American Journal of Respiratory Cell and Molecular Biology

To date, increasing evidence suggests the possible involvement of various types of cell death in lung diseases. The recognized regulated cell death includes necrotic cell death that is immunogenic, releasing damage-associated molecular patterns and driving tissue inflammation. Necroptosis is a well-understood form of regulated necrosis that is executed by RIPK3 (receptor-interacting protein kinase 3) and the pseudokinase MLKL (mixed lineage kinase domain–like protein). Ferroptosis is a newly described caspase-independent form of regulated necrosis that is characterized by the increase of detrimental lipid reactive oxygen species produced via iron-dependent lipid peroxidation. The role of these two cell death pathways differs depending on the disease, cell type, and microenvironment. Moreover, some experimental cell death models have demonstrated shared ferroptotic and necroptotic cell death and the synergistic effect of simultaneous inhibition. This review examines the role of regulated necrotic cell death, particularly necroptosis and ferroptosis, in lung disease pathogenesis in the context of recent insights into the roles of the key effector molecules of these two cell death pathways.

Cell death is a crucial process for dealing with injury or stress caused by perturbations of the cellular microenvironment in multicellular organisms. Over the past decade, the mechanism known as “regulated cell death” (RCD) has been recognized as an integral part of tissue homeostasis, specifically in response to stress conditions (1, 2). Apoptosis, known as a prototypical form of RCD, has been well studied and is considered to eliminate unnecessary and harmful cells, including virus-infected cells, senescent cells, and cancer cells (35). However, the mechanism by which apoptosis, an immunologically silent form of cell death, affects disease pathogenesis, including inflammatory diseases, has not been well understood. Conversely, necrosis has long been considered a form of merely accidental cell death triggered by severe stimuli and is thus conceived of as an uncontrollable process. Over the past decade, a spectrum of investigations have disclosed regulated necrosis (RN) as a nonapoptotic form of RCD that relies on genetically encoded molecular machinery (6). Thus far, various forms of RN pathways have been established that emit abnormal signals such as damage-associated molecular patterns (DAMPs) to alert environmental cells of danger (7) (Table 1). Necrotic forms of RCD appear to be connected to each other via the release of DAMPs and form a necroinflammatory autoamplification loop, resulting in tissue damage and organ dysfunction (7). Among the several types of morphologically classified RN, such as necroptosis, parthanatos, mitochondrial permeability transition, and ferroptosis, the most comprehensively established subroutine of RN is necroptosis (8). Necroptosis was confirmed in 2005 as a possible nonapoptotic cell death pathway triggered by TNFR1 (TNF-α receptor 1) in the absence of caspase 8–dependent intracellular apoptotic signaling (9). Nec-1 (necrostatin 1) was discovered at the same time as a specific small-molecule inhibitor of necroptosis (9), followed by RIPK1 (receptor-interacting kinase 1) as the cellular target of Nec-1 (10, 11), leading to significant advancements in the understanding of the mechanism of necroptosis (Table 1). Subsequent research has revealed that the multiprotein complex termed the “necrosome”—the complex of RIPK1/RIPK3/MLKL (mixed lineage kinase domain–like protein)—can effectively trigger necroptosis in response to activation of the death receptors of TNFR1 (12) (Table 1). Necroptosis is observed in a variety of disease states, such as stroke (13), myocardial infarction (14), ischemia-reperfusion injury (IRI) (15), and other inflammatory diseases (16), via releasing DAMPs from dying cells.

Table 1. Glossary

Damage-associated molecular patterns (DAMPs): DAMPs are released from necrotic cells, which triggers the production of inflammatory cytokines and chemokines
RIPK1 (receptor-interacting protein kinase 1): a representative mediator of necroptosis, RIPK1 regulates caspase 8–mediated apoptosis
RIPK3 (receptor-interacting protein kinase 3): critical regulator of necroptosis
MLKL (mixed lineage kinase domain-like protein): phosphorylated MLKL executes necroptosis by disrupting the cytomembrane
Receptor-interacting protein homotypic interaction motif (RHIM): RHIM is a protein domain that is found in RIPK1, RIPK3, TRIF, and DAI. RIPK3 interacts with RIPK1, TRIF, and DAI via the RHIM domain, which is important for necroptosis induction
Toll-like receptor–Toll-IL-1 receptor domain–containing adapter-inducing IFN-β (TRIF): one of the triggers of necroptosis downstream of Toll-like receptors
DNA-dependent activator of IFN-regulatory factor (DAI): a cytosolic DNA sensor that can promote type I IFN responses in response to viral infection. RHIM-mediated interaction between DAI and RIP3 leads to necroptosis of the infected cells
Parkin/PARK2: the cytosolic E3 ubiquitin ligase that has been linked to Parkinson’s disease. Parkin is known as a pivotal regulator of mitophagy
Glutathione peroxidase 4 (GPx4): GPx4 is a selenoprotein that catalyzes the reduction of hydrogen peroxide
NCOA4 (nuclear receptor coactivator 4): a selective cargo receptor for the autophagic degradation of ferritin (termed “ferritinophagy”)
Deferoxamine (DFO): the iron chelator that binds free iron in a stable complex
Ferrostatin-1 (Fer-1): Fer-1 is an antioxidant that inhibits ferroptosis much more effectively than phenolic antioxidants
Necrostatin-1 (Nec-1): Nec-1 is an allosteric inhibitor of the death receptor RIPK1 in the necroptotic pathway

Ferroptosis is a newly described form of caspase-independent RCD characterized by cellular accumulation of reactive oxygen species (ROS) driven through iron-dependent lipid peroxidation (17), which is induced by erastin and Ras synthetic lethality molecule 3 (RSL3). Because the cell membrane is damaged directly by lethal lipid peroxidation and subsequent lipid ROS production, ferroptosis shows a necrotic morphotype, and dying cells release DAMPs and immunogenic metabolites (7, 18), resulting in the inflammatory disease pathogenesis. Accumulating evidence has demonstrated the involvement of ferroptosis in experimental models of multiple human diseases, including acute renal injury (19), neurodegeneration (2022), IRI (23, 24), and Parkinson’s disease (21).

In this review, we present increasing evidence supporting the involvement of necroptosis and ferroptosis in the pathogenic process of various lung diseases, and we recapitulate the molecular mechanism of necroptosis and ferroptosis in the lung. Understanding the cellular mechanism by which small molecules protect from RCD in the lung will help in the development of specific therapeutic strategies targeting different forms of cell death in lung diseases (Table 2).

Table 2. Role of Regulated Necrosis in Lung Disease Pathogenesis

Disease RN Role of RN Cell Type Pathogenesis References
IPF Necroptosis and apoptosis Toxic Lung epithelial cells Increase of DAMPs, lung fibrosis (60, 66)
COPD Necroptosis Toxic Bronchial epithelial cells Increase of DAMPs, emphysema (38, 51)
  Ferroptosis Toxic Bronchial epithelial cells Increase of DAMPs, lipid peroxidation, emphysema (39)
Viral infection Necroptosis Protective 3T3 fibroblasts, MEFs Elimination of infected cells (7375)
  Ferroptosis Toxic T cells Immune response downregulated, susceptible to infection (82)
Bacterial infection Apoptosis–necroptosis axis Protective Bone marrow–derived macrophages Host immune response (76)
  Necroptosis Toxic Alveolar macrophages, lung epithelial cells Increase of ion dysregulation, tissue damage, pneumonia (78)
  Ferroptosis Toxic Bronchial epithelial cells Biofilm formation, colonization (80)
  Ferroptosis Toxic Macrophages Pulmonary necrosis, bacterial load (81)
Acute lung injury Necroptosis Toxic N/A Inflammasome activation (6871)
Lung cancer Necroptosis Protective Adenocarcinoma Inhibition of tumorigenesis (83)
  Ferroptosis Protective Adenocarcinoma Inhibition of tumorigenesis (87)
Bronchial asthma Necroptosis Toxic Bronchial epithelial cells Th2 inflammation (9092)
  Ferroptosis Toxic Bronchial epithelial cells Th2 inflammation (93)

Definition of abbreviations: 3T3 = 3-day transfer, inoculum 3 × 105 cells; COPD = chronic obstructive pulmonary disease; DAMP = damage-associated molecular pattern; IPF = idiopathic pulmonary fibrosis; MEFs = mouse embryonic fibroblasts; N/A = not available; RN = regulated necrosis; Th2 = T-helper cell type 2.

Necroptosis is a form of RN that has gained special attention because its inhibition, including genetic modification of RIPK1, RIPK3, and MLKL or small-molecule inhibitor Nec-1, can regulate disease progression in several mouse models (1316). Necroptosis is triggered by signaling from various death receptors, such as TNFR, Toll-like receptor–Toll-IL-1 receptor domain–containing adapter-inducing IFN-β (TRIF) pathway, TRAILR (TNF-related apoptosis-inducing ligand receptor), FAS (known as CD95 and TNFRSF6 [TNF receptor superfamily member 6]), IFN receptor–RIPK1 pathway, and DNA-dependent activator of IFN-regulatory factors (DAI) pathway (7, 2528) (Table 1) (Figure 1). Activation of RIPK is a crucial step in the induction of necroptosis signaling. RIPK1 and RIPK3 are serine/threonine kinases, and both have a receptor-interacting protein homotypic interaction motif (RHIM) in the C-terminal domain. RIPK1 combines with RIPK3 via the RHIM domain, forming an amyloid-like complex called the “necrosome” (29). The necrosome is now considered to contain four proteins: RIPK1, RIPK3, TRIF, and DAI (30). As a consequence of necrosome formation, phosphorylation of RIPK3 at Ser345 occurs, enabling the phosphorylation of MLKL (31). The phosphorylation of MLKL elicits an oligomer formation by binding to phosphatidylinositol lipids and cardiolipin, which allows MLKL to translocate from the cytosol to the plasma membranes and form a hole in the membrane. These properties disrupt the integrity of the plasma membrane, resulting in necrotic cell death (32) (Figure 1). A novel and interesting mechanism to regulate necroptosis has emerged whereby the E3 ubiquitin ligase of Parkin, known as a mitophagy activator, regulates necroptosis and inflammation via inhibiting necrosome formation (33). Parkin activated by AMPK (AMP-activated protein kinase) prevents the formation of the RIPK1–RIPK3 complex by promoting polyubiquitination of RIPK3. Parkin-knockout mice show increased inflammation and spontaneous tumor formation via activation of RIPK3 phosphorylation and necroptosis (33) (Figure 1). This AMPK–Parkin–RIPK3 pathway is a promising regulatory mechanism of necroptosis, and therefore further experiments based on lung inflammation models should be conducted in the near future.

Ferroptosis, like necroptosis, is a form of necrotic cell death because it is potently regulated by lipid repair enzymes, including glutathione (GSH) and glutathione peroxidase 4 (GPx4) (Table 1). The term “ferroptosis” was coined in 2012 (17) to define a form of cell death elicited by the small molecule erastin in Ras-mutant cells, which suppresses the import of cystine, leading to GSH reduction and downregulation of the phospholipid peroxidase GPx4 (34). GPx4 efficiently shifts toxic phospholipid hydroperoxides to nontoxic lipid alcohols. Downregulation of GPx4 via inhibition of GSH with erastin, or directly with (1S,3R)-RSL3, leads to an increase in detrimental lipid peroxidation, resulting in induction of cell death. During ferroptosis, labile iron accumulation induced by the disrupted iron metabolism regulation system, such as transferrin receptor and divalent metal transporter 1, evokes the Fenton reaction, resulting in phospholipid peroxidation of plasma membranes caused by ROS. These two representative characteristics of ferroptosis—disrupted iron homeostasis and accelerated lipid peroxidation—are associated with different pathologies across many animal species during various stages of life (Figure 1).

Emerging evidence suggests the involvement of both ferroptosis and necroptosis in diverse experimental models. An experimental neuronal death model after hemorrhagic stroke in vivo and in vitro shows shared ferroptotic and necroptotic cell death but not caspase-dependent apoptosis or autophagy (35). Mitochondrial complex I inhibition triggers mitophagy-dependent ROS production via depolarization of the mitochondrial membrane potential, leading to activation of combined necroptotic and ferroptotic cell death in melanoma cells (36). Treatment of 1-methyl-4-phenylpyridium on the human neuroblastoma cell line (a widely used model of Parkinson’s disease) reportedly elicits necrotic and nonapoptotic cell death, which is sensitive to both Nec-1 and ferrostatin 1 (Fer-1) (37). In addition, we have demonstrated that cigarette smoke extract–induced epithelial cell death is significantly inhibited by Fer-1, marginally inhibited by Nec-1 and pan-caspase inhibitor zVAD-FMK treatment, and significantly inhibited by Fer-1 (38). Several different cell death pathways or multiple cell death pathways may be detected on the basis of cell type, time point, and triggers of cell death. Collectively, these findings indicate a possible involvement of ferroptosis and necroptosis in shared disease pathogenesis, such as stroke, cancer, neurodegenerative disease, and chronic obstructive pulmonary disease (COPD).

The cross-talk between several cell death pathways, including ferroptosis and necroptosis, via the release of DAMPs has been proposed in regulation of inflammatory diseases (7). In addition, ferroptosis mediates synchronized cell death regulated by Nec-1 and compounds that inhibit mitochondrial permeability transition in an IRI and acute kidney injury model, triggering a toxic immune response (39). Ferroptosis and necroptosis act as alternative cell death pathways and notably show synergism in vivo in acute ischemic kidney injury (40). Further studies are needed to clarify whether dual targeting of these pathways by combination therapies is necessary for efficient clinical intervention.

In contrast to apoptosis, RN is more immunogenic because of plasma membrane rupture and release of DAMPs from dying cells. DAMPs are host-derived molecules, including ATP, HMGB1 (high mobility group box 1 protein), IL-33, and heat shock proteins, by which the immune response is triggered with binding to pattern recognition receptors, such as Toll-like receptors (41). Releasing DAMPs has been widely implicated in various lung inflammatory diseases, such as acute lung injury (42) and COPD (4345) (Figure 1). Accordingly, DAMPs could potentially become a common therapeutic target because they are downstream of the ferroptosis and necroptosis pathways in lung inflammation.

Autophagy is a lysosome-mediated catabolic pathway that maintains cellular viability and homeostasis by eliminating unnecessary and harmful components. During the process of autophagy, intracellular substrates such as proteins, molecules, lipids, and organelles are sequestered into double-membraned autophagosomes that are subsequently degraded after autophagosome–lysosome fusion. Selective autophagy that recycles specific components (e.g., mitochondria/mitophagy, ferritin/ferritinophagy, and lipids/lipophagy) has been employed in response to various cellular stressors. An increase of autophagosomes is often shown in dying cells, which is morphologically classified as type 2 programmed cell death and termed “autophagic cell death.” Cell death often occurs concomitantly with autophagy rather than being induced by autophagy (46). Hence, this term has been changed to “autophagy-dependent cell death” in the presence of experimental evidence of a mechanistic or functional link between RCD and the autophagy apparatus. Moreover, pharmacological or genetic manipulation of autophagy can modulate cell death (47). Autophagic inhibition promotes cell death in various pathological disorders, such as cancer, cardiovascular disease, and inflammatory disorders, indicating the cytoprotective ability of autophagy to maintain cell viability and homeostasis (48, 49). In contrast, selective autophagy has been shown to contribute to RCD in various models. Selective degradation of Fap-1 (Fas-associated phosphatase 1) by autophagy accelerates FAS apoptosis in a cell-type–specific manner (50). Cigarette smoke elicits mitophagy and autophagic degradation of mitochondria, contributing to necroptosis in COPD (51). Ferritinophagy, the autophagic degradation of ferritin to free iron mediated by specific adapter NCOA4 (nuclear receptor coactivator 4), contributes to ferroptosis development via lipid peroxidation (52). GPx4, a selenoprotein that inhibits ferroptosis by deoxidization of lipid ROS, is diminished by chaperone-mediated autophagic degradation, resulting in increased ferroptosis (53). Collectively, although autophagy plays a protective role against cell death by maintaining cellular metabolic homeostasis in the steady state, organelle- and protein-selective autophagy appear to induce RCD in various experimental models, including cigarette smoke exposure.

COPD is characterized by irreversible airway narrowing and distal airspace destruction as a result of prolonged smoke exposure; it is refractory to currently available therapies and is now one of the leading causes of morbidity and mortality worldwide (5456). Increasing studies suggest that necrotic forms of RCD are implicated in the pathogenesis of COPD. Airway epithelial cell necroptosis via mitophagy is implicated in COPD pathogenesis (51) (Table 2). In the same set of studies, the increase of RIPK3 expression is observed in the lungs of cigarette smoke–exposed wild-type mice. Another group has also revealed that cigarette smoke exposure induces necrotic cell death and DAMP release in the BEAS2B cell line. Furthermore, cigarette smoke exposure of wild-type mice increases neutrophils and DAMPs in BAL, which is attenuated by Nec-1 treatment (43). However, both of these studies seem to have potential limitations because they lack experiments with mice with knockout of RIPK3 or MLKL (major necroptosis regulators). Thus, further in vivo experiments are needed to evaluate the involvement of necroptosis in COPD pathogenesis.

Alternatively, we have previously demonstrated that lung epithelial cell ferroptosis induced via autophagic degradation of ferritin plays an important role in the generation of a COPD phenotype (39). Labile iron accumulation and augmented lipid peroxidation are shown with concomitant necrotic cell death during cigarette smoke exposure, which is enhanced by GPx4 downregulation in in vivo and in vitro experiments (39). Treatment with deferoxamine and Fer-1 and GPx4-knockdown experiments also support the role of ferroptosis in cigarette smoke–treated lung epithelial cells. Ferroptosis caused by labile iron accumulation in epithelial cells is initiated by autophagic ferritin degradation (ferritinophagy) via NCOA4 (nuclear receptor coactivator 4) in response to cigarette smoke treatment (39). Moreover, cigarette smoke–exposed GPx4+/− mice show significantly higher degrees of lipid peroxidation, nonapoptotic cell death, DAMP release, and enhanced COPD phenotypes than wild-type mice, all of which were attenuated in GPx4-transgenic mice (39). These data indicate the important role of cigarette smoke in epithelial cell ferroptosis in COPD pathogenesis. Thus, suppression of lipid peroxidation by GPx4 and antioxidants such as Fer-1 and of iron chelation by deferoxamine is a possible target of an antiferroptotic treatment to prevent COPD progression.

To date, there are no successful clinical trials using antioxidant therapy for COPD. Unsaturated lipids lead to constant propagation of free radical autoxidation because of the weak carbon–hydrogen bond in the methylene group. Hence, the targeting of lipid peroxidation is a potential antioxidant therapy. This is supported by our data showing that both the presence of the GPx4 transgene and treatment with Fer-1 rescued COPD phenotype. Our data indicate that it is necessary to develop lipid-specific antioxidant drugs for treatment of COPD.

Idiopathic pulmonary fibrosis (IPF) is a refractory and inexorably progressive lung fibrotic disease pathologically characterized by lung epithelial injury and subsequent fibroblastic proliferation and deposition of extracellular matrix in lung parenchyma (57, 58). The lung epithelium acts as the first barrier to prevent access to inspired external stimuli. Alveolar epithelial cell (AEC) or airway epithelial cell destruction during lung injury leads to dysregulated wound healing, including proinflammatory stress response, thereby resulting in myofibroblast differentiation and aberrant collagen deposition in the lung interstitium (58, 59). Epithelial cell apoptosis that is considered a major form of RCD in IPF pathogenesis was first described in 1996 (60). There are significantly higher numbers of TUNEL-positive bronchiolar epithelial cells and AECs in the lungs of patients with IPF than in normal lungs and lungs of patients with COPD (60) Table 2. Furthermore, the Fas–Fas ligand pathway, a novel inducer of apoptosis, is upregulated in the BAL and frozen lung sections of patients with IPF compared with those of healthy control subjects, indicating the involvement of apoptosis in IPF pathogenesis (61). Lung epithelial cells have been considered a key player within the context of apoptosis in IPF pathogenesis (62). However, the mechanisms by which apoptotic epithelial cells contribute to lung fibrosis are still poorly understood. Nonapoptotic DNA fragmentation was detected by TUNEL assay, indicating that TUNEL-positive cells include not only apoptotic cells but also necrotic cells. Epithelial–mesenchymal interactions are believed to be important in IPF pathogenesis, as shown by AEC apoptosis/necrosis adjacent to underlying myofibroblasts in the lungs of human patients (63). In a previous study, IL-1β secretion from senescent bronchial epithelial cells was shown to induce myofibroblast differentiation in fibroblasts (58). DAMPs secreted by dying necrotic cells are involved in some lung diseases (64, 65), indicating the potential role of necrotic cell death in IPF. Earlier, we found that RIPK3-mediated necroptosis in AECs plays a role in IPF development via the release of DAMPs (66) (Table 2). Immunohistochemistry and Western blotting show that RIPK3 and p-MLKL expression levels are significantly higher in the lungs of patients with IPF than in lungs of healthy control subjects. Bleomycin (BLM)-treated AECs isolated from RIPK3-knockout mice show attenuation of cell death with decreased p-MLKL expression. RIPK3-knockout mice efficiently inhibit BLM-induced DAMP secretion, cell death, and lung fibrosis without decrease of cleaved caspase 3 expression level. According to the in vitro experimental results using zVAD-fmk and Nec-1, both apoptosis and necroptosis coexist in BLM-treated AECs. BLM injection into wild-type murine lung elicits equally both a cleaved caspase 3–positive cell death that is efficiently inhibited by zVAD-fmk and a cleaved caspase 3–negative cell death that is efficiently inhibited by Nec-1 in AECs, suggesting that both apoptosis and necroptosis are important steps during BLM-induced lung fibrosis. These two RCD pathways are believed to suppress each other, but necroptosis works as an alternative when caspase-dependent apoptosis is absent (67). However, given that the aforementioned in vitro experiment shows that zVAD-fmk and Nec-1 synergistically suppress cell death, we speculate that the simultaneous blockage of apoptosis and necroptosis may be a promising target for IPF treatment.

RIPK3-mediated necroptosis and subsequent activation of the NLRP3 (nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3) inflammasome are observed in neonatal mice with hypoxia-induced lung injury, which is attenuated by genetic deletion in RIPK3 (68). Similarly, contributions of RIPK3-mediated necroptosis and inflammasome pathways in the development of an LPS-induced acute lung injury mouse model have been reported. GSK872, a selective inhibitor of RIPK3, significantly reduces LPS-induced necroptosis and NLRP inflammasome activation, with concomitant attenuation of IL-1β and IL-18 production and inflammatory cell infiltration (69). RIPK3-deficient mice are protected against ventilator-induced lung injury in a fatty acid β-oxidation–dependent manner (70). Inhibition of RIPK1 by Nec-1 is shown to decrease systemic and lung inflammation and increase survival in neonatal mice with sepsis (71). Thus, these studies suggest that necroptosis and inflammasome activation contribute to various forms of acute lung injury.

Cell death pathways, including apoptosis and RN, have evolved as a first-line host defense system against virus-encoded cell death suppressors during viral infection (72). As a preliminary stage to RN, apoptosis plays a defensive role to eliminate virus-infected cells, subsequently providing the adaptation for some viruses to acquire virus-encoded cell death suppressors. RN is considered an adaptation against caspase 8–targeted apoptosis suppressors in a RIP3-dependent manner (72). Some viruses, including vaccinia, are susceptible to RIP3-dependent RN (73), whereas other viruses, including murine cytomegalovirus, are no longer susceptible because of cytomegalovirus-encoded RIP3 suppressors that limit the efficacy of cell death pathways (74). Mice deficient in RIPK3 activity are reportedly more susceptible to influenza A infection than their wild-type counterparts (75). Thus, the prevailing consensus is that necroptosis plays a protective role during viral pneumonia by eliminating infected cells, thus reducing viral replication (Table 2).

With respect to the association between RCD and bacterial infections, RIPK1, caspase 8, and RIPK3 contribute to Yersinia pestis infection–induced macrophage cell death, and caspase 8– and RIPK3-knockout mice are highly susceptible to Y. pestis infection (76). These knockout mouse models also reduce caspase 1–associated inflammasome activity, which is crucial to host responses against Y. pestis and other infections (76). These results suggest that necrosis plays a protective role in innate immunity during bacterial infections. Likewise, necroptosis promotes Staphylococcus aureus elimination by suppressing excessive inflammatory signaling (77). Although several groups have pointed out the detrimental role of necroptosis during bacterial infection (78), the vast majority of studies have indicated a protective role for necroptosis via inhibition of bacterial load and inflammation.

In stark contrast, some recent research studies have shed light on the adverse role of ferroptosis in bacterial infection and polymicrobial sepsis (79). Human epithelial cell ferroptosis is initiated by the prokaryotic bacterium Pseudomonas aeruginosa via oxidizing host membrane arachidonic acid phosphatidylethanolamines by lipoxygenase (pLoxA). Furthermore, P. aeruginosa–induced ferroptosis of host epithelial cells promotes biofilm formation, enhancing colonization by the pathogen (80). Similarly, Mycobacterium tuberculosis (Mtb) elicits macrophage necrosis associated with reduced concentrations of GPx4 concomitantly with increased free iron, mitochondrial superoxide, and lipid peroxidation, all of which are notable features of ferroptosis. Interestingly, Fer-1 treatment remarkably reduces lung pathology, including pulmonary necrosis and Mtb bacterial burden, in Mtb-infected mice (81). Moreover, ferroptosis occurs in T cells during lymphocyte-responsive infections such as lymphocytic choriomeningitis virus and Leishmania major parasite infection. GPx4, a scavenger of phospholipid hydroperoxide, prevents T-cell ferroptosis, which plays a crucial role in the immune response. T-cell–specific GPx4-deficient mouse experiments reveal that GPx4-deficient T cells rapidly accumulate lipid peroxides and die by ferroptosis (82). GPx4-deficient T cells fail to prevent viral and parasitic infection and are rescued by high-dose vitamin E exposure. This finding suggests the detrimental role of ferroptosis by weakening T-cell immunity and subsequently suggests a beneficial role for vitamin E and GPx4 inhibition of ferroptosis during viral and parasitic infection (82). Taken together, whether the role of RN in infectious disease is protective or injurious may depend on cell type and on the kinds of pathogens involved (Table 2).

In 2013, Saddoughi and colleagues were the first to report a role for necroptosis in lung tumor growth inhibition. In this study, targeting of oncoprotein I2PP2A/SET using the sphingosine analog drug FTY720 suppressed lung tumor growth via PP2A (protein phosphatase 2A) activation and necroptosis mediated by RIPK1 (83) (Table 2). Accumulated evidence suggests that anticancer drugs trigger necroptosis in lung cancer cells. Cisplatin and paclitaxel still play a central role in lung cancer chemotherapy. Paclitaxel induces necroptosis in lung adenocarcinoma, which is promoted by dasatinib, a c-Src inhibitor, via dephosphorylation of caspase 8 by c-Src (84). Long-term cisplatin treatment is known to enhance tumor resistance to cell death induction via diverse mechanisms. Overexpression of PDIA6 (protein disulfide isomerase, family A, member 6) is observed in cisplatin-resistant non–small cell lung cancer (NSCLC) cells and in the lungs of patients with adenocarcinoma. PDIA6-targeting siRNA reverses the cisplatin-resistant phenotype by restoring a noncanonical cell death pathway that overlaps with some necroptosis pathways (85).

Despite an increasing number of studies reporting the close relationship of ferroptosis with progression of various tumors, a paucity of material is available with respect to lung tumors. Alvarez and colleagues revealed the mechanism by which lung adenocarcinoma is protected from ferroptosis. The iron-sulfur cluster biosynthetic enzyme NFS1 that lies in a region of genomic amplification plays an important role in surviving the high-oxygen environment of early-stage lung tumors. Suppression of NFS1 cooperates with the inhibition of cysteine transport to trigger ferroptosis and aid in the gradual progression of lung adenocarcinoma (86) (Table 2). Therefore, lung adenocarcinoma highly expressed NFS1 to protect from ongoing ferroptosis in response to oxidative damage (81, 86). GPx4 is highly expressed in radioresistant A549 and H460 cells (NSCLC cell line). Erastin, a representative ferroptosis inducer, partially suppresses radioresistance of NSCLC cells by inducing GPx4-mediated ferroptosis (87). The network of long noncoding RNA and miRNA regulation of ferroptosis is reported to be an important mechanism in NSCLC tumorigenesis (88). Collectively, these observations indicate an inhibitory role for ferroptosis in the development and progression of lung cancer (Table 2). Despite the presence of in vitro reports suggesting the clinical importance of RN targeting therapy, the in vivo evidence is scarce. Therefore, further evidence including in vivo studies is needed to elucidate the role of RN in human lung cancer.

Recent studies indicate the involvement of RN in the pathogenesis of bronchial asthma. Virus-induced asthma exacerbation, mimicked by IFN-β–knockout mice treated with house dust mite, is associated with necroptosis in terms of increased necroptosis markers, pMLKL, and lactate dehydrogenase in BAL fluid (89). IL-33, a major proinflammatory cytokine in the type 2 immune response in inflammatory diseases, including asthma, is released in response to necroptosis, resulting in activation of basophils and eosinophils (90). Furthermore, the necroptosis inhibitor GW806742X abrogates necroptosis and IL-33 reaction in vitro and attenuates eosinophilia in a mouse model of Aspergillus fumigatus extract–induced asthma, which is potently dependent on IL-33 (90). TNF-α–induced necroptosis in human bronchial epithelial cells, which partially mimics severe asthma, is enhanced by MUC1 (mucin 1) knockdown, which is attenuated by Nec-1 (91). The same research group proposed that the resistance of glucocorticoids against asthma may depend on blocked glucocorticoid receptor-α nuclear translocation and p-p65 phosphorylation induced by MUC1 ablation in TNF-α–induced necroptosis in human bronchial epithelial cells (92). The phenotype of bronchial asthma is known to be heterogeneous with respect to T-helper cell type 2 (Th2) inflammation dominance. Necroptosis seems to be involved in multiple aspects of asthma, including Th2 inflammation via release of IL-33 from necrotic cells, as well as TNF-α–induced non-Th2 inflammation, often observed in steroid-refractory asthma.

With respect to ferroptosis in lung epithelial cells, little is known about its role in the pathogenesis of asthma. The PEBP1 (phosphatidylethanolamine-binding protein 1)–15-lipoxygenase (LO) complex, known to stimulate IL-13/IL-4–induced Th2 inflammation, is found to be a master regulator of ferroptosis as well as GPx4. Higher degrees of colocalization of PEBP1 with 15-LO are seen in human bronchial epithelial cells from patients with asthma than in those from healthy individuals. In addition, a strong correlation has been reported between this colocalization in asthma and the fractional exhaled nitric oxide in human bronchial epithelial cells, suggesting the importance of PEBP1/15-LO–driven ferroptosis in Th2 inflammation during asthma pathogenesis (93).

In summary, evidence from these research studies suggests the involvement of RN in allergic airway inflammation and asthma exacerbation. Therapeutic targeting of necroptotic and ferroptotic signaling may lead to future developments in asthma treatment.

With respect to necroptosis and ferroptosis, the involved signaling pathways and induction mechanisms of the identified RN have been well documented by virtue of steady progress in related research. However, the role of RN in diverse lung diseases remains incompletely understood in spite of mounting evidence revealing that RN is also implicated in several other organ diseases. In addition, compared with necroptosis, there is less evidence to support a clinical role for ferroptosis in lung disease pathogenesis, which can most likely be attributed to its recent discovery. Accordingly, accumulation of clinically relevant evidence for ferroptosis is expected in the future.

In this review, we have attempted to clarify that RN plays contradictory roles—disease protection or disease progression—depending on the type of cell and pathogenesis. In addition, some in vivo or in vitro experimental cell death models have demonstrated shared roles for ferroptotic and necroptotic cell death and the synergistic effects of Nec-1 and Fer-1. Therefore, it would be useful to further investigate the therapeutic potential of simultaneous inhibition of both cell death pathways in complex disease models. We believe that necroptosis and ferroptosis will become the new target for treating various lung diseases that currently have no cure.

The authors thank Stephanie Cambier for comments on the manuscript and thoughtful suggestions.

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Correspondence and requests for reprints should be addressed to Shunsuke Minagawa, M.D., Ph.D., Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo 105-8461, Japan. E-mail: .

Originally Published in Press as DOI: 10.1165/rcmb.2019-0337TR on February 4, 2020

Author disclosures are available with the text of this article at www.atsjournals.org.

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