases, organ failure, such as in ARDS (179). In a murine model of hindlimb ischemia-reperfusion, LXA4 (48), MCTR1, and MCTR2 treatment provide significant protection from leukocyte-mediated lung injury (66).

Exuberant and dysregulated innate responses underlie ARDS pathophysiology; however, adaptive cellular responses can also play key roles in resolution of acute lung injury. Mice deficient in T cells demonstrate delayed resolution of LPS-induced lung injury (65), an effect related to the specific lack of Tregs. Although SPM regulation of Tregs in models of ARDS has yet to be demonstrated, de novo generation of Tregs by MaR1 in vivo in allergic lung inflammation (146) suggests SPM induction of Tregs is also relevant to the resolution of acute lung injury.

B. Fibrosis and Interstitial Lung Disease

Interstitial lung disease resulting in fibrosis affects 50–200 patients per 100,000 and is a disease largely of older individuals greater than age 60 yr (87). While the etiology is most frequently unknown, pulmonary fibrosis can be associated with systemic connective tissue diseases, such as rheumatoid arthritis and scleroderma (94). Of interest, SPM formation can decrease with aging (104). Similar to earlier findings in severe asthma (212), patients with scleroderma-associated lung fibrosis demonstrate a relative deficiency in LXA4 levels in bronchoalveolar lavage fluid (145). Lung fibrosis pathogenesis may represent a maladaptive attempt to heal repetitively injured lung parenchyma, although the exact mechanisms remain unknown. In a murine model of bleomycin-induced pulmonary fibrosis, individual SPMs, including 15-epi-LXA4 (178), 17-epi-RvD1 (290), and MaR1 (278), decrease lung inflammation and measures of lung fibrosis with decreased levels of the profibrotic cytokine TGF-β. Direct actions for SPMs on myofibroblasts and epithelial cells are potential mechanisms (224, 278, 286).

C. COPD and Environmental Toxins

COPD is a disease of global importance, resulting from repetitive exposure to cigarette smoke or environmental toxins with excess morbidity and mortality (81). Long after tobacco cessation, many COPD patients have ongoing inflammation, yet are subject to frequent exacerbations from bacterial and viral infection. SAA is an acute phase reactant and biomarker for COPD exacerbation (29). During COPD exacerbation, levels of SAA increase by ≥2 logs, which far outpaces concomitant increases in SPMs, such as LXA4 (29). The proinflammatory effect of SAA on ALX/FPR2 receptors dominates the ineffective counterregulation by LXA4 or other SPMs at ALX/FPR2 receptors, leading to a positive feed-forward inflammatory mechanism (30). Corticosteroids are frequently used in an attempt to control the acute inflammation; however, steroids increase, rather than decrease, extrahepatic SAA production by lung macrophages to perpetuate the disease’s lung inflammation (30). Cellular studies have identified protective roles for SPMs in smoke-induced lung inflammation via regulation of epithelial and macrophage responses (64, 126, 203, 262), and RvD1 signaling is altered in human lung samples of COPD (127). Of note, RvD1 treatment of mice exposed to long-term cigarette smoke was associated with a reduced development of emphysematous air space enlargement, with concurrent reductions in inflammation, oxidative stress, and cell death (127). RvD1 treatment also increased levels of the anti-inflammatory cytokine IL-10, promoted macrophage polarization to M2 macrophages, and enhanced macrophage efferocytosis of apoptotic neutrophils (126). Exposure of mice to low concentrations of wood smoke enhances cigarette smoke-induced inflammation, in part by suppressing levels of LXA4 (15). SPM can also protect lungs from organic dust-induced injury. MaR1 was found to protect murine lungs from single or repetitive organic dust exposure with decreased levels of inflammatory cytokines and endothelial integrin expression (202).

D. Cystic Fibrosis

CF is a genetic disorder characterized by viscous respiratory tract secretions, recurrent airway infections, and an over-exuberant immune response, eventually resulting in the deterioration of lung function. Patients with CF have decreased airway tissue stores of DHA compared with control subjects (97) and have decreased levels of the SPMs LXA4 and RvE1 (79, 136, 223, 289). The functional importance of impaired SPM production is evident from the observation that higher airway levels of RvD1 and RvE1 correlate with improved lung function (79, 289). Pathogenic bacteria that colonize airways of CF patients can contribute to decreased SPM levels. For example, Pseudomonas aeruginosa can sabotage 15-epi-LXA4 biosynthesis via the epoxide hydrolase enzymatic action of the CF transmembrane conductance regulator inhibitory factor (Cif) (96). Investigation in animal models and with human bronchial epithelial cells from patients with CF demonstrate that LXA4 can regulate bronchial epithelial ion channels for enhanced tissue repair (33), epithelial liquid height (273), and bronchial epithelial cell defense against Pseudomonas with prevention of bacterial colonization (122). Lipoxin administration in a mouse model of CF reduces bacterial burden and disease severity (136), emphasizing a potential role of SPMs for treatment of CF-specific abnormalities, namely bacterial colonization and impaired epithelial function.

E. Pathogen-Mediated Inflammatory Lung Diseases

In addition to signaling the arrest of inflammation, SPMs activate proresolving cellular responses such as phagocytosis and tissue regeneration, distinguishing them from immunosuppressive molecules (see above). In this section, we detail investigations using various preclinical models of infectious diseases that demonstrate host-directed anti-infective SPM actions in the resolution of pathogen-mediated tissue inflammation that complements antibiotic therapy (47, 258). In the following sections we consider the roles of SPMs in bacterial, viral, and fungal pneumonia. The roles of SPM in bacterial containment in CF are discussed in the previous section.

F. Bacterial Pneumonia

The ideal outcome of pathogen-initiated lung inflammation in pneumonia is the eradication of the infectious agent, clearance of infiltrated leukocytes, restoration of barrier integrity, and the return of normal organ function. SPMs are produced in patients with pneumonia (153). In preclinical murine models, several SPMs promote timely resolution of bacterial pneumonia, including LXA4 (84), RvE1 (82, 234), RvD1 (57), and 17-epi-RvD1 (2). In E. coli-initiated pneumonia, LXA4 accelerates the resolution of pulmonary inflammation by redirecting neutrophils to caspase-mediated cell death and facilitating their removal by macrophages (84), whereas RvE1 activates caspases via reactive oxygen species generation to promote neutrophil apoptosis (82). Efferocytosis of these apoptotic neutrophils is also increased by RvE1 (82) and 17-epi-RvD1 (2). In addition to promoting resolution of inflammation, RvE1 and 17-epi-RvD1 enhance bacterial clearance in these models (2, 234). 17-Epi-RvD1 enhanced clearance of E.coli and P. aeruginosa by increasing levels of the anti-bacterial peptide lipocalin 2 and stimulating macrophage phagocytosis of bacteria (2, 57). These host-directed actions are additive when combined with antibiotics (2, 57). Of particular interest, the addition of SPM to antibiotics was more effective than antibiotics alone for clearing the tissue inflammation, related in part to the enhanced clearance of LPS with the SPM (2). In these models, the SPM proresolving and anti-infective actions also improve survival (57, 82, 234).

G. Mycobacterium tuberculosis

The protective roles for SPMs are also integral to the host innate immune response to Mycobacterium tuberculosis (MTB). In this host response, a balance between proinflammatory and proresolving mediators can dictate the magnitude of the pathogen-mediated lung inflammation and microbial clearance (16). In a mouse model of MTB infection, levels of both the proinflammatory LTB4 and the proresolving LXA4 are increased, with high levels of LXA4 persistent throughout chronic infection (16). Excessive LTB4 or LXA4 production can result in aberrant host responses to MTB infection; however, mice deficient in 5-LOX demonstrate enhanced survival after MTB infection (16). Modulation of LTA4 hydrolase locus in zebrafish and humans controls the balance of LTB4 and LXA4 production and leads to two distinct molecular routes to mycobacterial susceptibility, namely inadequate inflammation caused by excess LXA4 and hyperinflammation driven by excess LTB4 (269).

H. Influenza

SPMs can also regulate host responses to viral pathogens. Influenza remains an important health hazard, resulting in many hospitalizations and excess (210). In preclinical murine studies that compare more virulent strains of the influenza virus to less virulent strains, SPMs inversely correlate with biological activity and dissemination of the virus (264). PD1 levels are significantly decreased during infection with the highly virulent H5N1 influenza strain. Treatment with PD1 decreases viral titers and lung inflammation with a resulting improved survival (17, 193). The anti-viral protective effect of PD1 was mediated by interfering with the viral-RNA replication machinery, by blocking nuclear export of viral transcripts in infected epithelial cells (193).

I. Respiratory Syncytial Virus

Respiratory syncytial virus (RSV) infection targets vulnerable populations, including children, elderly, and immunocompromised patients (182). RSV infection is the most common cause of viral mortality in children under the age of 5 yr worldwide (198). Resolution of RSV-triggered bronchiolitis is mediated in part by alternatively activated macrophages (249). Although alternatively activated macrophages produce type 2 cytokines IL-4 and IL-13 that perpetuate RSV-induced pathology, these cells can also accelerate resolution by increasing the production of lipoxygenase products (248). Deficiency of 5-LO or 15-LO impairs the generation of alternatively activated macrophages, resulting in delayed resolution of lung inflammation, whereas treatment with LXA4 or RvE1 restores alternatively activated macrophage generation (248). In addition, mice genetically deficient in ERV1/CMKLR1 have impaired CD8+ T-cell recruitment and an over-exuberant recruitment of neutrophils with lung viral infection (27). RSV infection can impair host responses to secondary bacterial infections, an effect prevented by treatment with 17-epi-RvD1 (275).

J. Cryptococcus neoformans

Two contrasting murine strain responses to Cryptococcus neoformans fungal pneumonia demonstrate that adequate pathogen clearance correlates with enhanced signaling through the LXA4-ALX/FPR2 axis (60). The C.B-17 murine strain responds to cryptococcal pneumonia by increasing epithelial ALX/FPR2 expression; activated CD4+ T cells are recruited into the lungs and type 1 cytokine production is increased, resulting in clearance of the pathogens. In contrast, the C57BL/6 murine strain increases LXA4 biosynthesis during the same cryptococcal pneumonia, but it does not augment ALX/FPR2 expression in lung tissue. The resulting C57BL/6 host response is marked by increased eosinophilia, lower recruitment of CD4+ T cells into the lungs, increased type 2 cytokine production, and impaired pathogen clearance (60).

K. Parasitic Protozoa

SPMs can also regulate host responses to parasitic infections, which are particularly prevalent in developing countries. LXA4 exerts a regulatory role on dendritic cell IL-12 production triggered by Toxoplasma gondii (T. gondii), and a stable LXA4 analog rescued animals from T. gondii-related mortality (6, 7). Similarly, LXA4 prevents exuberant IL-12 and INF-γ production and endothelial dysfunction during cerebral malaria and improves survival of the infected animals (250, 256). Aspirin can protect mice infected with Trypanosoma cruzi (T. cruzi) (196), the parasitic infection responsible for Chagas’ disease. This aspirin-mediated protection stems in part from increased 15-epi-LXA4 production (189). Exogenous administration of 15-epi-LXA4 can also improve the survival of mice infected with T. cruzi (189).

L. Asthma and Allergic Inflammation

SPMs have effects on cells of innate and adaptive immunity critical for the control of asthma severity in humans and for the attenuation of allergic inflammation in murine models, as reviewed in this section. Discussion of the cell-type specific effects of SPMs is provided in the sections above and illustrated in FIGURE 7.

In humans, severe asthma is associated with lower levels of specific SPMs compared with healthy controls, suggesting that the pathogenesis of this chronic inflammatory disease is related to defective resolution mechanisms. In samples from blood, sputum, exhaled breath condensates, and bronchoalveolar lavage fluid, LXA4 levels are decreased in patients with severe asthma compared with those with moderate or nonsevere asthma (139, 155, 212, 272). Similarly, PD1 is decreased in the exhaled breath condensates of patients with status asthmaticus compared with healthy controls (160).

In addition to impaired SPM biosynthesis, SPM signaling is affected by alterations in receptor expression in asthma. For example, expression of ALX/FPR2 on peripheral blood granulocytes is lower in patients with severe asthma than nonsevere asthma, and both cohorts have lower ALX/FPR2 expression than that of healthy controls, suggesting that decreased SPM signaling through ALX/FPR2 impairs the resolution of inflammation and facilitates a transition to chronic airway inflammation (212).

Airway hyperresponsiveness is a criterion for the diagnosis of asthma. In model systems, SPMs can attenuate airway hyperreactivity. Impaired SPM signaling is linked to severe asthma pathogenesis, as LXA4 levels positively correlate with lung function, measured by the forced expiratory volume in 1 s (155, 222). SPMs antagonize airway smooth muscle contraction. In the first human SPM intervention trial, the dose response for bronchoprovocation with LTC4 in asthmatic patients was shifted by inhalation of LXA4 (53). Using human lung sections, TNF-α-mediated increases in bronchial contraction to methacholine, histamine, and a thromboxane analog were all reversed by 15-epi-LXA4 (206). In translational studies in the Severe Asthma Research Program, the relative abundance in bronchoalveolar lavage fluids of the ALX/FPR2 ligands LXA4 and SAA correlate to lung function, neutrophilia, and asthma symptom control (222). An individual’s ratio of SAA to LXA4 is strongly correlated with bronchoalveolar lavage fluid neutrophilia, severe asthma clinical phenotypes, and asthma comorbidities, including acute exacerbations, sinusitis, gastroesophageal reflux, and obesity (222).

In murine models of allergic airway responses, treatment with LXA4 analogs reduces airway hyperreactivity, leukocyte recruitment into the lungs, and type 2 cytokine production, including IL-4, IL-5, and IL-13 (161). LXB4 treatment reduces IL-4 and allergen-specific IgE levels (137). Treatment with RvD1 and 17-epi-RvD1 decreases type 2 cytokine production, leukocyte recruitment into the lungs, and airway hyperreactivity (225). RvE1 treatment also reduces production of IL-13, secretion of allergen-specific IgE antibodies, recruitment of lymphocytes to the lungs, and airway hyperresponsiveness (8, 95). SPM-mediated decrease in IL-4 levels in the BAL fluid also has a direct impact on total and antigen-specific IgE levels. In a murine model of allergic inflammation, transgenic mice expressing human ALX/FPR2 receptors in CD11b+ leukocytes exhibit reduced eosinophilia and IgE levels (158). Similarly, the administration of RvE1 and MaR1 during the acute phase of inflammation decreases IgE levels (118, 146).

Similarly, PD1 treatment before inhaled aerosol challenge reduces airway hyperresponsiveness and inflammation by blocking the upregulation of IL-13, cysteinyl leukotrienes, and PGD2, as well as blocking lymphocyte recruitment and type 2 cytokine-mediated recruitment of eosinophils (160). In addition, MaR1 attenuates murine allergic airway inflammation by promoting the generation of Tregs in vivo and inhibiting type 2 cytokine production from ILC2 and CD4 TH2 (146). In these models of allergic inflammation, exposure to the SPM after the sensitization phase was found to accelerate resolution, indicating that SPMs can regulate cytokine production from primed CD4+ T cells. The changes in lung function mediated by SPMs are outlined in TABLE 3.

Of interest in these murine models, treatment with RvE1 increases endogenous LXA4 biosynthesis, correlating with suppression of allergic airway inflammation as well as decreased production of IL-23, IL-6, and IL-17 (118). Endogenous resolution signaling is likely amplified by individual SPMs triggering the production of other SPMs, such as this example of RvE1 enhancing LXA4 biosynthesis in a positive feedback loop (118). This interconnectedness and redundancy of the resolution pathways collectively transition an acute inflammatory response to its termination. Lipid mediator metabololipidomics demonstrate the time-dependent engagement of multiple resolution mediators and proresolving receptors during self-limited inflammatory responses. How these multiple signals are orchestrated to restore homeostasis is an area of active research.

M. Vaccination

Lipoxins, maresins, and precursors to D-series resolvins have distinct effects on B cell differentiation and secretion of antibodies. Treatment with LXA4 or MaR1 reduces the production of allergen-specific antibodies in murine models in vivo, and LXA4 inhibits memory B cell maturation in murine allergic asthma models (146, 216). In contrast to allergen-specific antibody production, 17-hydroxy-docosahexaenoic acid, a precursor to D-series resolvins, enhances antibody production against influenza antigens in a viral vaccination murine model (215). These findings suggest a potential for an adjuvant effect of SPMs in vaccination.

N. Organ Transplantation

In addition to protective effects in asthma and allergic airway inflammation, emerging studies suggest that SPM signaling is protective in the setting of solid organ transplantation. In the BAL fluid of human lung transplant patients, LXA4 levels correlate with the severity of lung allograft rejection as determined by vascular and airway pathological scoring. Additionally, exposure of healthy human neutrophils to LXA4 decreases agonist-initiated calcineurin activity and TNF-α-mediated production of proinflammatory cytokines (167). These are particularly relevant effects because inhibition of calcineurin and T cell activity represents the mainstay of posttransplant immunosuppression, but lipoxin treatment would not be predicted to be associated with the infectious risks of calcineurin inhibitors and other current immunosuppressive agents used to prevent allograft rejection. Importantly, in murine models, enhanced signaling through the ALX/FPR2 axis also decreases neutrophil accumulation in heterotopic transplanted hearts, prevents acute rejection in liver transplantation, and prolongs graft survival of transplanted kidney and corneal tissue (129, 167, 168).

O. Clinical Trials

In clinical trials, LXA4 and LXA4 stable analogs have shown safety and efficacy in the treatment of asthma and atopic dermatitis. In a phase I trial of six patients with mild asthma and two healthy controls, inhaled LXA4 abrogated the bronchoconstriction induced by LTC4 and did not alter airway caliber when given alone, suggesting that LXA4 serves as an endogenous leukotriene antagonist in human airways (53). In a double-blind, randomized, controlled trial of 60 infants with eczema, a topical analog of LXA4 reduced the severity of eczema and improved quality of life compared with placebo, with an efficacy similar to topical corticosteroid cream, which is the current standard of care (285). There are also apparent benefits to the precursors of SPMs, DHA and EPA, in clinical trials of patients with liver disease, colonic polyps, and ARDS (100, 176, 279). In a double-blind, randomized, placebo-controlled trial, high-dose supplementation of EPA and DHA to pregnant mothers in the third trimester of pregnancy significantly decreased the risk of persistent wheeze and asthma (the primary outcome) during the first 5 yr of a child’s life (26). One of the potential mechanisms for this benefit of omega-3 supplementation would be increased SPM production (214, 218). Other potential mechanisms exist, including signaling via specific omega-3 essential fatty acid receptors such as GPR120/FFA4 (186); however, these are beyond the scope of this SPM review. It is also important to point out that several supplementation trials have been performed with omega-3 fatty acids with mixed results. Additional research to better understand potentially beneficial mechanisms for omega-3 fatty acids and to better target clinical interventions is needed.

Together, these preclinical disease models and early human trials present many opportunities to harness SPM signaling to optimize adaptive immune responses to pathogens and allergens, promote resolution of inflammation, and drive a return to tissue homeostasis and organ function. Additional clinical trials are underway to evaluate the therapeutic effects of SPMs and their analogs, their biosynthetic enzymes, or their fatty acid precursors on other inflammatory diseases. Further research in preclinical models and ongoing clinical trials will help identify the protective mechanisms of SPMs that could be leveraged in new host-directed therapeutic approaches to resolve pathological lung inflammation.

VIII. SUMMARY AND CONCLUSIONS

Innate and adaptive immune responses in the lung need to be carefully tailored to the nature of inhalable potential triggers, as the lung is repetitively subjected to provocation by allergens, pathogens, particulate matter, air pollution, as well as innocuous materials. The ability of the lung to maintain mucosal immune homeostasis and mount appropriate responses to pathogens and noxious stimuli requires the orchestration of cellular and biochemical pathways (22). Over-exuberant immune responses can rapidly lead to life threatening impairment of gas exchange, and unrestrained immune responses can lead to pathological chronic inflammation. The underlying pathobiology of several lung diseases, such as asthma, COPD, ARDS, and CF, is linked to unresolved inflammation coupled with impaired production of SPMs (26, 102, 155, 180, 282).

The identification and characterization of several families of SPMs highlight not only their importance in tempering inflammation via their anti-inflammatory properties, but also their proresolving actions that are critical for tissue catabasis and pathogen clearance. The identification of proresolving properties of lipoxins paved the way for the discovery of other SPMs from omega-3 fatty acids. We have reviewed several SPMs, their biosynthesis from essential fatty acids, their structure and stereochemistry, their signaling pathways, and their cellular effectors of particular relevance to lung health and disease.

By definition, SPMs have the ability to accelerate resolution and restore tissue homeostasis. However, these endogenous lipid mediators have other cell and tissue-specific actions outlined in TABLE 3 and FIGURES 6 and 7. It is apparent that some of the actions mediated by SPMs may have converging and redundant functions, in particular those that are crucial to timely resolution of inflammation, including stopping granulocyte activation and recruitment and enhancing macrophage clearance mechanisms for pathogens and apoptotic cells. SPMs convey additional proresolving actions via their influence on Tregs. For example, Treg cells, via the secretion of TGF-β, are a potent suppressive cell type. The ability of MaR1 to promote their de novo generation and induce secretion of amphiregulin in the airway underscores the pivotal proresolving role these cells can also play in restoration of mucosal homeostasis (52, 146).

Preclinical disease models and early human trials utilizing SPMs and their precursor fatty acid biosynthetic intermediates present many opportunities to better understand lung physiology and pathophysiology. Regulation of innate and adaptive immune responses by SPMs to promote catabasis and improve lung health has led to several clinical trials that are evaluating the potential therapeutic benefits of SPMs and their analogs. Together, the discovery of the SPMs and investigation of their biological properties have provided a new and exciting window into the active processes of resolution in health and has linked defective resolution mechanisms to several common and important lung diseases.

GRANTS

This work was funded by U.S. National Institutes of Health Grants HL122531, U10HL109172, U01HL108712, K08HL130540, T32HL7633-31, and P01GM095467.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

ACKNOWLEDGMENTS

N. Krishnamoorthy and R. E. Abdulnour contributed equally to this work.

Address for reprint requests and other correspondence: B. D. Levy, Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, BTM 3016, 60 Fenwood Rd., Boston, MA, 02115 (e-mail: [email protected]).

REFERENCES

  • 1. Abdulnour RE, Dalli J, Colby JK, Krishnamoorthy N, Timmons JY, Tan SH, Colas RA, Petasis NA, Serhan CN, Levy BD. Maresin 1 biosynthesis during platelet-neutrophil interactions is organ-protective. Proc Natl Acad Sci USA 111: 16526–16531, 2014. doi:10.1073/pnas.1407123111.
    Crossref | PubMed | ISI | Google Scholar
  • 2. Abdulnour RE, Sham HP, Douda DN, Colas RA, Dalli J, Bai Y, Ai X, Serhan CN, Levy BD. Aspirin-triggered resolvin D1 is produced during self-resolving gram-negative bacterial pneumonia and regulates host immune responses for the resolution of lung inflammation. Mucosal Immunol 9: 1278–1287, 2016. doi:10.1038/mi.2015.129.
    Crossref | PubMed | ISI | Google Scholar
  • 3. Acharya KR, Ackerman SJ. Eosinophil granule proteins: form and function. J Biol Chem 289: 17406–17415, 2014. doi:10.1074/jbc.R113.546218.
    Crossref | PubMed | ISI | Google Scholar
  • 4. Aggarwal NR, King LS, D’Alessio FR. Diverse macrophage populations mediate acute lung inflammation and resolution. Am J Physiol Lung Cell Mol Physiol 306: L709–L725, 2014. doi:10.1152/ajplung.00341.2013.
    Link | ISI | Google Scholar
  • 5. Albert CM, Campos H, Stampfer MJ, Ridker PM, Manson JE, Willett WC, Ma J. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N Engl J Med 346: 1113–1118, 2002. doi:10.1056/NEJMoa012918.
    Crossref | PubMed | ISI | Google Scholar
  • 6. Aliberti J, Hieny S, Reis e Sousa C, Serhan CN, Sher A. Lipoxin-mediated inhibition of IL-12 production by DCs: a mechanism for regulation of microbial immunity. Nat Immunol 3: 76–82, 2002. doi:10.1038/ni745.
    Crossref | PubMed | ISI | Google Scholar
  • 7. Aliberti J, Serhan C, Sher A. Parasite-induced lipoxin A4 is an endogenous regulator of IL-12 production and immunopathology in Toxoplasma gondii infection. J Exp Med 196: 1253–1262, 2002. doi:10.1084/jem.20021183.
    Crossref | PubMed | ISI | Google Scholar
  • 8. Aoki H, Hisada T, Ishizuka T, Utsugi M, Kawata T, Shimizu Y, Okajima F, Dobashi K, Mori M. Resolvin E1 dampens airway inflammation and hyperresponsiveness in a murine model of asthma. Biochem Biophys Res Commun 367: 509–515, 2008. doi:10.1016/j.bbrc.2008.01.012.
    Crossref | PubMed | ISI | Google Scholar
  • 9. Ariel A, Chiang N, Arita M, Petasis NA, Serhan CN. Aspirin-triggered lipoxin A4 and B4 analogs block extracellular signal-regulated kinase-dependent TNF-α secretion from human T cells. J Immunol 170: 6266–6272, 2003. doi:10.4049/jimmunol.170.12.6266.
    Crossref | PubMed | ISI | Google Scholar
  • 10. Ariel A, Fredman G, Sun YP, Kantarci A, Van Dyke TE, Luster AD, Serhan CN. Apoptotic neutrophils and T cells sequester chemokines during immune response resolution through modulation of CCR5 expression. Nat Immunol 7: 1209–1216, 2006. doi:10.1038/ni1392.
    Crossref | PubMed | ISI | Google Scholar
  • 11. Ariel A, Li PL, Wang W, Tang WX, Fredman G, Hong S, Gotlinger KH, Serhan CN. The docosatriene protectin D1 is produced by TH2 skewing and promotes human T cell apoptosis via lipid raft clustering. J Biol Chem 280: 43079–43086, 2005. doi:10.1074/jbc.M509796200.
    Crossref | PubMed | ISI | Google Scholar
  • 12. Arita M, Bianchini F, Aliberti J, Sher A, Chiang N, Hong S, Yang R, Petasis NA, Serhan CN. Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J Exp Med 201: 713–722, 2005. doi:10.1084/jem.20042031.
    Crossref | PubMed | ISI | Google Scholar
  • 13. Arita M, Ohira T, Sun YP, Elangovan S, Chiang N, Serhan CN. Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation. J Immunol 178: 3912–3917, 2007. doi:10.4049/jimmunol.178.6.3912.
    Crossref | PubMed | ISI | Google Scholar
  • 14. Arnardottir H, Orr SK, Dalli J, Serhan CN. Human milk proresolving mediators stimulate resolution of acute inflammation. Mucosal Immunol 9: 757–766, 2016. doi:10.1038/mi.2015.99.
    Crossref | PubMed | ISI | Google Scholar
  • 15. Awji EG, Chand H, Bruse S, Smith KR, Colby JK, Mebratu Y, Levy BD, Tesfaigzi Y. Wood smoke enhances cigarette smoke-induced inflammation by inducing the aryl hydrocarbon receptor repressor in airway epithelial cells. Am J Respir Cell Mol Biol 52: 377–386, 2015. doi:10.1165/rcmb.2014-0142OC.
    Crossref | PubMed | ISI | Google Scholar
  • 16. Bafica A, Scanga CA, Serhan C, Machado F, White S, Sher A, Aliberti J. Host control of Mycobacterium tuberculosis is regulated by 5-lipoxygenase-dependent lipoxin production. J Clin Invest 115: 1601–1606, 2005. doi:10.1172/JCI23949.
    Crossref | PubMed | ISI | Google Scholar
  • 17. Baillie JK, Digard P. Influenza—time to target the host? N Engl J Med 369: 191–193, 2013. doi:10.1056/NEJMcibr1304414.
    Crossref | PubMed | ISI | Google Scholar
  • 18. Bandeira-Melo C, Bozza PT, Diaz BL, Cordeiro RS, Jose PJ, Martins MA, Serhan CN. Cutting edge: lipoxin (LX) A4 and aspirin-triggered 15-epi-LXA4 block allergen-induced eosinophil trafficking. J Immunol 164: 2267–2271, 2000. doi:10.4049/jimmunol.164.5.2267.
    Crossref | PubMed | ISI | Google Scholar
  • 19. Bannenberg G, Moussignac R-L, Gronert K, Devchand PR, Schmidt BA, Guilford WJ, Bauman JG, Subramanyam B, Perez HD, Parkinson JF, Serhan CN. Lipoxins and novel 15-epi-lipoxin analogs display potent anti-inflammatory actions after oral administration. Br J Pharmacol 143: 43–52, 2004. doi:10.1038/sj.bjp.0705912.
    Crossref | PubMed | ISI | Google Scholar
  • 20. Bannenberg GL, Chiang N, Ariel A, Arita M, Tjonahen E, Gotlinger KH, Hong S, Serhan CN. Molecular circuits of resolution: formation and actions of resolvins and protectins. J Immunol 174: 4345–4355, 2005. doi:10.4049/jimmunol.174.7.4345.
    Crossref | PubMed | ISI | Google Scholar
  • 21. Barnig C, Cernadas M, Dutile S, Liu X, Perrella MA, Kazani S, Wechsler ME, Israel E, Levy BD. Lipoxin A4 regulates natural killer cell and type 2 innate lymphoid cell activation in asthma. Sci Transl Med 5: 174ra26, 2013. doi:10.1126/scitranslmed.3004812.
    Crossref | PubMed | ISI | Google Scholar
  • 22. Basil MC, Levy BD. Specialized pro-resolving mediators: endogenous regulators of infection and inflammation. Nat Rev Immunol 16: 51–67, 2016. doi:10.1038/nri.2015.4.
    Crossref | PubMed | ISI | Google Scholar
  • 23. Bena S, Brancaleone V, Wang JM, Perretti M, Flower RJ. Annexin A1 interaction with the FPR2/ALX receptor: identification of distinct domains and downstream associated signaling. J Biol Chem 287: 24690–24697, 2012. doi:10.1074/jbc.M112.377101.
    Crossref | PubMed | ISI | Google Scholar
  • 24. Birnbaum Y, Ye Y, Lin Y, Freeberg SY, Nishi SP, Martinez JD, Huang MH, Uretsky BF, Perez-Polo JR. Augmentation of myocardial production of 15-epi-lipoxin-a4 by pioglitazone and atorvastatin in the rat. Circulation 114: 929–935, 2006. doi:10.1161/CIRCULATIONAHA.106.629907.
    Crossref | PubMed | ISI | Google Scholar
  • 25. Birukov KG. Small GTPases in mechanosensitive regulation of endothelial barrier. Microvasc Res 77: 46–52, 2009. doi:10.1016/j.mvr.2008.09.006.
    Crossref | PubMed | ISI | Google Scholar
  • 26. Bisgaard H, Stokholm J, Chawes BL, Vissing NH, Bjarnadóttir E, Schoos A-MM, Wolsk HM, Pedersen TM, Vinding RK, Thorsteinsdóttir S, Følsgaard NV, Fink NR, Thorsen J, Pedersen AG, Waage J, Rasmussen MA, Stark KD, Olsen SF, Bønnelykke K. Fish oil-derived fatty acids in pregnancy and wheeze and asthma in offspring. N Engl J Med 375: 2530–2539, 2016. doi:10.1056/NEJMoa1503734.
    Crossref | PubMed | ISI | Google Scholar
  • 27. Bondue B, Vosters O, de Nadai P, Glineur S, De Henau O, Luangsay S, Van Gool F, Communi D, De Vuyst P, Desmecht D, Parmentier M. ChemR23 dampens lung inflammation and enhances anti-viral immunity in a mouse model of acute viral pneumonia. PLoS Pathog 7: e1002358, 2011. doi:10.1371/journal.ppat.1002358.
    Crossref | PubMed | ISI | Google Scholar
  • 28. Bonnans C, Fukunaga K, Levy MA, Levy BD. Lipoxin A(4) regulates bronchial epithelial cell responses to acid injury. Am J Pathol 168: 1064–1072, 2006. doi:10.2353/ajpath.2006.051056.
    Crossref | PubMed | ISI | Google Scholar
  • 29. Bozinovski S, Hutchinson A, Thompson M, Macgregor L, Black J, Giannakis E, Karlsson AS, Silvestrini R, Smallwood D, Vlahos R, Irving LB, Anderson GP. Serum amyloid A is a biomarker of acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 177: 269–278, 2008. doi:10.1164/rccm.200705-678OC.
    Crossref | PubMed | ISI | Google Scholar
  • 30. Bozinovski S, Uddin M, Vlahos R, Thompson M, McQualter JL, Merritt AS, Wark PA, Hutchinson A, Irving LB, Levy BD, Anderson GP. Serum amyloid A opposes lipoxin A4 to mediate glucocorticoid refractory lung inflammation in chronic obstructive pulmonary disease. Proc Natl Acad Sci USA 109: 935–940, 2012. doi:10.1073/pnas.1109382109.
    Crossref | PubMed | ISI | Google Scholar
  • 31. Brezinski ME, Gimbrone MA Jr, Nicolaou KC, Serhan CN. Lipoxins stimulate prostacyclin generation by human endothelial cells. FEBS Lett 245: 167–172, 1989. doi:10.1016/0014-5793(89)80214-5.
    Crossref | PubMed | ISI | Google Scholar
  • 32. Brink C, Dahlén SE, Drazen J, Evans JF, Hay DW, Nicosia S, Serhan CN, Shimizu T, Yokomizo T. International Union of Pharmacology XXXVII. Nomenclature for leukotriene and lipoxin receptors. Pharmacol Rev 55: 195–227, 2003. doi:10.1124/pr.55.1.8.
    Crossref | PubMed | ISI | Google Scholar
  • 33. Buchanan PJ, McNally P, Harvey BJ, Urbach V. Lipoxin A4-mediated KATP potassium channel activation results in cystic fibrosis airway epithelial repair. Am J Physiol Lung Cell Mol Physiol 305: L193–L201, 2013. doi:10.1152/ajplung.00058.2013.
    Link | ISI | Google Scholar
  • 34. Buckley CD, Gilroy DW, Serhan CN. Proresolving lipid mediators and mechanisms in the resolution of acute inflammation. Immunity 40: 315–327, 2014. doi:10.1016/j.immuni.2014.02.009.
    Crossref | PubMed | ISI | Google Scholar
  • 35. Campbell EL, Louis NA, Tomassetti SE, Canny GO, Arita M, Serhan CN, Colgan SP. Resolvin E1 promotes mucosal surface clearance of neutrophils: a new paradigm for inflammatory resolution. FASEB J 21: 3162–3170, 2007. doi:10.1096/fj.07-8473com.
    Crossref | PubMed | ISI | Google Scholar
  • 36. Carlo T, Kalwa H, Levy BD. 15-Epi-lipoxin A4 inhibits human neutrophil superoxide anion generation by regulating polyisoprenyl diphosphate phosphatase 1. FASEB J 27: 2733–2741, 2013. doi:10.1096/fj.12-223982.
    Crossref | PubMed | ISI | Google Scholar
  • 37. Carlo T, Petasis NA, Levy BD. Activation of polyisoprenyl diphosphate phosphatase 1 remodels cellular presqualene diphosphate. Biochemistry 48: 2997–3004, 2009. doi:10.1021/bi8020636.
    Crossref | PubMed | ISI | Google Scholar
  • 38. Cash JL, Hart R, Russ A, Dixon JP, Colledge WH, Doran J, Hendrick AG, Carlton MB, Greaves DR. Synthetic chemerin-derived peptides suppress inflammation through ChemR23. J Exp Med 205: 767–775, 2008. doi:10.1084/jem.20071601.
    Crossref | PubMed | ISI | Google Scholar
  • 39. Cezar-de-Mello PF, Nascimento-Silva V, Villela CG, Fierro IM. Aspirin-triggered Lipoxin A4 inhibition of VEGF-induced endothelial cell migration involves actin polymerization and focal adhesion assembly. Oncogene 25: 122–129, 2006. doi:10.1038/sj.onc.1209002.
    Crossref | PubMed | ISI | Google Scholar
  • 40. Chen F, Fan XH, Wu YP, Zhu JL, Wang F, Bo LL, Li JB, Bao R, Deng XM. Resolvin D1 improves survival in experimental sepsis through reducing bacterial load and preventing excessive activation of inflammatory response. Eur J Clin Microbiol Infect Dis 33: 457–464, 2014. doi:10.1007/s10096-013-1978-6.
    Crossref | PubMed | ISI | Google Scholar
  • 41. Chen L, Liu H, Wang Y, Xia H, Gong J, Li B, Yao S, Shang Y. Maresin 1 maintains the permeability of lung epithelial cells in vitro and in vivo. Inflammation 39: 1981–1989, 2016. doi:10.1007/s10753-016-0433-0.
    Crossref | PubMed | ISI | Google Scholar
  • 42. Cheng X, He S, Yuan J, Miao S, Gao H, Zhang J, Li Y, Peng W, Wu P. Lipoxin A4 attenuates LPS-induced mouse acute lung injury via Nrf2-mediated E-cadherin expression in airway epithelial cells. Free Radic Biol Med 93: 52–66, 2016. doi:10.1016/j.freeradbiomed.2016.01.026.
    Crossref | PubMed | ISI | Google Scholar
  • 43. Chiang N, Bermudez EA, Ridker PM, Hurwitz S, Serhan CN. Aspirin triggers antiinflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial. Proc Natl Acad Sci USA 101: 15178–15183, 2004. doi:10.1073/pnas.0405445101.
    Crossref | PubMed | ISI | Google Scholar
  • 44. Chiang N, Dalli J, Colas RA, Serhan CN. Identification of resolvin D2 receptor mediating resolution of infections and organ protection. J Exp Med 212: 1203–1217, 2015. doi:10.1084/jem.20150225.
    Crossref | PubMed | ISI | Google Scholar
  • 45. Chiang N, de la Rosa X, Libreros S, Serhan CN. Novel resolvin D2 receptor axis in infectious inflammation. J Immunol 198: 842–851, 2017. doi:10.4049/jimmunol.1601650.
    Crossref | PubMed | ISI | Google Scholar
  • 46. Chiang N, Fierro IM, Gronert K, Serhan CN. Activation of lipoxin A(4) receptors by aspirin-triggered lipoxins and select peptides evokes ligand-specific responses in inflammation. J Exp Med 191: 1197–1208, 2000. doi:10.1084/jem.191.7.1197.
    Crossref | PubMed | ISI | Google Scholar
  • 47. Chiang N, Fredman G, Bäckhed F, Oh SF, Vickery T, Schmidt BA, Serhan CN. Infection regulates pro-resolving mediators that lower antibiotic requirements. Nature 484: 524–528, 2012. doi:10.1038/nature11042.
    Crossref | PubMed | ISI | Google Scholar
  • 48. Chiang N, Gronert K, Clish CB, O’Brien JA, Freeman MW, Serhan CN. Leukotriene B4 receptor transgenic mice reveal novel protective roles for lipoxins and aspirin-triggered lipoxins in reperfusion. J Clin Invest 104: 309–316, 1999. doi:10.1172/JCI7016.
    Crossref | PubMed | ISI | Google Scholar
  • 49. Chiang N, Serhan CN. Structural elucidation and physiologic functions of specialized pro-resolving mediators and their receptors. Mol Aspects Med 58: 114–129, 2017. doi:10.1016/j.mam.2017.03.005.
    Crossref | PubMed | ISI | Google Scholar
  • 50. Chiang N, Serhan CN, Dahlén SE, Drazen JM, Hay DW, Rovati GE, Shimizu T, Yokomizo T, Brink C. The lipoxin receptor ALX: potent ligand-specific and stereoselective actions in vivo. Pharmacol Rev 58: 463–487, 2006. doi:10.1124/pr.58.3.4.
    Crossref | PubMed | ISI | Google Scholar
  • 51. Chiang N, Takano T, Arita M, Watanabe S, Serhan CN. A novel rat lipoxin A4 receptor that is conserved in structure and function. Br J Pharmacol 139: 89–98, 2003. doi:10.1038/sj.bjp.0705220.
    Crossref | PubMed | ISI | Google Scholar
  • 52. Chiurchiù V, Leuti A, Dalli J, Jacobsson A, Battistini L, Maccarrone M, Serhan CN. Proresolving lipid mediators resolvin D1, resolvin D2, and maresin 1 are critical in modulating T cell responses. Sci Transl Med 8: 353ra111, 2016. doi:10.1126/scitranslmed.aaf7483.
    Crossref | PubMed | ISI | Google Scholar
  • 53. Christie PE, Spur BW, Lee TH. The effects of lipoxin A4 on airway responses in asthmatic subjects. Am Rev Respir Dis 145: 1281–1284, 1992. doi:10.1164/ajrccm/145.6.1281.
    Crossref | PubMed | ISI | Google Scholar
  • 54. Clària J, Lee MH, Serhan CN. Aspirin-triggered lipoxins (15-epi-LX) are generated by the human lung adenocarcinoma cell line (A549)-neutrophil interactions and are potent inhibitors of cell proliferation. Mol Med 2: 583–596, 1996.
    Crossref | PubMed | ISI | Google Scholar
  • 55. Clària J, Serhan CN. Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions. Proc Natl Acad Sci USA 92: 9475–9479, 1995. doi:10.1073/pnas.92.21.9475.
    Crossref | PubMed | ISI | Google Scholar
  • 56. Clish CB, Levy BD, Chiang N, Tai HH, Serhan CN. Oxidoreductases in lipoxin A4 metabolic inactivation: a novel role for 15-onoprostaglandin 13-reductase/leukotriene B4 12-hydroxydehydrogenase in inflammation. J Biol Chem 275: 25372–25380, 2000. doi:10.1074/jbc.M002863200.
    Crossref | PubMed | ISI | Google Scholar
  • 57. Codagnone M, Cianci E, Lamolinara A, Mari VC, Nespoli A, Isopi E, Mattoscio D, Arita M, Bragonzi A, Iezzi M, Romano M, Recchiuti A. Resolvin D1 enhances the resolution of lung inflammation caused by long-term Pseudomonas aeruginosa infection. Mucosal Immunol 11: 35–49, 2018. doi:10.1038/mi.2017.36.
    Crossref | PubMed | ISI | Google Scholar
  • 58. Colas RA, Shinohara M, Dalli J, Chiang N, Serhan CN. Identification and signature profiles for pro-resolving and inflammatory lipid mediators in human tissue. Am J Physiol Cell Physiol 307: C39–C54, 2014. doi:10.1152/ajpcell.00024.2014.
    Link | ISI | Google Scholar
  • 59. Colby JK, Abdulnour RE, Sham HP, Dalli J, Colas RA, Winkler JW, Hellmann J, Wong B, Cui Y, El-Chemaly S, Petasis NA, Spite M, Serhan CN, Levy BD. Resolvin D3 and aspirin-triggered resolvin D3 are protective for injured epithelia. Am J Pathol 186: 1801–1813, 2016. doi:10.1016/j.ajpath.2016.03.011.
    Crossref | PubMed | ISI | Google Scholar
  • 60. Colby JK, Gott KM, Wilder JA, Levy BD. Lipoxin signaling in murine lung host responses to Cryptococcus neoformans infection. Am J Respir Cell Mol Biol 54: 25–33, 2016. doi:10.1165/rcmb.2014-0102OC.
    Crossref | PubMed | ISI | Google Scholar
  • 61. Colgan SP, Serhan CN, Parkos CA, Delp-Archer C, Madara JL. Lipoxin A4 modulates transmigration of human neutrophils across intestinal epithelial monolayers. J Clin Invest 92: 75–82, 1993. doi:10.1172/JCI116601.
    Crossref | PubMed | ISI | Google Scholar
  • 62. Cooray SN, Gobbetti T, Montero-Melendez T, McArthur S, Thompson D, Clark AJL, Flower RJ, Perretti M. Ligand-specific conformational change of the G-protein-coupled receptor ALX/FPR2 determines proresolving functional responses. Proc Natl Acad Sci USA 110: 18232–18237, 2013. doi:10.1073/pnas.1308253110.
    Crossref | PubMed | ISI | Google Scholar
  • 63. Cox R Jr, Phillips O, Fukumoto J, Fukumoto I, Parthasarathy PT, Arias S, Cho Y, Lockey RF, Kolliputi N. Enhanced resolution of hyperoxic acute lung injury as a result of aspirin triggered resolvin D1 treatment. Am J Respir Cell Mol Biol 53: 422–435, 2015. doi:10.1165/rcmb.2014-0339OC.
    Crossref | PubMed | ISI | Google Scholar
  • 64. Croasdell A, Thatcher TH, Kottmann RM, Colas RA, Dalli J, Serhan CN, Sime PJ, Phipps RP. Resolvins attenuate inflammation and promote resolution in cigarette smoke-exposed human macrophages. Am J Physiol Lung Cell Mol Physiol 309: L888–L901, 2015.
    Abstract | ISI | Google Scholar
  • 65. D’Alessio FR, Tsushima K, Aggarwal NR, West EE, Willett MH, Britos MF, Pipeling MR, Brower RG, Tuder RM, McDyer JF, King LS. CD4+CD25+Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury. J Clin Invest 119: 2898–2913, 2009. doi:10.1172/JCI36498.
    Crossref | PubMed | ISI | Google Scholar
  • 66. Dalli J, Chiang N, Serhan CN. Identification of 14-series sulfido-conjugated mediators that promote resolution of infection and organ protection. Proc Natl Acad Sci USA 111: E4753–E4761, 2014. doi:10.1073/pnas.1415006111.
    Crossref | PubMed | ISI | Google Scholar
  • 67. Dalli J, Colas RA, Arnardottir H, Serhan CN. Vagal regulation of group 3 innate lymphoid cells and the immunoresolvent PCTR1 controls infection resolution. Immunity 46: 92–105, 2017. doi:10.1016/j.immuni.2016.12.009.
    Crossref | PubMed | ISI | Google Scholar
  • 68. Dalli J, Colas RA, Serhan CN. Novel n-3 immunoresolvents: structures and actions. Sci Rep 3: 1940, 2013. [Erratum. Sci Rep 4:6726, 2014.] doi:10.1038/srep01940.
    Crossref | PubMed | ISI | Google Scholar
  • 69. Dalli J, Ramon S, Norris PC, Colas RA, Serhan CN. Novel proresolving and tissue-regenerative resolvin and protectin sulfido-conjugated pathways. FASEB J 29: 2120–2136, 2015. doi:10.1096/fj.14-268441.
    Crossref | PubMed | ISI | Google Scholar
  • 70. Dalli J, Zhu M, Vlasenko NA, Deng B, Haeggström JZ, Petasis NA, Serhan CN. The novel 13S,14S-epoxy-maresin is converted by human macrophages to maresin 1 (MaR1), inhibits leukotriene A4 hydrolase (LTA4H), and shifts macrophage phenotype. FASEB J 27: 2573–2583, 2013. doi:10.1096/fj.13-227728.
    Crossref | PubMed | ISI | Google Scholar
  • 71. De Caterina R. n-3 fatty acids in cardiovascular disease. N Engl J Med 364: 2439–2450, 2011. doi:10.1056/NEJMra1008153.
    Crossref | PubMed | ISI | Google Scholar
  • 72. Deng B, Wang CW, Arnardottir HH, Li Y, Cheng CY, Dalli J, Serhan CN. Maresin biosynthesis and identification of maresin 2, a new anti-inflammatory and pro-resolving mediator from human macrophages. PLoS One 9: e102362, 2014. doi:10.1371/journal.pone.0102362.
    Crossref | PubMed | ISI | Google Scholar
  • 73. Divanovic S, Dalli J, Jorge-Nebert LF, Flick LM, Gálvez-Peralta M, Boespflug ND, Stankiewicz TE, Fitzgerald JM, Somarathna M, Karp CL, Serhan CN, Nebert DW. Contributions of the three CYP1 monooxygenases to pro-inflammatory and inflammation-resolution lipid mediator pathways. J Immunol 191: 3347–3357, 2013. doi:10.4049/jimmunol.1300699.
    Crossref | PubMed | ISI | Google Scholar
  • 74. Du XY, Leung LL. Proteolytic regulatory mechanism of chemerin bioactivity. Acta Biochim Biophys Sin (Shanghai) 41: 973–979, 2009. doi:10.1093/abbs/gmp091.
    Crossref | PubMed | ISI | Google Scholar
  • 75. Duffield JS, Hong S, Vaidya VS, Lu Y, Fredman G, Serhan CN, Bonventre JV. Resolvin D series and protectin D1 mitigate acute kidney injury. J Immunol 177: 5902–5911, 2006. doi:10.4049/jimmunol.177.9.5902.
    Crossref | PubMed | ISI | Google Scholar
  • 76. Dufton N, Hannon R, Brancaleone V, Dalli J, Patel HB, Gray M, D’Acquisto F, Buckingham JC, Perretti M, Flower RJ. Anti-inflammatory role of the murine formyl-peptide receptor 2: ligand-specific effects on leukocyte responses and experimental inflammation. J Immunol 184: 2611–2619, 2010. doi:10.4049/jimmunol.0903526.
    Crossref | PubMed | ISI | Google Scholar
  • 77. Duvall MG, Barnig C, Cernadas M, Ricklefs I, Krishnamoorthy N, Grossman NL, Bhakta NR, Fahy JV, Bleecker ER, Castro M, Erzurum SC, Gaston BM, Jarjour NN, Mauger DT, Wenzel SE, Comhair SA, Coverstone AM, Fajt ML, Hastie AT, Johansson MW, Peters MC, Phillips BR, Israel E, Levy BD; National Heart, Lung, and Blood Institute’s Severe Asthma Research Program-3 Investigators. Natural killer cell-mediated inflammation resolution is disabled in severe asthma. Sci Immunol 2: eaam5446, 2017. doi:10.1126/sciimmunol.aam5446.
    Crossref | PubMed | ISI | Google Scholar
  • 78. Edenius C, Kumlin M, Björk T, Anggård A, Lindgren JA. Lipoxin formation in human nasal polyps and bronchial tissue. FEBS Lett 272: 25–28, 1990. doi:10.1016/0014-5793(90)80440-T.
    Crossref | PubMed | ISI | Google Scholar
  • 79. Eickmeier O, Fussbroich D, Mueller K, Serve F, Smaczny C, Zielen S, Schubert R. Pro-resolving lipid mediator Resolvin D1 serves as a marker of lung disease in cystic fibrosis. PLoS One 12: e0171249, 2017. doi:10.1371/journal.pone.0171249.
    Crossref | PubMed | ISI | Google Scholar
  • 80. Eickmeier O, Seki H, Haworth O, Hilberath JN, Gao F, Uddin M, Croze RH, Carlo T, Pfeffer MA, Levy BD. Aspirin-triggered resolvin D1 reduces mucosal inflammation and promotes resolution in a murine model of acute lung injury. Mucosal Immunol 6: 256–266, 2013. doi:10.1038/mi.2012.66.
    Crossref | PubMed | ISI | Google Scholar
  • 81. Eisner MD, Anthonisen N, Coultas D, Kuenzli N, Perez-Padilla R, Postma D, Romieu I, Silverman EK, Balmes JR; Committee on Nonsmoking COPD, Environmental and Occupational Health Assembly. An official American Thoracic Society public policy statement: Novel risk factors and the global burden of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 182: 693–718, 2010. doi:10.1164/rccm.200811-1757ST.
    Crossref | PubMed | ISI | Google Scholar
  • 82. El Kebir D, Gjorstrup P, Filep JG. Resolvin E1 promotes phagocytosis-induced neutrophil apoptosis and accelerates resolution of pulmonary inflammation. Proc Natl Acad Sci USA 109: 14983–14988, 2012. doi:10.1073/pnas.1206641109.
    Crossref | PubMed | ISI | Google Scholar
  • 83. El Kebir D, József L, Khreiss T, Pan W, Petasis NA, Serhan CN, Filep JG. Aspirin-triggered lipoxins override the apoptosis-delaying action of serum amyloid A in human neutrophils: a novel mechanism for resolution of inflammation. J Immunol 179: 616–622, 2007. doi:10.4049/jimmunol.179.1.616.
    Crossref | PubMed | ISI | Google Scholar
  • 84. El Kebir D, József L, Pan W, Wang L, Petasis NA, Serhan CN, Filep JG. 15-epi-lipoxin A4 inhibits myeloperoxidase signaling and enhances resolution of acute lung injury. Am J Respir Crit Care Med 180: 311–319, 2009. doi:10.1164/rccm.200810-1601OC.
    Crossref | PubMed | ISI | Google Scholar
  • 85. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7: 606–619, 2006. doi:10.1038/nrg1879.
    Crossref | PubMed | ISI | Google Scholar
  • 86. Ernst OP, Gramse V, Kolbe M, Hofmann KP, Heck M. Monomeric G protein-coupled receptor rhodopsin in solution activates its G protein transducin at the diffusion limit. Proc Natl Acad Sci USA 104: 10859–10864, 2007. doi:10.1073/pnas.0701967104.
    Crossref | PubMed | ISI | Google Scholar
  • 87. Evans CM, Fingerlin TE, Schwarz MI, Lynch D, Kurche J, Warg L, Yang IV, Schwartz DA. Idiopathic pulmonary fibrosis: a genetic disease that involves mucociliary dysfunction of the peripheral airways. Physiol Rev 96: 1567–1591, 2016. doi:10.1152/physrev.00004.2016.
    Link | ISI | Google Scholar
  • 88. Fang X, Abbott J, Cheng L, Colby JK, Lee JW, Levy BD, Matthay MA. Human mesenchymal stem (stromal) cells promote the resolution of acute lung injury in part through lipoxin A4. J Immunol 195: 875–881, 2015. doi:10.4049/jimmunol.1500244.
    Crossref | PubMed | ISI | Google Scholar
  • 89. Filep JG. Biasing the lipoxin A4/formyl peptide receptor 2 pushes inflammatory resolution. Proc Natl Acad Sci USA 110: 18033–18034, 2013. doi:10.1073/pnas.1317798110.
    Crossref | PubMed | ISI | Google Scholar
  • 90. Fiore S, Maddox JF, Perez HD, Serhan CN. Identification of a human cDNA encoding a functional high affinity lipoxin A4 receptor. J Exp Med 180: 253–260, 1994. doi:10.1084/jem.180.1.253.
    Crossref | PubMed | ISI | Google Scholar
  • 91. Fiore S, Ryeom SW, Weller PF, Serhan CN. Lipoxin recognition sites. Specific binding of labeled lipoxin A4 with human neutrophils. J Biol Chem 267: 16168–16176, 1992.
    Crossref | PubMed | ISI | Google Scholar
  • 92. Fiore S, Serhan CN. Formation of lipoxins and leukotrienes during receptor-mediated interactions of human platelets and recombinant human granulocyte/macrophage colony-stimulating factor-primed neutrophils. J Exp Med 172: 1451–1457, 1990. doi:10.1084/jem.172.5.1451.
    Crossref | PubMed | ISI | Google Scholar
  • 93. Fiore S, Serhan CN. Lipoxin A4 receptor activation is distinct from that of the formyl peptide receptor in myeloid cells: inhibition of CD11/18 expression by lipoxin A4-lipoxin A4 receptor interaction. Biochemistry 34: 16678–16686, 1995. doi:10.1021/bi00051a016.
    Crossref | PubMed | ISI | Google Scholar
  • 94. Fischer A, Antoniou KM, Brown KK, Cadranel J, Corte TJ, du Bois RM, Lee JS, Leslie KO, Lynch DA, Matteson EL, Mosca M, Noth I, Richeldi L, Strek ME, Swigris JJ, Wells AU, West SG, Collard HR, Cottin V; ERS/ATS Task Force on Undifferentiated Forms of CTD-ILD. An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features. Eur Respir J 46: 976–987, 2015. doi:10.1183/13993003.00150-2015.
    Crossref | PubMed | ISI | Google Scholar
  • 95. Flesher RP, Herbert C, Kumar RK. Resolvin E1 promotes resolution of inflammation in a mouse model of an acute exacerbation of allergic asthma. Clin Sci (Lond) 126: 805–818, 2014. doi:10.1042/CS20130623.
    Crossref | PubMed | ISI | Google Scholar
  • 96. Flitter BA, Hvorecny KL, Ono E, Eddens T, Yang J, Kwak DH, Bahl CD, Hampton TH, Morisseau C, Hammock BD, Liu X, Lee JS, Kolls JK, Levy BD, Madden DR, Bomberger JM. Pseudomonas aeruginosa sabotages the generation of host proresolving lipid mediators. Proc Natl Acad Sci USA 114: 136–141, 2017. doi:10.1073/pnas.1610242114.
    Crossref | PubMed | ISI | Google Scholar
  • 97. Freedman SD, Blanco PG, Zaman MM, Shea JC, Ollero M, Hopper IK, Weed DA, Gelrud A, Regan MM, Laposata M, Alvarez JG, O’Sullivan BP. Association of cystic fibrosis with abnormalities in fatty acid metabolism. N Engl J Med 350: 560–569, 2004. doi:10.1056/NEJMoa021218.
    Crossref | PubMed | ISI | Google Scholar
  • 98. Fukunaga K, Arita M, Takahashi M, Morris AJ, Pfeffer M, Levy BD. Identification and functional characterization of a presqualene diphosphate phosphatase. J Biol Chem 281: 9490–9497, 2006. doi:10.1074/jbc.M512970200.
    Crossref | PubMed | ISI | Google Scholar
  • 99. Fukunaga K, Kohli P, Bonnans C, Fredenburgh LE, Levy BD. Cyclooxygenase 2 plays a pivotal role in the resolution of acute lung injury. J Immunol 174: 5033–5039, 2005. doi:10.4049/jimmunol.174.8.5033.
    Crossref | PubMed | ISI | Google Scholar
  • 100. Gadek JEM, DeMichele SJP, Karlstad MDP, Pacht ERM, Donahoe M, Albertson TEM, Van Hoozen C, Wennberg AKR, Nelson JLP, Noursalehi M; Enteral Nutrition in ARDS Study Group. Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Crit Care Med 27: 1409–1420, 1999. doi:10.1097/00003246-199908000-00001.
    Crossref | PubMed | ISI | Google Scholar
  • 101. Galli C, Calder PC. Effects of fat and fatty acid intake on inflammatory and immune responses: a critical review. Ann Nutr Metab 55: 123–139, 2009. doi:10.1159/000228999.
    Crossref | PubMed | ISI | Google Scholar
  • 102. Galli C, Risé P; The Science and the Clinical Trials. Fish consumption, omega 3 fatty acids and cardiovascular disease. The science and the clinical trials. Nutr Health 20: 11–20, 2009. doi:10.1177/026010600902000102.
    Crossref | PubMed | Google Scholar
  • 103. Galli SJ, Tsai M. IgE and mast cells in allergic disease. Nat Med 18: 693–704, 2012. doi:10.1038/nm.2755.
    Crossref | PubMed | ISI | Google Scholar
  • 104. Gangemi S, Pescara L, D’Urbano E, Basile G, Nicita-Mauro V, Davì G, Romano M. Aging is characterized by a profound reduction in anti-inflammatory lipoxin A4 levels. Exp Gerontol 40: 612–614, 2005. doi:10.1016/j.exger.2005.04.004.
    Crossref | PubMed | ISI | Google Scholar
  • 105. Gao Y, Min K, Zhang Y, Su J, Greenwood M, Gronert K. Female-specific downregulation of tissue polymorphonuclear neutrophils drives impaired regulatory T cell and amplified effector T cell responses in autoimmune dry eye disease. J Immunol 195: 3086–3099, 2015. doi:10.4049/jimmunol.1500610.
    Crossref | PubMed | ISI | Google Scholar
  • 106. Godson C, Mitchell S, Harvey K, Petasis NA, Hogg N, Brady HR. Cutting edge: lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages. J Immunol 164: 1663–1667, 2000. doi:10.4049/jimmunol.164.4.1663.
    Crossref | PubMed | ISI | Google Scholar
  • 107. Gong J, Liu H, Wu J, Qi H, Wu ZY, Shu HQ, Li HB, Chen L, Wang YX, Li B, Tang M, Ji YD, Yuan SY, Yao SL, Shang Y. Maresin 1 prevents lipopolysaccharide-induced neutrophil survival and accelerates resolution of acute lung injury. Shock 44: 371–380, 2015. doi:10.1097/SHK.0000000000000434.
    Crossref | PubMed | ISI | Google Scholar
  • 108. Gong J, Wu ZY, Qi H, Chen L, Li HB, Li B, Yao CY, Wang YX, Wu J, Yuan SY, Yao SL, Shang Y. Maresin 1 mitigates LPS-induced acute lung injury in mice. Br J Pharmacol 171: 3539–3550, 2014. doi:10.1111/bph.12714.
    Crossref | PubMed | ISI | Google Scholar
  • 109. Goulding NJ, Godolphin JL, Sharland PR, Peers SH, Sampson M, Maddison PJ, Flower RJ. Anti-inflammatory lipocortin 1 production by peripheral blood leucocytes in response to hydrocortisone. Lancet 335: 1416–1418, 1990. doi:10.1016/0140-6736(90)91445-G.
    Crossref | PubMed | ISI | Google Scholar
  • 110. Gronert K, Gewirtz A, Madara JL, Serhan CN. Identification of a human enterocyte lipoxin A4 receptor that is regulated by interleukin (IL)-13 and interferon gamma and inhibits tumor necrosis factor alpha-induced IL-8 release. J Exp Med 187: 1285–1294, 1998. doi:10.1084/jem.187.8.1285.
    Crossref | PubMed | ISI | Google Scholar
  • 111. Gronert K, Martinsson-Niskanen T, Ravasi S, Chiang N, Serhan CN. Selectivity of recombinant human leukotriene D(4), leukotriene B(4), and lipoxin A(4) receptors with aspirin-triggered 15-epi-LXA(4) and regulation of vascular and inflammatory responses. Am J Pathol 158: 3–9, 2001. doi:10.1016/S0002-9440(10)63937-5.
    Crossref | PubMed | ISI | Google Scholar
  • 112. Gu Z, Lamont GJ, Lamont RJ, Uriarte SM, Wang H, Scott DA. Resolvin D1, resolvin D2 and maresin 1 activate the GSK3β anti-inflammatory axis in TLR4-engaged human monocytes. Innate Immun 22: 186–195, 2016. doi:10.1177/1753425916628618.
    Crossref | PubMed | ISI | Google Scholar
  • 113. Gupta N, Su X, Popov B, Lee JW, Serikov V, Matthay MA. Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol 179: 1855–1863, 2007. doi:10.4049/jimmunol.179.3.1855.
    Crossref | PubMed | ISI | Google Scholar
  • 114. Hamza B, Wong E, Patel S, Cho H, Martel J, Irimia D. Retrotaxis of human neutrophils during mechanical confinement inside microfluidic channels. Integr Biol 6: 175–183, 2014. doi:10.1039/C3IB40175H.
    Crossref | PubMed | Google Scholar
  • 115. Hashimoto A, Murakami Y, Kitasato H, Hayashi I, Endo H. Glucocorticoids co-interact with lipoxin A4 via lipoxin A4 receptor (ALX) up-regulation. Biomed Pharmacother 61: 81–85, 2007. doi:10.1016/j.biopha.2006.06.023.
    Crossref | PubMed | ISI | Google Scholar
  • 116. Hasturk H, Kantarci A, Ohira T, Arita M, Ebrahimi N, Chiang N, Petasis NA, Levy BD, Serhan CN, Van Dyke TE. RvE1 protects from local inflammation and osteoclast- mediated bone destruction in periodontitis. FASEB J 20: 401–403, 2006. doi:10.1096/fj.05-4724fje.
    Crossref | PubMed | ISI | Google Scholar
  • 117. Haworth O, Cernadas M, Levy BD. NK cells are effectors for resolvin E1 in the timely resolution of allergic airway inflammation. J Immunol 186: 6129–6135, 2011. doi:10.4049/jimmunol.1004007.
    Crossref | PubMed | ISI | Google Scholar
  • 118. Haworth O, Cernadas M, Yang R, Serhan CN, Levy BD. Resolvin E1 regulates interleukin 23, interferon-gamma and lipoxin A4 to promote the resolution of allergic airway inflammation. Nat Immunol 9: 873–879, 2008. doi:10.1038/ni.1627.
    Crossref | PubMed | ISI | Google Scholar
  • 119. He R, Sang H, Ye RD. Serum amyloid A induces IL-8 secretion through a G protein-coupled receptor, FPRL1/LXA4R. Blood 101: 1572–1581, 2003. doi:10.1182/blood-2002-05-1431.
    Crossref | PubMed | ISI | Google Scholar
  • 120. Herold S, Tabar TS, Janssen H, Hoegner K, Cabanski M, Lewe-Schlosser P, Albrecht J, Driever F, Vadasz I, Seeger W, Steinmueller M, Lohmeyer J. Exudate macrophages attenuate lung injury by the release of IL-1 receptor antagonist in gram-negative pneumonia. Am J Respir Crit Care Med 183: 1380–1390, 2011. doi:10.1164/rccm.201009-1431OC.
    Crossref | PubMed | ISI | Google Scholar
  • 121. Herová M, Schmid M, Gemperle C, Hersberger M. ChemR23, the receptor for chemerin and resolvin E1, is expressed and functional on M1 but not on M2 macrophages. J Immunol 194: 2330–2337, 2015. doi:10.4049/jimmunol.1402166.
    Crossref | PubMed | ISI | Google Scholar
  • 122. Higgins G, Fustero Torre C, Tyrrell J, McNally P, Harvey BJ, Urbach V. Lipoxin A4 prevents tight junction disruption and delays the colonization of cystic fibrosis bronchial epithelial cells by Pseudomonas aeruginosa. Am J Physiol Lung Cell Mol Physiol 310: L1053–L1061, 2016. doi:10.1152/ajplung.00368.2015.
    Link | ISI | Google Scholar
  • 123. Hiram R, Rizcallah E, Marouan S, Sirois C, Sirois M, Morin C, Fortin S, Rousseau E. Resolvin E1 normalizes contractility, Ca2+ sensitivity and smooth muscle cell migration rate in TNF-α- and IL-6-pretreated human pulmonary arteries. Am J Physiol Lung Cell Mol Physiol 309: L776–L788, 2015. doi:10.1152/ajplung.00177.2015.
    Link | ISI | Google Scholar
  • 124. Hiram R, Rizcallah E, Sirois C, Sirois M, Morin C, Fortin S, Rousseau E. Resolvin D1 reverses reactivity and Ca2+ sensitivity induced by ET-1, TNF-α, and IL-6 in the human pulmonary artery. Am J Physiol Heart Circ Physiol 307: H1547–H1558, 2014. doi:10.1152/ajpheart.00452.2014.
    Link | ISI | Google Scholar
  • 125. Hong S, Gronert K, Devchand PR, Moussignac RL, Serhan CN. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in anti-inflammation. J Biol Chem 278: 14677–14687, 2003. doi:10.1074/jbc.M300218200.
    Crossref | PubMed | ISI | Google Scholar
  • 126. Hsiao HM, Sapinoro RE, Thatcher TH, Croasdell A, Levy EP, Fulton RA, Olsen KC, Pollock SJ, Serhan CN, Phipps RP, Sime PJ. A novel anti-inflammatory and pro-resolving role for resolvin D1 in acute cigarette smoke-induced lung inflammation. PLoS One 8: e58258, 2013. doi:10.1371/journal.pone.0058258.
    Crossref | PubMed | ISI | Google Scholar
  • 127. Hsiao HM, Thatcher TH, Colas RA, Serhan CN, Phipps RP, Sime PJ. Resolvin D1 reduces emphysema and chronic inflammation. Am J Pathol 185: 3189–3201, 2015. doi:10.1016/j.ajpath.2015.08.008.
    Crossref | PubMed | ISI | Google Scholar
  • 128. Hsiao HM, Thatcher TH, Levy EP, Fulton RA, Owens KM, Phipps RP, Sime PJ. Resolvin D1 attenuates polyinosinic-polycytidylic acid-induced inflammatory signaling in human airway epithelial cells via TAK1. J Immunol 193: 4980–4987, 2014. doi:10.4049/jimmunol.1400313.
    Crossref | PubMed | ISI | Google Scholar
  • 129. Hua J, Jin Y, Chen Y, Inomata T, Lee H, Chauhan SK, Petasis NA, Serhan CN, Dana R. The resolvin D1 analogue controls maturation of dendritic cells and suppresses alloimmunity in corneal transplantation. Invest Ophthalmol Vis Sci 55: 5944–5951, 2014. doi:10.1167/iovs.14-14356.
    Crossref | PubMed | ISI | Google Scholar
  • 130. Isobe Y, Arita M, Iwamoto R, Urabe D, Todoroki H, Masuda K, Inoue M, Arai H. Stereochemical assignment and anti-inflammatory properties of the omega-3 lipid mediator resolvin E3. J Biochem 153: 355–360, 2013. doi:10.1093/jb/mvs151.
    Crossref | PubMed | ISI | Google Scholar
  • 131. Isobe Y, Arita M, Matsueda S, Iwamoto R, Fujihara T, Nakanishi H, Taguchi R, Masuda K, Sasaki K, Urabe D, Inoue M, Arai H. Identification and structure determination of novel anti-inflammatory mediator resolvin E3, 17,18-dihydroxyeicosapentaenoic acid. J Biol Chem 287: 10525–10534, 2012. doi:10.1074/jbc.M112.340612.
    Crossref | PubMed | ISI | Google Scholar
  • 132. Janssen WJ, Barthel L, Muldrow A, Oberley-Deegan RE, Kearns MT, Jakubzick C, Henson PM. Fas determines differential fates of resident and recruited macrophages during resolution of acute lung injury. Am J Respir Crit Care Med 184: 547–560, 2011. doi:10.1164/rccm.201011-1891OC.
    Crossref | PubMed | ISI | Google Scholar
  • 133. Jin SW, Zhang L, Lian QQ, Liu D, Wu P, Yao SL, Ye DY. Posttreatment with aspirin-triggered lipoxin A4 analog attenuates lipopolysaccharide-induced acute lung injury in mice: the role of heme oxygenase-1. Anesth Analg 104: 369–377, 2007. doi:10.1213/01.ane.0000252414.00363.c4.
    Crossref | PubMed | ISI | Google Scholar
  • 134. József L, Zouki C, Petasis NA, Serhan CN, Filep JG. Lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 inhibit peroxynitrite formation, NF-κB and AP-1 activation, and IL-8 gene expression in human leukocytes. Proc Natl Acad Sci USA 99: 13266–13271, 2002. doi:10.1073/pnas.202296999.
    Crossref | PubMed | ISI | Google Scholar
  • 135. Kang Y, Taddeo B, Varai G, Varga J, Fiore S. Mutations of serine 236-237 and tyrosine 302 residues in the human lipoxin A4 receptor intracellular domains result in sustained signaling. Biochemistry 39: 13551–13557, 2000. doi:10.1021/bi001196i.
    Crossref | PubMed | ISI | Google Scholar
  • 136. Karp CL, Flick LM, Park KW, Softic S, Greer TM, Keledjian R, Yang R, Uddin J, Guggino WB, Atabani SF, Belkaid Y, Xu Y, Whitsett JA, Accurso FJ, Wills-Karp M, Petasis NA. Defective lipoxin-mediated anti-inflammatory activity in the cystic fibrosis airway. Nat Immunol 5: 388–392, 2004. doi:10.1038/ni1056.
    Crossref | PubMed | ISI | Google Scholar
  • 137. Karra L, Haworth O, Priluck R, Levy BD, Levi-Schaffer F. Lipoxin B4 promotes the resolution of allergic inflammation in the upper and lower airways of mice. Mucosal Immunol 8: 852–862, 2015. doi:10.1038/mi.2014.116.
    Crossref | PubMed | ISI | Google Scholar
  • 138. Kasuga K, Yang R, Porter TF, Agrawal N, Petasis NA, Irimia D, Toner M, Serhan CN. Rapid appearance of resolvin precursors in inflammatory exudates: novel mechanisms in resolution. J Immunol 181: 8677–8687, 2008. doi:10.4049/jimmunol.181.12.8677.
    Crossref | PubMed | ISI | Google Scholar
  • 139. Kazani S, Planaguma A, Ono E, Bonini M, Zahid M, Marigowda G, Wechsler ME, Levy BD, Israel E. Exhaled breath condensate eicosanoid levels associate with asthma and its severity. J Allergy Clin Immunol 132: 547–553, 2013. doi:10.1016/j.jaci.2013.01.058.
    Crossref | PubMed | ISI | Google Scholar
  • 140. Khaddaj-Mallat R, Sirois C, Sirois M, Rizcallah E, Marouan S, Morin C, Rousseau É. Pro-resolving effects of resolvin D2 in LTD4 and TNF-α pre-treated human bronchi. PLoS One 11: e0167058, 2016. doi:10.1371/journal.pone.0167058.
    Crossref | PubMed | ISI | Google Scholar
  • 141. Kim JH, Sherman ME, Curriero FC, Guengerich FP, Strickland PT, Sutter TR. Expression of cytochromes P450 1A1 and 1B1 in human lung from smokers, non-smokers, and ex-smokers. Toxicol Appl Pharmacol 199: 210–219, 2004. doi:10.1016/j.taap.2003.11.015.
    Crossref | PubMed | ISI | Google Scholar
  • 142. Kim N, Ramon S, Thatcher TH, Woeller CF, Sime PJ, Phipps RP. Specialized proresolving mediators (SPMs) inhibit human B-cell IgE production. Eur J Immunol 46: 81–91, 2016. doi:10.1002/eji.201545673.
    Crossref | PubMed | ISI | Google Scholar
  • 143. Kim N, Thatcher TH, Sime PJ, Phipps RP. Corticosteroids inhibit anti-IgE activities of specialized proresolving mediators on B cells from asthma patients. JCI Insight 2: e88588, 2017. doi:10.1172/jci.insight.88588.
    Crossref | PubMed | ISI | Google Scholar
  • 144. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol 13: 159–175, 2013. doi:10.1038/nri3399.
    Crossref | PubMed | ISI | Google Scholar
  • 145. Kowal-Bielecka O, Kowal K, Distler O, Rojewska J, Bodzenta-Lukaszyk A, Michel BA, Gay RE, Gay S, Sierakowski S. Cyclooxygenase- and lipoxygenase-derived eicosanoids in bronchoalveolar lavage fluid from patients with scleroderma lung disease: an imbalance between proinflammatory and antiinflammatory lipid mediators. Arthritis Rheum 52: 3783–3791, 2005. doi:10.1002/art.21432.
    Crossref | PubMed | Google Scholar
  • 146. Krishnamoorthy N, Burkett PR, Dalli J, Abdulnour RE, Colas R, Ramon S, Phipps RP, Petasis NA, Kuchroo VK, Serhan CN, Levy BD. Cutting edge: maresin-1 engages regulatory T cells to limit type 2 innate lymphoid cell activation and promote resolution of lung inflammation. J Immunol 194: 863–867, 2015. doi:10.4049/jimmunol.1402534.
    Crossref | PubMed | ISI | Google Scholar
  • 147. Krishnamoorthy S, Recchiuti A, Chiang N, Fredman G, Serhan CN. Resolvin D1 receptor stereoselectivity and regulation of inflammation and proresolving microRNAs. Am J Pathol 180: 2018–2027, 2012. doi:10.1016/j.ajpath.2012.01.028.
    Crossref | PubMed | ISI | Google Scholar
  • 148. Krishnamoorthy S, Recchiuti A, Chiang N, Yacoubian S, Lee CH, Yang R, Petasis NA, Serhan CN. Resolvin D1 binds human phagocytes with evidence for proresolving receptors. Proc Natl Acad Sci USA 107: 1660–1665, 2010. doi:10.1073/pnas.0907342107.
    Crossref | PubMed | ISI | Google Scholar
  • 149. Laidlaw TM, Boyce JA. Aspirin-exacerbated respiratory disease—new prime suspects. N Engl J Med 374: 484–488, 2016. doi:10.1056/NEJMcibr1514013.
    Crossref | PubMed | ISI | Google Scholar
  • 150. Lämmermann T, Afonso PV, Angermann BR, Wang JM, Kastenmüller W, Parent CA, Germain RN. Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo. Nature 498: 371–375, 2013. doi:10.1038/nature12175.
    Crossref | PubMed | ISI | Google Scholar
  • 151. Lee CR, Zeldin DC. Resolvin infectious inflammation by targeting the host response. N Engl J Med 373: 2183–2185, 2015. doi:10.1056/NEJMcibr1511280.
    Crossref | PubMed | ISI | Google Scholar
  • 152. Lee JW, Krasnodembskaya A, McKenna DH, Song Y, Abbott J, Matthay MA. Therapeutic effects of human mesenchymal stem cells in ex vivo human lungs injured with live bacteria. Am J Respir Crit Care Med 187: 751–760, 2013. doi:10.1164/rccm.201206-0990OC.
    Crossref | PubMed | ISI | Google Scholar
  • 153. Lee TH, Crea AE, Gant V, Spur BW, Marron BE, Nicolaou KC, Reardon E, Brezinski M, Serhan CN. Identification of lipoxin A4 and its relationship to the sulfidopeptide leukotrienes C4, D4, and E4 in the bronchoalveolar lavage fluids obtained from patients with selected pulmonary diseases. Am Rev Respir Dis 141: 1453–1458, 1990. doi:10.1164/ajrccm/141.6.1453.
    Crossref | PubMed | ISI | Google Scholar
  • 154. Lee TH, Horton CE, Kyan-Aung U, Haskard D, Crea AE, Spur BW. Lipoxin A4 and lipoxin B4 inhibit chemotactic responses of human neutrophils stimulated by leukotriene B4 and N-formyl-L-methionyl-L-leucyl-L-phenylalanine. Clin Sci (Lond) 77: 195–203, 1989. doi:10.1042/cs0770195.
    Crossref | PubMed | ISI | Google Scholar
  • 155. Levy BD, Bonnans C, Silverman ES, Palmer LJ, Marigowda G, Israel E; Severe Asthma Research Program, National Heart, Lung, and Blood Institute. Diminished lipoxin biosynthesis in severe asthma. Am J Respir Crit Care Med 172: 824–830, 2005. doi:10.1164/rccm.200410-1413OC.
    Crossref | PubMed | ISI | Google Scholar
  • 156. Levy BD, Choi AMK. Acute respiratory distress syndrome. In: Harrison’s Principles of Internal Medicine (19th Ed.), edited by Kasper D, Fauci A, Hauser S, Longo D, Jameson JL, Loscalzo J. New York: McGraw-Hill Education, 2015.
    Google Scholar
  • 157. Levy BD, Clish CB, Schmidt B, Gronert K, Serhan CN. Lipid mediator class switching during acute inflammation: signals in resolution. Nat Immunol 2: 612–619, 2001. doi:10.1038/89759.
    Crossref | PubMed | ISI | Google Scholar
  • 158. Levy BD, De Sanctis GT, Devchand PR, Kim E, Ackerman K, Schmidt BA, Szczeklik W, Drazen JM, Serhan CN. Multi-pronged inhibition of airway hyper-responsiveness and inflammation by lipoxin A(4). Nat Med 8: 1018–1023, 2002. doi:10.1038/nm748.
    Crossref | PubMed | ISI | Google Scholar
  • 159. Levy BD, Fokin VV, Clark JM, Wakelam MJ, Petasis NA, Serhan CN. Polyisoprenyl phosphate (PIPP) signaling regulates phospholipase D activity: a ‘stop’ signaling switch for aspirin-triggered lipoxin A4. FASEB J 13: 903–911, 1999. doi:10.1096/fasebj.13.8.903.
    Crossref | PubMed | ISI | Google Scholar
  • 160. Levy BD, Kohli P, Gotlinger K, Haworth O, Hong S, Kazani S, Israel E, Haley KJ, Serhan CN. Protectin D1 is generated in asthma and dampens airway inflammation and hyperresponsiveness. J Immunol 178: 496–502, 2007. doi:10.4049/jimmunol.178.1.496.
    Crossref | PubMed | ISI | Google Scholar
  • 161. Levy BD, Lukacs NW, Berlin AA, Schmidt B, Guilford WJ, Serhan CN, Parkinson JF. Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism. FASEB J 21: 3877–3884, 2007. doi:10.1096/fj.07-8653com.
    Crossref | PubMed | ISI | Google Scholar
  • 162. Levy BD, Petasis NA, Serhan CN. Polyisoprenyl phosphates in intracellular signalling. Nature 389: 985–990, 1997. doi:10.1038/40180.
    Crossref | PubMed | ISI | Google Scholar
  • 163. Levy BD, Romano M, Chapman HA, Reilly JJ, Drazen J, Serhan CN. Human alveolar macrophages have 15-lipoxygenase and generate 15(S)-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid and lipoxins. J Clin Invest 92: 1572–1579, 1993. doi:10.1172/JCI116738.
    Crossref | PubMed | ISI | Google Scholar
  • 164. Levy BD, Serhan CN. A novel polyisoprenyl phosphate signaling cascade in human neutrophils. Ann N Y Acad Sci 905: 69–80, 2000. doi:10.1111/j.1749-6632.2000.tb06539.x.
    Crossref | PubMed | ISI | Google Scholar
  • 165. Levy BD, Serhan CN. Resolution of acute inflammation in the lung. Annu Rev Physiol 76: 467–492, 2014. doi:10.1146/annurev-physiol-021113-170408.
    Crossref | PubMed | ISI | Google Scholar
  • 166. Levy BD, Vachier I, Serhan CN. Resolution of inflammation in asthma. Clin Chest Med 33: 559–570, 2012. doi:10.1016/j.ccm.2012.06.006.
    Crossref | PubMed | ISI | Google Scholar
  • 167. Levy BD, Zhang QY, Bonnans C, Primo V, Reilly JJ, Perkins DL, Liang Y, Amin Arnaout M, Nikolic B, Serhan CN. The endogenous pro-resolving mediators lipoxin A4 and resolvin E1 preserve organ function in allograft rejection. Prostaglandins Leukot Essent Fatty Acids 84: 43–50, 2011. doi:10.1016/j.plefa.2010.09.002.
    Crossref | PubMed | ISI | Google Scholar
  • 168. Liao W, Zeng F, Kang K, Qi Y, Yao L, Yang H, Ling L, Wu N, Wu D. Lipoxin A4 attenuates acute rejection via shifting TH1/TH2 cytokine balance in rat liver transplantation. Transplant Proc 45: 2451–2454, 2013. doi:10.1016/j.transproceed.2013.01.069.
    Crossref | PubMed | ISI | Google Scholar
  • 169. Liu Y, Zhou D, Long FW, Chen KL, Yang HW, Lv ZY, Zhou B, Peng ZH, Sun XF, Li Y, Zhou ZG. Resolvin D1 protects against inflammation in experimental acute pancreatitis and associated lung injury. Am J Physiol Gastrointest Liver Physiol 310: G303–G309, 2016. doi:10.1152/ajpgi.00355.2014.
    Link | ISI | Google Scholar
  • 170. Lohse MJ. Dimerization in GPCR mobility and signaling. Curr Opin Pharmacol 10: 53–58, 2010. doi:10.1016/j.coph.2009.10.007.
    Crossref | PubMed | ISI | Google Scholar
  • 171. Maddox JF, Hachicha M, Takano T, Petasis NA, Fokin VV, Serhan CN. Lipoxin A4 stable analogs are potent mimetics that stimulate human monocytes and THP-1 cells via a G-protein-linked lipoxin A4 receptor. J Biol Chem 272: 6972–6978, 1997. doi:10.1074/jbc.272.11.6972.
    Crossref | PubMed | ISI | Google Scholar
  • 172. Maddox JF, Serhan CN. Lipoxin A4 and B4 are potent stimuli for human monocyte migration and adhesion: selective inactivation by dehydrogenation and reduction. J Exp Med 183: 137–146, 1996. doi:10.1084/jem.183.1.137.
    Crossref | PubMed | ISI | Google Scholar
  • 173. Maderna P, Cottell DC, Toivonen T, Dufton N, Dalli J, Perretti M, Godson C. FPR2/ALX receptor expression and internalization are critical for lipoxin A4 and annexin-derived peptide-stimulated phagocytosis. FASEB J 24: 4240–4249, 2010. doi:10.1096/fj.10-159913.
    Crossref | PubMed | ISI | Google Scholar
  • 174. Mantovani A, Cassatella MA, Costantini C, Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 11: 519–531, 2011. doi:10.1038/nri3024.
    Crossref | PubMed | ISI | Google Scholar
  • 175. Marcheselli VL, Hong S, Lukiw WJ, Tian XH, Gronert K, Musto A, Hardy M, Gimenez JM, Chiang N, Serhan CN, Bazan NG. Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J Biol Chem 278: 43807–43817, 2003. doi:10.1074/jbc.M305841200.
    Crossref | PubMed | ISI | Google Scholar
  • 176. Martin CR, Blanco PG, Keach JC, Petz JL, Zaman MM, Bhaskar KR, Cluette-Brown JE, Gautam S, Sheth S, Afdhal NH, Lindor KD, Freedman SD. The safety and efficacy of oral docosahexaenoic acid supplementation for the treatment of primary sclerosing cholangitis - a pilot study. Aliment Pharmacol Ther 35: 255–265, 2012. doi:10.1111/j.1365-2036.2011.04926.x.
    Crossref | PubMed | ISI | Google Scholar
  • 177. Martin CR, Zaman MM, Gilkey C, Salguero MV, Hasturk H, Kantarci A, Van Dyke TE, Freedman SD. Resolvin D1 and lipoxin A4 improve alveolarization and normalize septal wall thickness in a neonatal murine model of hyperoxia-induced lung injury. PLoS One 9: e98773, 2014. doi:10.1371/journal.pone.0098773.
    Crossref | PubMed | ISI | Google Scholar
  • 178. Martins V, Valença SS, Farias-Filho FA, Molinaro R, Simões RL, Ferreira TP, e Silva PM, Hogaboam CM, Kunkel SL, Fierro IM, Canetti C, Benjamim CF. ATLa, an aspirin-triggered lipoxin A4 synthetic analog, prevents the inflammatory and fibrotic effects of bleomycin-induced pulmonary fibrosis. J Immunol 182: 5374–5381, 2009. doi:10.4049/jimmunol.0802259.
    Crossref | PubMed | ISI | Google Scholar
  • 179. Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest 122: 2731–2740, 2012. doi:10.1172/JCI60331.
    Crossref | PubMed | ISI | Google Scholar
  • 180. Matute-Bello G, Downey G, Moore BB, Groshong SD, Matthay MA, Slutsky AS, Kuebler WM; Acute Lung Injury in Animals Study Group. An official American Thoracic Society workshop report: features and measurements of experimental acute lung injury in animals. Am J Respir Cell Mol Biol 44: 725–738, 2011. doi:10.1165/rcmb.2009-0210ST.
    Crossref | PubMed | ISI | Google Scholar
  • 181. Maugeri N, Evangelista V, Celardo A, Dell’Elba G, Martelli N, Piccardoni P, de Gaetano G, Cerletti C. Polymorphonuclear leukocyte-platelet interaction: role of P-selectin in thromboxane B2 and leukotriene C4 cooperative synthesis. Thromb Haemost 72: 450–456, 1994.
    Crossref | PubMed | ISI | Google Scholar
  • 182. Meissner HC. Viral bronchiolitis in children. N Engl J Med 374: 62–72, 2016. doi:10.1056/NEJMra1413456.
    Crossref | PubMed | ISI | Google Scholar
  • 183. Meng F, Mambetsariev I, Tian Y, Beckham Y, Meliton A, Leff A, Gardel ML, Allen MJ, Birukov KG, Birukova AA. Attenuation of lipopolysaccharide-induced lung vascular stiffening by lipoxin reduces lung inflammation. Am J Respir Cell Mol Biol 52: 152–161, 2015. doi:10.1165/rcmb.2013-0468OC.
    Crossref | PubMed | ISI | Google Scholar
  • 184. Merad M, Sathe P, Helft J, Miller J, Mortha A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol 31: 563–604, 2013. doi:10.1146/annurev-immunol-020711-074950.
    Crossref | PubMed | ISI | Google Scholar
  • 185. Miki Y, Yamamoto K, Taketomi Y, Sato H, Shimo K, Kobayashi T, Ishikawa Y, Ishii T, Nakanishi H, Ikeda K, Taguchi R, Kabashima K, Arita M, Arai H, Lambeau G, Bollinger JM, Hara S, Gelb MH, Murakami M. Lymphoid tissue phospholipase A2 group IID resolves contact hypersensitivity by driving antiinflammatory lipid mediators. J Exp Med 210: 1217–1234, 2013. doi:10.1084/jem.20121887.
    Crossref | PubMed | ISI | Google Scholar
  • 186. Milligan G, Alvarez-Curto E, Watterson KR, Ulven T, Hudson BD. Characterizing pharmacological ligands to study the long-chain fatty acid receptors GPR40/FFA1 and GPR120/FFA4. Br J Pharmacol 172: 3254–3265, 2015. doi:10.1111/bph.12879.
    Crossref | PubMed | ISI | Google Scholar
  • 187. Mitchell S, Thomas G, Harvey K, Cottell D, Reville K, Berlasconi G, Petasis NA, Erwig L, Rees AJ, Savill J, Brady HR, Godson C. Lipoxins, aspirin-triggered epi-lipoxins, lipoxin stable analogues, and the resolution of inflammation: stimulation of macrophage phagocytosis of apoptotic neutrophils in vivo. J Am Soc Nephrol 13: 2497–2507, 2002. doi:10.1097/01.ASN.0000032417.73640.72.
    Crossref | PubMed | ISI | Google Scholar
  • 188. Miyata J, Fukunaga K, Iwamoto R, Isobe Y, Niimi K, Takamiya R, Takihara T, Tomomatsu K, Suzuki Y, Oguma T, Sayama K, Arai H, Betsuyaku T, Arita M, Asano K. Dysregulated synthesis of protectin D1 in eosinophils from patients with severe asthma. J Allergy Clin Immunol 131: 353–360.e2, 2013. doi:10.1016/j.jaci.2012.07.048.
    Crossref | PubMed | ISI | Google Scholar
  • 189. Molina-Berríos A, Campos-Estrada C, Henriquez N, Faúndez M, Torres G, Castillo C, Escanilla S, Kemmerling U, Morello A, López-Muñoz RA, Maya JD. Protective role of acetylsalicylic acid in experimental Trypanosoma cruzi infection: evidence of a 15-epi-lipoxin A4-mediated effect. PLoS Negl Trop Dis 7: e2173, 2013. doi:10.1371/journal.pntd.0002173.
    Crossref | PubMed | ISI | Google Scholar
  • 190. Morin C, Cantin AM, Rousseau É, Sirois M, Sirois C, Rizcallah E, Fortin S. Proresolving action of docosahexaenoic acid monoglyceride in lung inflammatory models related to cystic fibrosis. Am J Respir Cell Mol Biol 53: 574–583, 2015. doi:10.1165/rcmb.2014-0223OC.
    Crossref | PubMed | ISI | Google Scholar
  • 191. Morin C, Fortin S, Cantin AM, Rousseau E. Docosahexaenoic acid derivative prevents inflammation and hyperreactivity in lung: implication of PKC-Potentiated inhibitory protein for heterotrimeric myosin light chain phosphatase of 17 kD in asthma. Am J Respir Cell Mol Biol 45: 366–375, 2011. doi:10.1165/rcmb.2010-0156OC.
    Crossref | PubMed | ISI | Google Scholar
  • 192. Morin C, Rousseau E. Enhanced Ca2+ sensitivity in hyperresponsive cultured bronchi is mediated by TNFalpha and NF-kappaB. Can J Physiol Pharmacol 84: 1029–1041, 2006. doi:10.1139/y06-048.
    Crossref | PubMed | ISI | Google Scholar
  • 193. Morita M, Kuba K, Ichikawa A, Nakayama M, Katahira J, Iwamoto R, Watanebe T, Sakabe S, Daidoji T, Nakamura S, Kadowaki A, Ohto T, Nakanishi H, Taguchi R, Nakaya T, Murakami M, Yoneda Y, Arai H, Kawaoka Y, Penninger JM, Arita M, Imai Y. The lipid mediator protectin D1 inhibits influenza virus replication and improves severe influenza. Cell 153: 112–125, 2013. doi:10.1016/j.cell.2013.02.027.
    Crossref | PubMed | ISI | Google Scholar
  • 194. Morris T, Stables M, Colville-Nash P, Newson J, Bellingan G, de Souza PM, Gilroy DW. Dichotomy in duration and severity of acute inflammatory responses in humans arising from differentially expressed proresolution pathways. Proc Natl Acad Sci USA 107: 8842–8847, 2010. doi:10.1073/pnas.1000373107.
    Crossref | PubMed | ISI | Google Scholar
  • 195. Mukherjee PK, Marcheselli VL, Serhan CN, Bazan NG. Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc Natl Acad Sci USA 101: 8491–8496, 2004. doi:10.1073/pnas.0402531101.
    Crossref | PubMed | ISI | Google Scholar
  • 196. Mukherjee S, Machado FS, Huang H, Oz HS, Jelicks LA, Prado CM, Koba W, Fine EJ, Zhao D, Factor SM, Collado JE, Weiss LM, Tanowitz HB, Ashton AW. Aspirin treatment of mice infected with Trypanosoma cruzi and implications for the pathogenesis of Chagas disease. PLoS One 6: e16959, 2011. doi:10.1371/journal.pone.0016959.
    Crossref | PubMed | ISI | Google Scholar
  • 197. Muniz VS, Weller PF, Neves JS. Eosinophil crystalloid granules: structure, function, and beyond. J Leukoc Biol 92: 281–288, 2012. doi:10.1189/jlb.0212067.
    Crossref | PubMed | ISI | Google Scholar
  • 198. Nair H, Nokes DJ, Gessner BD, Dherani M, Madhi SA, Singleton RJ, O’Brien KL, Roca A, Wright PF, Bruce N, Chandran A, Theodoratou E, Sutanto A, Sedyaningsih ER, Ngama M, Munywoki PK, Kartasasmita C, Simões EA, Rudan I, Weber MW, Campbell H. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet 375: 1545–1555, 2010. doi:10.1016/S0140-6736(10)60206-1.
    Crossref | PubMed | ISI | Google Scholar
  • 199. Narasaraju T, Yang E, Samy RP, Ng HH, Poh WP, Liew AA, Phoon MC, van Rooijen N, Chow VT. Excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis. Am J Pathol 179: 199–210, 2011. doi:10.1016/j.ajpath.2011.03.013.
    Crossref | PubMed | ISI | Google Scholar
  • 200. Nascimento-Silva V, Arruda MA, Barja-Fidalgo C, Fierro IM. Aspirin-triggered lipoxin A4 blocks reactive oxygen species generation in endothelial cells: a novel antioxidative mechanism. Thromb Haemost 97: 88–98, 2007.
    Crossref | PubMed | ISI | Google Scholar
  • 201. Nathan C, Ding A. Nonresolving inflammation. Cell 140: 871–882, 2010. doi:10.1016/j.cell.2010.02.029.
    Crossref | PubMed | ISI | Google Scholar
  • 202. Nordgren TM, Bauer CD, Heires AJ, Poole JA, Wyatt TA, West WW, Romberger DJ. Maresin-1 reduces airway inflammation associated with acute and repetitive exposures to organic dust. Transl Res 166: 57–69, 2015. doi:10.1016/j.trsl.2015.01.001.
    Crossref | PubMed | ISI | Google Scholar
  • 203. Nordgren TM, Heires AJ, Wyatt TA, Poole JA, LeVan TD, Cerutis DR, Romberger DJ. Maresin-1 reduces the pro-inflammatory response of bronchial epithelial cells to organic dust. Respir Res 14: 51, 2013. doi:10.1186/1465-9921-14-51.
    Crossref | PubMed | ISI | Google Scholar
  • 204. Norling LV, Dalli J, Flower RJ, Serhan CN, Perretti M. Resolvin D1 limits polymorphonuclear leukocyte recruitment to inflammatory loci: receptor-dependent actions. Arterioscler Thromb Vasc Biol 32: 1970–1978, 2012. doi:10.1161/ATVBAHA.112.249508.
    Crossref | PubMed | ISI | Google Scholar
  • 205. Oh SF, Dona M, Fredman G, Krishnamoorthy S, Irimia D, Serhan CN. Resolvin E2 formation and impact in inflammation resolution. J Immunol 188: 4527–4534, 2012. doi:10.4049/jimmunol.1103652.
    Crossref | PubMed | ISI | Google Scholar
  • 206. Ono E, Dutile S, Kazani S, Wechsler ME, Yang J, Hammock BD, Douda DN, Tabet Y, Khaddaj-Mallat R, Sirois M, Sirois C, Rizcallah E, Rousseau E, Martin R, Sutherland ER, Castro M, Jarjour NN, Israel E, Levy BD; National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network. Lipoxin generation is related to soluble epoxide hydrolase activity in severe asthma. Am J Respir Crit Care Med 190: 886–897, 2014. doi:10.1164/rccm.201403-0544OC.
    Crossref | PubMed | ISI | Google Scholar
  • 207. Opitz B, van Laak V, Eitel J, Suttorp N. Innate immune recognition in infectious and noninfectious diseases of the lung. Am J Respir Crit Care Med 181: 1294–1309, 2010. doi:10.1164/rccm.200909-1427SO.
    Crossref | PubMed | ISI | Google Scholar
  • 208. Ortiz-Muñoz G, Mallavia B, Bins A, Headley M, Krummel MF, Looney MR. Aspirin-triggered 15-epi-lipoxin A4 regulates neutrophil-platelet aggregation and attenuates acute lung injury in mice. Blood 124: 2625–2634, 2014. doi:10.1182/blood-2014-03-562876.
    Crossref | PubMed | ISI | Google Scholar
  • 209. Papayianni A, Serhan CN, Brady HR. Lipoxin A4 and B4 inhibit leukotriene-stimulated interactions of human neutrophils and endothelial cells. J Immunol 156: 2264–2272, 1996.
    PubMed | ISI | Google Scholar
  • 210. Paules C, Subbarao K. Influenza. Lancet 390: 697–708, 2017. doi:10.1016/S0140-6736(17)30129-0.
    Crossref | PubMed | ISI | Google Scholar
  • 211. Perretti M, Chiang N, La M, Fierro IM, Marullo S, Getting SJ, Solito E, Serhan CN. Endogenous lipid- and peptide-derived anti-inflammatory pathways generated with glucocorticoid and aspirin treatment activate the lipoxin A4 receptor. Nat Med 8: 1296–1302, 2002. doi:10.1038/nm786.
    Crossref | PubMed | ISI | Google Scholar
  • 212. Planagumà A, Kazani S, Marigowda G, Haworth O, Mariani TJ, Israel E, Bleecker ER, Curran-Everett D, Erzurum SC, Calhoun WJ, Castro M, Chung KF, Gaston B, Jarjour NN, Busse WW, Wenzel SE, Levy BD. Airway lipoxin A4 generation and lipoxin A4 receptor expression are decreased in severe asthma. Am J Respir Crit Care Med 178: 574–582, 2008. doi:10.1164/rccm.200801-061OC.
    Crossref | PubMed | ISI | Google Scholar
  • 213. Planagumà A, Pfeffer MA, Rubin G, Croze R, Uddin M, Serhan CN, Levy BD. Lovastatin decreases acute mucosal inflammation via 15-epi-lipoxin A4. Mucosal Immunol 3: 270–279, 2010. doi:10.1038/mi.2009.141.
    Crossref | PubMed | ISI | Google Scholar
  • 214. Ramaswami R, Serhan CN, Levy BD, Makrides M. Fish oil supplementation in pregnancy. N Engl J Med 375: 2599–2601, 2016. doi:10.1056/NEJMclde1614333.
    Crossref | PubMed | ISI | Google Scholar
  • 215. Ramon S, Baker SF, Sahler JM, Kim N, Feldsott EA, Serhan CN, Martínez-Sobrido L, Topham DJ, Phipps RP. The specialized proresolving mediator 17-HDHA enhances the antibody-mediated immune response against influenza virus: a new class of adjuvant? J Immunol 193: 6031–6040, 2014. doi:10.4049/jimmunol.1302795.
    Crossref | PubMed | ISI | Google Scholar
  • 216. Ramon S, Bancos S, Serhan CN, Phipps RP. Lipoxin A4 modulates adaptive immunity by decreasing memory B-cell responses via an ALX/FPR2-dependent mechanism. Eur J Immunol 44: 357–369, 2014. doi:10.1002/eji.201343316.
    Crossref | PubMed | ISI | Google Scholar
  • 217. Ramon S, Gao F, Serhan CN, Phipps RP. Specialized proresolving mediators enhance human B cell differentiation to antibody-secreting cells. J Immunol 189: 1036–1042, 2012. doi:10.4049/jimmunol.1103483.
    Crossref | PubMed | ISI | Google Scholar
  • 218. Ramsden CE. Breathing easier with fish oil—a new approach to preventing asthma? N Engl J Med 375: 2596–2598, 2016. doi:10.1056/NEJMe1611723.
    Crossref | PubMed | ISI | Google Scholar
  • 219. Ramstedt U, Serhan CN, Nicolaou KC, Webber SE, Wigzell H, Samuelsson B. Lipoxin A-induced inhibition of human natural killer cell cytotoxicity: studies on stereospecificity of inhibition and mode of action. J Immunol 138: 266–270, 1987.
    PubMed | ISI | Google Scholar
  • 220. Ray A, Khare A, Krishnamoorthy N, Qi Z, Ray P. Regulatory T cells in many flavors control asthma. Mucosal Immunol 3: 216–229, 2010. doi:10.1038/mi.2010.4.
    Crossref | PubMed | ISI | Google Scholar
  • 221. Resnati M, Pallavicini I, Wang JM, Oppenheim J, Serhan CN, Romano M, Blasi F. The fibrinolytic receptor for urokinase activates the G protein-coupled chemotactic receptor FPRL1/LXA4R. Proc Natl Acad Sci USA 99: 1359–1364, 2002. doi:10.1073/pnas.022652999.
    Crossref | PubMed | ISI | Google Scholar
  • 222. Ricklefs I, Barkas I, Duvall MG, Cernadas M, Grossman NL, Israel E, Bleecker ER, Castro M, Erzurum SC, Fahy JV, Gaston BM, Denlinger LC, Mauger DT, Wenzel SE, Comhair SA, Coverstone AM, Fajt ML, Hastie AT, Johansson MW, Peters MC, Phillips BR, Levy BD; National Heart Lung and Blood Institute’s Severe Asthma Research Program-3 Investigators. ALX receptor ligands define a biochemical endotype for severe asthma. JCI Insight 2: e93534, 2017. doi:10.1172/jci.insight.93534.
    Crossref | PubMed | ISI | Google Scholar
  • 223. Ringholz FC, Buchanan PJ, Clarke DT, Millar RG, McDermott M, Linnane B, Harvey BJ, McNally P, Urbach V. Reduced 15-lipoxygenase 2 and lipoxin A4/leukotriene B4 ratio in children with cystic fibrosis. Eur Respir J 44: 394–404, 2014. doi:10.1183/09031936.00106013.
    Crossref | PubMed | ISI | Google Scholar
  • 224. Roach KM, Feghali-Bostwick CA, Amrani Y, Bradding P. Lipoxin A4 attenuates constitutive and TGF-β1-dependent profibrotic activity in human lung myofibroblasts. J Immunol 195: 2852–2860, 2015. doi:10.4049/jimmunol.1500936.
    Crossref | PubMed | ISI | Google Scholar
  • 225. Rogerio AP, Haworth O, Croze R, Oh SF, Uddin M, Carlo T, Pfeffer MA, Priluck R, Serhan CN, Levy BD. Resolvin D1 and aspirin-triggered resolvin D1 promote resolution of allergic airways responses. J Immunol 189: 1983–1991, 2012. doi:10.4049/jimmunol.1101665.
    Crossref | PubMed | ISI | Google Scholar
  • 226. Roux PP, Blenis J. ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev 68: 320–344, 2004. doi:10.1128/MMBR.68.2.320-344.2004.
    Crossref | PubMed | ISI | Google Scholar
  • 227. Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, Stern EJ, Hudson LD. Incidence and outcomes of acute lung injury. N Engl J Med 353: 1685–1693, 2005. doi:10.1056/NEJMoa050333.
    Crossref | PubMed | ISI | Google Scholar
  • 228. Samson M, Edinger AL, Stordeur P, Rucker J, Verhasselt V, Sharron M, Govaerts C, Mollereau C, Vassart G, Doms RW, Parmentier M. ChemR23, a putative chemoattractant receptor, is expressed in monocyte-derived dendritic cells and macrophages and is a coreceptor for SIV and some primary HIV-1 strains. Eur J Immunol 28: 1689–1700, 1998. doi:10.1002/(SICI)1521-4141(199805)28:05<1689::AID-IMMU1689>3.0.CO;2-I.
    Crossref | PubMed | ISI | Google Scholar
  • 229. Sawada Y, Honda T, Hanakawa S, Nakamizo S, Murata T, Ueharaguchi-Tanada Y, Ono S, Amano W, Nakajima S, Egawa G, Tanizaki H, Otsuka A, Kitoh A, Dainichi T, Ogawa N, Kobayashi Y, Yokomizo T, Arita M, Nakamura M, Miyachi Y, Kabashima K. Resolvin E1 inhibits dendritic cell migration in the skin and attenuates contact hypersensitivity responses. J Exp Med 212: 1921–1930, 2015. doi:10.1084/jem.20150381.
    Crossref | PubMed | ISI | Google Scholar
  • 230. Sawmynaden P, Perretti M. Glucocorticoid upregulation of the annexin-A1 receptor in leukocytes. Biochem Biophys Res Commun 349: 1351–1355, 2006. doi:10.1016/j.bbrc.2006.08.179.
    Crossref | PubMed | ISI | Google Scholar
  • 231. Schaldach CM, Riby J, Bjeldanes LF. Lipoxin A4: a new class of ligand for the Ah receptor. Biochemistry 38: 7594–7600, 1999. doi:10.1021/bi982861e.
    Crossref | PubMed | ISI | Google Scholar
  • 232. Schif-Zuck S, Gross N, Assi S, Rostoker R, Serhan CN, Ariel A. Saturated-efferocytosis generates pro-resolving CD11b low macrophages: modulation by resolvins and glucocorticoids. Eur J Immunol 41: 366–379, 2011. doi:10.1002/eji.201040801.
    Crossref | PubMed | ISI | Google Scholar
  • 233. Schwab JM, Chiang N, Arita M, Serhan CN. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature 447: 869–874, 2007. doi:10.1038/nature05877.
    Crossref | PubMed | ISI | Google Scholar
  • 234. Seki H, Fukunaga K, Arita M, Arai H, Nakanishi H, Taguchi R, Miyasho T, Takamiya R, Asano K, Ishizaka A, Takeda J, Levy BD. The anti-inflammatory and proresolving mediator resolvin E1 protects mice from bacterial pneumonia and acute lung injury. J Immunol 184: 836–843, 2010. doi:10.4049/jimmunol.0901809.
    Crossref | PubMed | ISI | Google Scholar
  • 235. Serhan CN. Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annu Rev Immunol 25: 101–137, 2007. doi:10.1146/annurev.immunol.25.022106.141647.
    Crossref | PubMed | ISI | Google Scholar
  • 236. Serhan CN, Clish CB, Brannon J, Colgan SP, Chiang N, Gronert K. Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing. J Exp Med 192: 1197–1204, 2000. doi:10.1084/jem.192.8.1197.
    Crossref | PubMed | ISI | Google Scholar
  • 237. Serhan CN, Clish CB, Brannon J, Colgan SP, Gronert K, Chiang N. Anti-microinflammatory lipid signals generated from dietary N-3 fatty acids via cyclooxygenase-2 and transcellular processing: a novel mechanism for NSAID and N-3 PUFA therapeutic actions. J Physiol Pharmacol 51: 643–654, 2000.
    PubMed | ISI | Google Scholar
  • 238. Serhan CN, Dalli J, Karamnov S, Choi A, Park CK, Xu ZZ, Ji RR, Zhu M, Petasis NA. Macrophage proresolving mediator maresin 1 stimulates tissue regeneration and controls pain. FASEB J 26: 1755–1765, 2012. doi:10.1096/fj.11-201442.
    Crossref | PubMed | ISI | Google Scholar
  • 239. Serhan CN, Gotlinger K, Hong S, Lu Y, Siegelman J, Baer T, Yang R, Colgan SP, Petasis NA. Anti-inflammatory actions of neuroprotectin D1/protectin D1 and its natural stereoisomers: assignments of dihydroxy-containing docosatrienes. J Immunol 176: 1848–1859, 2006. doi:10.4049/jimmunol.176.3.1848.
    Crossref | PubMed | ISI | Google Scholar
  • 240. Serhan CN, Hamberg M, Samuelsson B. Lipoxins: novel series of biologically active compounds formed from arachidonic acid in human leukocytes. Proc Natl Acad Sci USA 81: 5335–5339, 1984. doi:10.1073/pnas.81.17.5335.
    Crossref | PubMed | ISI | Google Scholar
  • 241. Serhan CN, Hamberg M, Samuelsson B. Trihydroxytetraenes: a novel series of compounds formed from arachidonic acid in human leukocytes. Biochem Biophys Res Commun 118: 943–949, 1984. doi:10.1016/0006-291X(84)91486-4.
    Crossref | PubMed | ISI | Google Scholar
  • 242. Serhan CN, Hong S, Gronert K, Colgan SP, Devchand PR, Mirick G, Moussignac RL. Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J Exp Med 196: 1025–1037, 2002. doi:10.1084/jem.20020760.
    Crossref | PubMed | ISI | Google Scholar
  • 243. Serhan CN, Maddox JF, Petasis NA, Akritopoulou-Zanze I, Papayianni A, Brady HR, Colgan SP, Madara JL. Design of lipoxin A4 stable analogs that block transmigration and adhesion of human neutrophils. Biochemistry 34: 14609–14615, 1995. doi:10.1021/bi00044a041.
    Crossref | PubMed | ISI | Google Scholar
  • 244. Serhan CN, Petasis NA. Resolvins and protectins in inflammation resolution. Chem Rev 111: 5922–5943, 2011. doi:10.1021/cr100396c.
    Crossref | PubMed | ISI | Google Scholar
  • 245. Serhan CN, Sheppard KA. Lipoxin formation during human neutrophil-platelet interactions. Evidence for the transformation of leukotriene A4 by platelet 12-lipoxygenase in vitro. J Clin Invest 85: 772–780, 1990. doi:10.1172/JCI114503.
    Crossref | PubMed | ISI | Google Scholar
  • 246. Serhan CN, Yang R, Martinod K, Kasuga K, Pillai PS, Porter TF, Oh SF, Spite M. Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions. J Exp Med 206: 15–23, 2009. doi:10.1084/jem.20081880.
    Crossref | PubMed | ISI | Google Scholar
  • 247. Shirasaki H, Himi T. Role of cysteinyl leukotrienes in allergic rhinitis. Adv Otorhinolaryngol 77: 40–45, 2016. doi:10.1159/000441871.
    Crossref | PubMed | Google Scholar
  • 248. Shirey KA, Lai W, Pletneva LM, Karp CL, Divanovic S, Blanco JC, Vogel SN. Role of the lipoxygenase pathway in RSV-induced alternatively activated macrophages leading to resolution of lung pathology. Mucosal Immunol 7: 549–557, 2014. doi:10.1038/mi.2013.71.
    Crossref | PubMed | ISI | Google Scholar
  • 249. Shirey KA, Pletneva LM, Puche AC, Keegan AD, Prince GA, Blanco JC, Vogel SN. Control of RSV-induced lung injury by alternatively activated macrophages is IL-4R alpha-, TLR4-, and IFN-beta-dependent. Mucosal Immunol 3: 291–300, 2010. doi:10.1038/mi.2010.6.
    Crossref | PubMed | ISI | Google Scholar
  • 250. Shryock N, McBerry C, Salazar Gonzalez RM, Janes S, Costa FT, Aliberti J. Lipoxin A4 and 15-epi-lipoxin A4 protect against experimental cerebral malaria by inhibiting IL-12/IFN-γ in the brain. PLoS One 8: e61882, 2013. doi:10.1371/journal.pone.0061882.
    Crossref | PubMed | ISI | Google Scholar
  • 251. Simiele F, Recchiuti A, Mattoscio D, De Luca A, Cianci E, Franchi S, Gatta V, Parolari A, Werba JP, Camera M, Favaloro B, Romano M. Transcriptional regulation of the human FPR2/ALX gene: evidence of a heritable genetic variant that impairs promoter activity. FASEB J 26: 1323–1333, 2012. doi:10.1096/fj.11-198069.
    Crossref | PubMed | ISI | Google Scholar
  • 252. Simões RL, Fierro IM. Involvement of the Rho-kinase/myosin light chain kinase pathway on human monocyte chemotaxis induced by ATL-1, an aspirin-triggered lipoxin A4 synthetic analog. J Immunol 175: 1843–1850, 2005. doi:10.4049/jimmunol.175.3.1843.
    Crossref | PubMed | ISI | Google Scholar
  • 253. Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly-Y M, Glickman JN, Garrett WS. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341: 569–573, 2013. doi:10.1126/science.1241165.
    Crossref | PubMed | ISI | Google Scholar
  • 254. Sobrado M, Pereira MP, Ballesteros I, Hurtado O, Fernández-López D, Pradillo JM, Caso JR, Vivancos J, Nombela F, Serena J, Lizasoain I, Moro MA. Synthesis of lipoxin A4 by 5-lipoxygenase mediates PPARgamma-dependent, neuroprotective effects of rosiglitazone in experimental stroke. J Neurosci 29: 3875–3884, 2009. doi:10.1523/JNEUROSCI.5529-08.2009.
    Crossref | PubMed | ISI | Google Scholar
  • 255. Solito E, Kamal A, Russo-Marie F, Buckingham JC, Marullo S, Perretti M. A novel calcium-dependent proapoptotic effect of annexin 1 on human neutrophils. FASEB J 17: 1544–1546, 2003. doi:10.1096/fj.02-0941fje.
    Crossref | PubMed | ISI | Google Scholar
  • 256. Souza MC, Padua TA, Henriques MG. Endothelial-Leukocyte Interaction in Severe Malaria: Beyond the Brain. Mediators Inflamm 2015: 168937, 2015. doi:10.1155/2015/168937.
    Crossref | PubMed | ISI | Google Scholar
  • 257. Soyombo O, Spur BW, Lee TH. Effects of lipoxin A4 on chemotaxis and degranulation of human eosinophils stimulated by platelet-activating factor and N-formyl-L-methionyl-L-leucyl-L-phenylalanine. Allergy 49: 230–234, 1994. doi:10.1111/j.1398-9995.1994.tb02654.x.
    Crossref | PubMed | ISI | Google Scholar
  • 258. Spite M, Norling LV, Summers L, Yang R, Cooper D, Petasis NA, Flower RJ, Perretti M, Serhan CN. Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis. Nature 461: 1287–1291, 2009. doi:10.1038/nature08541.
    Crossref | PubMed | ISI | Google Scholar
  • 259. Spits H, Di Santo JP. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat Immunol 12: 21–27, 2011. doi:10.1038/ni.1962.
    Crossref | PubMed | ISI | Google Scholar
  • 260. Steinke JW, Payne SC, Borish L. Eosinophils and mast cells in aspirin-exacerbated respiratory disease. Immunol Allergy Clin North Am 36: 719–734, 2016. doi:10.1016/j.iac.2016.06.008.
    Crossref | PubMed | ISI | Google Scholar
  • 261. Sun YP, Oh SF, Uddin J, Yang R, Gotlinger K, Campbell E, Colgan SP, Petasis NA, Serhan CN. Resolvin D1 and its aspirin-triggered 17R epimer. Stereochemical assignments, anti-inflammatory properties, and enzymatic inactivation. J Biol Chem 282: 9323–9334, 2007. doi:10.1074/jbc.M609212200.
    Crossref | PubMed | ISI | Google Scholar
  • 262. Takamiya R, Fukunaga K, Arita M, Miyata J, Seki H, Minematsu N, Suematsu M, Asano K. Resolvin E1 maintains macrophage function under cigarette smoke-induced oxidative stress. FEBS Open Bio 2: 328–333, 2012. doi:10.1016/j.fob.2012.10.001.
    Crossref | PubMed | ISI | Google Scholar
  • 263. Takano T, Fiore S, Maddox JF, Brady HR, Petasis NA, Serhan CN. Aspirin-triggered 15-epi-lipoxin A4 (LXA4) and LXA4 stable analogues are potent inhibitors of acute inflammation: evidence for anti-inflammatory receptors. J Exp Med 185: 1693–1704, 1997. doi:10.1084/jem.185.9.1693.
    Crossref | PubMed | ISI | Google Scholar
  • 264. Tam VC, Quehenberger O, Oshansky CM, Suen R, Armando AM, Treuting PM, Thomas PG, Dennis EA, Aderem A. Lipidomic profiling of influenza infection identifies mediators that induce and resolve inflammation. Cell 154: 213–227, 2013. doi:10.1016/j.cell.2013.05.052.
    Crossref | PubMed | ISI | Google Scholar
  • 265. Tani Y, Isobe Y, Imoto Y, Segi-Nishida E, Sugimoto Y, Arai H, Arita M. Eosinophils control the resolution of inflammation and draining lymph node hypertrophy through the proresolving mediators and CXCL13 pathway in mice. FASEB J 28: 4036–4043, 2014. doi:10.1096/fj.14-251132.
    Crossref | PubMed | ISI | Google Scholar
  • 266. Thorén FB, Riise RE, Ousbäck J, Della Chiesa M, Alsterholm M, Marcenaro E, Pesce S, Prato C, Cantoni C, Bylund J, Moretta L, Moretta A. Human NK cells induce neutrophil apoptosis via an NKp46- and Fas-dependent mechanism. J Immunol 188: 1668–1674, 2012. doi:10.4049/jimmunol.1102002.
    Crossref | PubMed | ISI | Google Scholar
  • 267. Titos E, Rius B, López-Vicario C, Alcaraz-Quiles J, García-Alonso V, Lopategi A, Dalli J, Lozano JJ, Arroyo V, Delgado S, Serhan CN, Clària J. Signaling and immunoresolving actions of resolvin D1 in inflamed human visceral adipose tissue. J Immunol 197: 3360–3370, 2016. doi:10.4049/jimmunol.1502522.
    Crossref | PubMed | ISI | Google Scholar
  • 268. Tjonahen E, Oh SF, Siegelman J, Elangovan S, Percarpio KB, Hong S, Arita M, Serhan CN. Resolvin E2: identification and anti-inflammatory actions: pivotal role of human 5-lipoxygenase in resolvin E series biosynthesis. Chem Biol 13: 1193–1202, 2006. doi:10.1016/j.chembiol.2006.09.011.
    Crossref | PubMed | Google Scholar
  • 269. Tobin DM, Roca FJ, Oh SF, McFarland R, Vickery TW, Ray JP, Ko DC, Zou Y, Bang ND, Chau TT, Vary JC, Hawn TR, Dunstan SJ, Farrar JJ, Thwaites GE, King MC, Serhan CN, Ramakrishnan L. Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell 148: 434–446, 2012. doi:10.1016/j.cell.2011.12.023.
    Crossref | PubMed | ISI | Google Scholar
  • 270. Tsao FH, Meyer KC, Chen X, Rosenthal NS, Hu J. Degradation of annexin I in bronchoalveolar lavage fluid from patients with cystic fibrosis. Am J Respir Cell Mol Biol 18: 120–128, 1998. doi:10.1165/ajrcmb.18.1.2808.
    Crossref | PubMed | ISI | Google Scholar
  • 271. Tungen JE, Aursnes M, Vik A, Ramon S, Colas RA, Dalli J, Serhan CN, Hansen TV. Synthesis and anti-inflammatory and pro-resolving activities of 22-OH-PD1, a monohydroxylated metabolite of protectin D1. J Nat Prod 77: 2241–2247, 2014. doi:10.1021/np500498j.
    Crossref | PubMed | ISI | Google Scholar
  • 272. Vachier I, Bonnans C, Chavis C, Farce M, Godard P, Bousquet J, Chanez P. Severe asthma is associated with a loss of LX4, an endogenous anti-inflammatory compound. J Allergy Clin Immunol 115: 55–60, 2005. doi:10.1016/j.jaci.2004.09.038.
    Crossref | PubMed | ISI | Google Scholar
  • 273. Verrière V, Higgins G, Al-Alawi M, Costello RW, McNally P, Chiron R, Harvey BJ, Urbach V. Lipoxin A4 stimulates calcium-activated chloride currents and increases airway surface liquid height in normal and cystic fibrosis airway epithelia. PLoS One 7: e37746, 2012. doi:10.1371/journal.pone.0037746.
    Crossref | PubMed | ISI | Google Scholar
  • 274. Wakai K, Ito Y, Kojima M, Tokudome S, Ozasa K, Inaba Y, Yagyu K, Tamakoshi A; JACC Study Group. Intake frequency of fish and serum levels of long-chain n-3 fatty acids: a cross-sectional study within the Japan Collaborative Cohort Study. J Epidemiol 15: 211–218, 2005. doi:10.2188/jea.15.211.
    Crossref | PubMed | ISI | Google Scholar
  • 275. Wang H, Anthony D, Yatmaz S, Wijburg O, Satzke C, Levy B, Vlahos R, Bozinovski S. Aspirin-triggered resolvin D1 reduces pneumococcal lung infection and inflammation in a viral and bacterial co-infection pneumonia model. Clin Sci (Lond) 131: 2347–2362, 2017. doi:10.1042/CS20171006.
    Crossref | PubMed | ISI | Google Scholar
  • 276. Wang Q, Lian QQ, Li R, Ying BY, He Q, Chen F, Zheng X, Yang Y, Wu DR, Zheng SX, Huang CJ, Smith FG, Jin SW. Lipoxin A(4) activates alveolar epithelial sodium channel, Na,K-ATPase, and increases alveolar fluid clearance. Am J Respir Cell Mol Biol 48: 610–618, 2013. doi:10.1165/rcmb.2012-0274OC.
    Crossref | PubMed | ISI | Google Scholar
  • 277. Wang Q, Zheng X, Cheng Y, Zhang YL, Wen HX, Tao Z, Li H, Hao Y, Gao Y, Yang LM, Smith FG, Huang CJ, Jin SW. Resolvin D1 stimulates alveolar fluid clearance through alveolar epithelial sodium channel, Na,K-ATPase via ALX/cAMP/PI3K pathway in lipopolysaccharide-induced acute lung injury. J Immunol 192: 3765–3777, 2014. doi:10.4049/jimmunol.1302421.
    Crossref | PubMed | ISI | Google Scholar
  • 278. Wang Y, Li R, Chen L, Tan W, Sun Z, Xia H, Li B, Yu Y, Gong J, Tang M, Ji Y, Yuan S, Shanglong Yao , Shang Y. Maresin 1 inhibits epithelial-to-mesenchymal transition in vitro and attenuates bleomycin induced lung fibrosis in vivo. Shock 44: 496–502, 2015. doi:10.1097/SHK.0000000000000446.
    Crossref | PubMed | ISI | Google Scholar
  • 279. West NJ, Clark SK, Phillips RK, Hutchinson JM, Leicester RJ, Belluzzi A, Hull MA. Eicosapentaenoic acid reduces rectal polyp number and size in familial adenomatous polyposis. Gut 59: 918–925, 2010. doi:10.1136/gut.2009.200642.
    Crossref | PubMed | ISI | Google Scholar
  • 280. Winkler JW, Orr SK, Dalli J, Cheng CY, Sanger JM, Chiang N, Petasis NA, Serhan CN. Resolvin D4 stereoassignment and its novel actions in host protection and bacterial clearance. Sci Rep 6: 18972, 2016. doi:10.1038/srep18972.
    Crossref | PubMed | ISI | Google Scholar
  • 281. Wittamer V, Franssen JD, Vulcano M, Mirjolet JF, Le Poul E, Migeotte I, Brézillon S, Tyldesley R, Blanpain C, Detheux M, Mantovani A, Sozzani S, Vassart G, Parmentier M, Communi D. Specific recruitment of antigen-presenting cells by chemerin, a novel processed ligand from human inflammatory fluids. J Exp Med 198: 977–985, 2003. doi:10.1084/jem.20030382.
    Crossref | PubMed | ISI | Google Scholar
  • 282. Wong J, Magun BE, Wood LJ. Lung inflammation caused by inhaled toxicants: a review. Int J Chron Obstruct Pulmon Dis 11: 1391–1401, 2016. doi:10.2147/COPD.S106009.
    Crossref | PubMed | ISI | Google Scholar
  • 283. Wu D, Molofsky AB, Liang HE, Ricardo-Gonzalez RR, Jouihan HA, Bando JK, Chawla A, Locksley RM. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332: 243–247, 2011. doi:10.1126/science.1201475.
    Crossref | PubMed | ISI | Google Scholar
  • 284. Wu D, Zheng S, Li W, Yang L, Liu Y, Zheng X, Yang Y, Yang L, Wang Q, Smith FG, Jin S. Novel biphasic role of resolvin D1 on expression of cyclooxygenase-2 in lipoolysaccharide-stimulated lung fibroblasts is partly through PI3K/AKT and ERK2 pathways. Mediators Inflamm 2013 11, 2013. doi:10.1155/2013/964012.
    Crossref | PubMed | ISI | Google Scholar
  • 285. Wu SH, Chen XQ, Liu B, Wu HJ, Dong L. Efficacy and safety of 15(R/S)-methyl-lipoxin A(4) in topical treatment of infantile eczema. Br J Dermatol 168: 172–178, 2013. doi:10.1111/j.1365-2133.2012.11177.x.
    Crossref | PubMed | ISI | Google Scholar
  • 286. Wu SH, Wu XH, Lu C, Dong L, Chen ZQ. Lipoxin A4 inhibits proliferation of human lung fibroblasts induced by connective tissue growth factor. Am J Respir Cell Mol Biol 34: 65–72, 2006. doi:10.1165/rcmb.2005-0184OC.
    Crossref | PubMed | ISI | Google Scholar
  • 287. Yamada T, Tani Y, Nakanishi H, Taguchi R, Arita M, Arai H. Eosinophils promote resolution of acute peritonitis by producing proresolving mediators in mice. FASEB J 25: 561–568, 2011. doi:10.1096/fj.10-170027.
    Crossref | PubMed | ISI | Google Scholar
  • 288. Yang D, Chen Q, Su SB, Zhang P, Kurosaka K, Caspi RR, Michalek SM, Rosenberg HF, Zhang N, Oppenheim JJ. Eosinophil-derived neurotoxin acts as an alarmin to activate the TLR2-MyD88 signal pathway in dendritic cells and enhances Th2 immune responses. J Exp Med 205: 79–90, 2008. doi:10.1084/jem.20062027.
    Crossref | PubMed | ISI | Google Scholar
  • 289. Yang J, Eiserich JP, Cross CE, Morrissey BM, Hammock BD. Metabolomic profiling of regulatory lipid mediators in sputum from adult cystic fibrosis patients. Free Radic Biol Med 53: 160–171, 2012. doi:10.1016/j.freeradbiomed.2012.05.001.
    Crossref | PubMed | ISI | Google Scholar
  • 290. Yatomi M, Hisada T, Ishizuka T, Koga Y, Ono A, Kamide Y, Seki K, Aoki-Saito H, Tsurumaki H, Sunaga N, Kaira K, Dobashi K, Yamada M, Okajima F. 17(R)-resolvin D1 ameliorates bleomycin-induced pulmonary fibrosis in mice. Physiol Rep 3: e12628, 2015. doi:10.14814/phy2.12628.
    Crossref | PubMed | ISI | Google Scholar
  • 291. Yokomizo T, Izumi T, Chang K, Takuwa Y, Shimizu T. A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis. Nature 387: 620–624, 1997. doi:10.1038/42506.
    Crossref | PubMed | ISI | Google Scholar
  • 292. Zarbock A, Singbartl K, Ley K. Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation. J Clin Invest 116: 3211–3219, 2006. doi:10.1172/JCI29499.
    Crossref | PubMed | ISI | Google Scholar
  • 293. Zheng S, Wang Q, D’Souza V, Bartis D, Dancer R, Parekh D, Gao F, Lian Q, Jin S, Thickett DR. ResolvinD1 stimulates epithelial wound repair and inhibits TGF-beta-induced EMT whilst reducing fibroproliferation and collagen production. Lab Invest 98: 130–140, 2018. doi:10.1038/labinvest.2017.114.
    Crossref | PubMed | ISI | Google Scholar