Comments Abstract
The bidirectional epidemiological association between asthma and obesity is well known. Recent evidence suggests that there is an intersection of the pathophysiological molecular pathways leading to either obesity or asthma, at the level of mitochondria. This is not surprising, because mitochondria, beyond their roles as the metabolic powerhouses of the cell, serve as sensors of threats, regulators of stress signaling, and effectors of cytotoxicity. Reduced mitochondrial function and low metabolic activity are well-recognized features of obesity. Three distinct lines of experimental evidences connect mitochondrial dysfunction with asthma. First, asthma is associated with aberrant mitochondrial metabolism. Second, mitochondrial dysfunction may either induce asthma-like features or increase asthma severity. Third, mitochondria-targeted therapies appear effective in preventing or reversing asthma features. Importantly, mitochondrial dysfunction in airway epithelial cells appears to be a powerful trigger for airway remodeling that is independent of cellular inflammation. This is clinically relevant to the obese–asthma phenotype, with exaggerated symptoms despite apparently low levels of inflammation, and poor response to antiinflammatory treatment. In summary, mitochondrial dysfunction is a common thread tying together the twin epidemics of obesity and asthma. Environmental and lifestyle factors leading to primary mitochondrial dysfunction may be increasing the risk for either disease. Further, secondary mitochondrial dysfunction emerging from the pathogenesis of either obesity or asthma may increase the risk of the other. Mitochondrial health–centric strategies may be relevant to prevention and treatment of both obesity and asthma, and should be actively considered.
Obesity has been identified as an important risk factor for asthma (1). Conversely, metabolic changes associated with obesity are more frequently seen in subjects with asthma, independent of body mass (2, 3). Experimental models of obesity and asthma support these epidemiological associations and further extend the obesity–asthma link to the metabolic and functional changes associated with obesity (4, 5). Mice with diet-induced metabolic syndrome, but without obesity or adiposity, seem predisposed to asthma-like airway hyperresponsiveness and remodeling, similar to obese mice (5). However, unlike mice with allergic airway inflammation, mice with obese or nonobese metabolic syndrome have low levels of exhaled nitric oxide (NO) and minimal airway inflammation. This resembles a well studied cluster of obese–asthma in humans that has low markers of allergic inflammation, such as exhaled NO or sputum eosinophils, but is symptomatic (6, 7). Furthermore, when subjected to allergen sensitization and challenge, such mice develop enhanced allergic inflammation and airway remodeling (8). Human studies support this cross-talk, with subjects with obesity with asthma being overrepresented in severe asthma. Although an obese atopic variety of asthma was not a major cluster in the human studies cited previously here, this does not rule out its existence. One of the limitations in the human studies is that measures of obesity do not fully capture molecular metabolic changes that are mechanistically connected with asthma. In studies of mice with obese or nonobese metabolic syndrome, the key metabolic abnormalities were abnormal arginine metabolism, mitochondrial dysfunction, and insulin resistance (5, 8). Insulin resistance, a hallmark of the metabolic syndrome, has been independently associated with asthma risk in humans (9, 10). These observations suggest that the obesity–asthma link extends beyond the consequences of obesity to the molecular changes that precede obesity. Mitochondrial dysfunction is an early pathophysiological event in the development of insulin resistance and obesity, and is also considered to be critical to asthma pathophysiology (11–13). The origin of mitochondrial dysfunction may relate to a variety of processes ranging from inflammation to epigenetic inheritance (12, 14). Mitochondria, beyond their roles as the metabolic powerhouses of the cell, serve as sensors of threats, regulators of stress signaling, and effectors of cytotoxicity (15). Due to their central positioning in the cellular metabolic flux, they are uniquely adapted to sense changes, such as altered availability of nutrients and oxygen and presence of electron steal by intracellular pathogens, among other threats. This leads to mitochondrial depolarization and/or release of reactive oxygen species (ROS), which activate the evolutionarily conserved cell danger response system (16). This set of graded responses is designed to limit pathogen replication, contain the source of danger, and protect the cell. Inappropriate activation of such responses sets into motion a proinflammatory cascade that may result in disease. An intricate homeostatic system regulates and maintains optimal mitochondrial function in healthy cells, the failure of which is seen in obesity, asthma, and metabolic syndrome. Details of mitochondrial biology and the cell danger response system can be found elsewhere (16, 17). Subsequent sections will focus on the etiology and role of mitochondrial dysfunction as a link between obesity, metabolic syndrome, and asthma.
Mitochondrial function is governed by heritable, environmental, and lifestyle elements. Genetic and epigenetic influences govern the mitochondrial metabolic capacity at birth, and are subsequently modified by factors, such as caloric intake, pollutants, and infections (12, 14). Caloric excess and high fat consumption, the most common cause of obesity, leads to nutritional overload, excess electron flux, increased oxidative stress, accumulation of partially oxidized substrates, and, eventually, damage (18, 19). This mitochondrial dysfunction leads to activation of stress pathways that reduce cellular sensitivity to insulin, limiting nutrient influx and preventing further damage. Chronically, this manifests as reduced mitochondrial metabolism, insulin resistance in organs, such as liver and skeletal muscle, with consequent hyperinsulinemia and diversion of nutrients to storage as adipose tissue (20). In addition, the redox state and, thereby, mitochondrial function dictate flux through many other critical metabolic pathways, such as glutathione, homocysteine, and methionine metabolism. Thus, mitochondrial dysfunction, with rising intracellular oxygen and oxidative stress, leads to increase in metabolites, such as homocysteine and asymmetric dimethyl arginine (ADMA). This reduces arginine bioavailability, interferes with NO synthesis, and leads to oxonitrative stress in epithelial and vascular endothelial cells (21). This pattern underlies the metabolic syndrome with obesity, diabetes, dyslipidemia, and hypertension as the phenotypic components. Importantly, the mitochondrial dysfunction can be systemic. In mice with diet-induced metabolic syndrome, loss of cristae and mitochondrial swelling, suggestive of mitochondrial dysfunction, was observed in the bronchial epithelial cells (8). Interestingly, fructose-fed mice that retain a normal body weight, but develop metabolic changes typically associated with obesity, also show such changes (5).
The first reports of mitochondrial abnormalities in airways of subjects with asthma were in ultrastructural descriptions of bronchial epithelium of children with asthma (22). Mabalirajan and colleagues (23) found mitochondrial dysfunction in airway epithelium to be an integral part of an allergic asthma model in mice, and, subsequently, Aguilera-Aguirre and colleagues (24) found that pre-existing mitochondrial dysfunction increases the severity of asthma in a similar model. Subsequent work from our laboratory showed that allergically inflamed lungs had very high levels of ADMA, and that IL-4, a classical T-helper cell type 2 inflammation cytokine, increased ADMA synthesis via protein arginine methyl transferases and inhibited its degradation via dimethylarginine dimethylaminohydrolase 2. The combination of IL-4 and ADMA potently induced oxonitrative stress and the cellular hypoxic response, despite normoxic conditions (25, 26). For self-evident reasons, the hypoxic response regulates aerobic metabolism and transcriptionally represses mitochondrial biogenesis. We have previously shown that excessive induction of the hypoxic response leads to a severe asthma phenotype where the mice can even develop fatal bronchoconstriction during challenge (27). Together, IL-4 and ADMA led to fragmentation and swelling of mitochondria, increased release of mitochondrial ROS, and, finally, reduced mitochondrial mass in airway epithelial cells. The mitochondrial loss could be partially blocked by knocking down hypoxia response factor 1α. This showed how obesity, with high ADMA levels, and asthma, with high IL-4 levels, would potentiate each other via increasing severity of mitochondrial dysfunction (Figure 1). Interestingly, in a model of allergic asthma, high-dose arginine supplementation restored arginine bioavailability, inhibited the mitochondrial dysfunction, and attenuated asthma features (28, 29). Given prior data for the efficacy of high-dose arginine therapy to reverse ADMA-induced endothelial dysfunction in metabolic syndrome, this could be an important intersection point for both diseases (21).
Figure 1. A schematic overview of the overlapping inflammatory and metabolic pathways underlying mitochondrial dysfunction common to asthma, obesity and metabolic syndrome. ADMA = asymmetric dimethyl arginine; HIF-1α = hypoxia-inducible factor 1α.; ROS = reactive oxygen species
[More] [Minimize]Clinical data partially support the experimental insights described previously here. Holguin and colleagues (30, 31) have shown that the obese–asthma phenotype is associated with high plasma levels of ADMA, as predicted from experimental models. However, cultured airway epithelial cells from patients with mild atopic asthma exhibited preserved total cellular mitochondrial respiration through increased number or volume of mitochondria (32). The increase in mitochondrial number has also been observed in airway smooth muscle (ASM) from subjects with nonsevere asthma (8, 33). This was due to increased de novo arginine synthesis and increased mitochondrial arginine metabolism by arginase 2 (ARG2), thereby increasing the tricarboxylic acid cycle flux and maintaining the cellular bioenergetics. Arg2 knockout mice had metabolic dysfunction, hypertension, and increased susceptibility to asthma. Genetic variants of Arg2 are associated with risk and severity of asthma in genome-wide association studies. Together, the data suggest that arginine metabolism is strongly connected to mitochondrial health and, together, they play important roles in asthma and the metabolic syndrome. Genetic associations between mitochondrial genes and asthma have been reported (11, 34, 35). In a genome-wide study examining mitochondrially encoded genes, sex-specific associations of polymorphisms in cytochrome B (boys) and nicotinamide adenine dinucleotide reduced dehydrogenase 2/16S RNA (girls) were found (36). These genes are strongly associated with mitochondrial ROS production, fitting the overall model described previously here.
Mitochondria-targeted therapeutics in asthma or metabolic syndrome can be considered under three major types, referred to as the “3R model”: repair via scavenging harmful ROS; reprogramming mitochondrial function via its regulatory system; and replacement by exogenous healthy mitochondria (Figure 2).
Figure 2. A schematic overview of strategies to rejuvenate mitochondrial health based on the 3R model (repair via scavenging harmful ROS, reprogramming mitochondrial function via its regulatory system, and replacement by exogenous healthy mitochondria). Antagomirs = antagomirs to mitotoxic microRNAs; L-Arg = L-arginine; Metf = metformin; Mito-Q = mitoquinone mesylate; Mito-TEMPO = mitochondria-targeted antioxidant; NO = nitric oxide; Nrf2 = nuclear factor (erythroid-derived 2)–like 2; PQQ = pyrroloquinoline quinone; TNT = tunneling nanotube. For a more detailed understanding of these strategies, please see Reference 15.
[More] [Minimize]In both asthma and metabolic syndrome, there has been wide interest in the use of antioxidants, such as α-tocopherol (vitamin E). These do not target mitochondria, and no benefit has been reported in humans, although there are some benefits in mouse models of asthma (11). Supplementation with coenzyme Q10 (CoQ10), a redox component of the mitochondrial electron transport chain, has been more effective, with some evidence of benefit. In a small trial, 100 mg CoQ10 supplementation for 8 weeks improved insulin resistance in patients with metabolic syndrome (37). In an open-label study of steroid-dependent patients with asthma, supplementation with a daily antioxidant cocktail, consisting of CoQ10 (120 mg) plus 400 mg α-tocopherol plus 250 mg vitamin C, was associated with a reduction in steroid usage (38, 39). Newer-generation mitochondria-targeted antioxidants, such as mitoquinone mesylate, that contain a charged triphenylphosphonium group to enter mitochondria, may be more effective, but human data are awaited.
It is now shown that exercise and fasting have lasting effects on mitochondrial function through epigenetic programming (12). Benefits of aerobic exercise or fasting in restoring insulin sensitivity in obesity and metabolic syndrome are extremely well established. Weight loss and aerobic exercise are also associated with improved asthma control (40, 41). Although diet and exercise remain the most reliable ways to improve mitochondrial function, multiple studies have found that metformin improves insulin sensitivity and induces weight loss, possibly via effects on the gut microbiome (42, 43). Metformin has also been shown to improve asthma features in obese mice (44). The microbe–mitochondrion link is an important new direction in mitochondrial reprogramming, and the gut microbiome has been associated with both asthma and obesity (45–47). Microbiome-derived molecules, such as pyroquinoline quinone, that are mitochondrial antioxidants and also stimulate mitochondrial biogenesis merit further attention (15). Endogenous regulatory mechanisms, such as mitochondria targeting miRNA (mitomirs) could be therapeutically used to modulate mitochondrial function. Of these, microRNA-210 is transcribed by hypoxia response factor 1α (hypoxamir), and may be important in connecting the aberrant cellular hypoxic response to mitochondrial dysfunction.
Others and we have shown that mesenchymal stem cells (MSCs) are effective donors of mitochondria to dysfunctional lung epithelial cells (48, 49). In experimental models of asthma, we found that MSC-mediated mitochondrial transfer was a critical component of the therapeutic response (49). Our data suggested that peribronchial proliferation of fibroblasts and ASM in asthma may be due to their weak ability to donate mitochondria to airway epithelium. In support of this concept, MSCs overexpressing mitochondrial Rho GTPase 1, a guanosine triphosphatase that regulates mitochondrial trafficking, had greater efficacy than conventional MSCs and completely reversed airway remodeling by preventing fibroblast and ASM proliferation. However, MSCs with mitochondrial Rho GTPase 1–knockdown that produced normal levels of antiinflammatory mediators, but could not donate mitochondria, did not suppress firoblast/ASM proliferation and did not reduce either airway hyperresponsiveness or airway remodeling. This highlights the important role of mitochondrial dysfunction in asthma. Although we are not aware of similar data in obesity or metabolic syndrome, MSC therapy has been found to be effective in some studies (50).
Mitochondrial dysfunction is a common link between obesity, metabolic syndrome, and asthma. It contributes to the pathogenesis of each of these, and thus explains the shared epidemiologic risks, such that presence of one increases the likelihood of the other. Mitochondria-targeted therapies have shown high efficacy in experimental models, but clinical data are still scanty. It is plausible that patients with asthma with obesity or metabolic syndrome may benefit from such therapies as L-arginine supplementation, mitochondrial antioxidants, or metformin. These, of the various possibilities discussed, appear the most feasible at this time. Well-designed trials focusing on this subset are needed.
| 1 . | Dixon AE, Holguin F, Sood A, Salome CM, Pratley RE, Beuther DA, Celedón JC, Shore SA; American Thoracic Society Ad Hoc Subcommittee on Obesity and Lung Disease. An official American Thoracic Society Workshop report: obesity and asthma. Proc Am Thorac Soc 2010;7:325–335. |
| 2 . | Cottrell L, Neal WA, Ice C, Perez MK, Piedimonte G. Metabolic abnormalities in children with asthma. Am J Respir Crit Care Med 2011;183:441–448. |
| 3 . | Perez MK, Piedimonte G. Metabolic asthma: is there a link between obesity, diabetes, and asthma? Immunol Allergy Clin North Am 2014;34:777–784. |
| 4 . | Agrawal A, Mabalirajan U, Ahmad T, Ghosh B. Emerging interface between metabolic syndrome and asthma. Am J Respir Cell Mol Biol 2011;44:270–275. |
| 5 . | Singh VP, Aggarwal R, Singh S, Banik A, Ahmad T, Patnaik BR, Nappanveettil G, Singh KP, Aggarwal ML, Ghosh B, et al. Metabolic syndrome is associated with increased oxo-nitrative stress and asthma-like changes in lungs. PLoS One 2015;10:e0129850. |
| 6 . | Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE, Wardlaw AJ, Green RH. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 2008;178:218–224. |
| 7 . | Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, D’Agostino R Jr, Castro M, Curran-Everett D, Fitzpatrick AM, et al.; National Heart, Lung, and Blood Institute’s Severe Asthma Research Program. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med 2010;181:315–323. |
| 8 . | Leishangthem GD, Mabalirajan U, Singh VP, Agrawal A, Ghosh B, Dinda AK. Ultrastructural changes of airway in murine models of allergy and diet-induced metabolic syndrome. ISRN Allergy 2013;2013:261297. |
| 9 . | Husemoen LLN, Glümer C, Lau C, Pisinger C, Mørch LS, Linneberg A. Association of obesity and insulin resistance with asthma and aeroallergen sensitization. Allergy 2008;63:575–582. |
| 10 . | Singh S, Prakash YS, Linneberg A, Agrawal A. Insulin and the lung: connecting asthma and metabolic syndrome. J Allergy (Cairo) 2013;2013:627384. |
| 11 . | Reddy PH. Mitochondrial dysfunction and oxidative stress in asthma: implications for mitochondria-targeted antioxidant therapeutics. Pharmaceuticals (Basel) 2011;4:429–456. |
| 12 . | Cheng Z, Almeida FA. Mitochondrial alteration in type 2 diabetes and obesity: an epigenetic link. Cell Cycle 2014;13:890–897. |
| 13 . | Szendroedi J, Phielix E, Roden M. The role of mitochondria in insulin resistance and type 2 diabetes mellitus. Nat Rev Endocrinol 2011;8:92–103. |
| 14 . | Lee HK, Park KS, Cho YM, Lee YY, Pak YK. Mitochondria-based model for fetal origin of adult disease and insulin resistance. Ann N Y Acad Sci 2005;1042:1–18. |
| 15 . | Agrawal A, Mabalirajan U. Rejuvenating cellular respiration for optimizing respiratory function: targeting mitochondria. Am J Physiol Lung Cell Mol Physiol 2016;310:L103–L113. |
| 16 . | Naviaux RK. Metabolic features of the cell danger response. Mitochondrion 2014;16:7–17. |
| 17 . | Chandel NS. Mitochondria as signaling organelles. BMC Biol 2014;12:34. |
| 18 . | Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O, Bain J, Stevens R, Dyck JRB, Newgard CB, et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 2008;7:45–56. |
| 19 . | Watt MJ, Hevener AL. Fluxing the mitochondria to insulin resistance. Cell Metab 2008;7:5–6. |
| 20 . | Martin SD, McGee SL. The role of mitochondria in the aetiology of insulin resistance and type 2 diabetes. Biochim Biophys Acta 2014;1840:1303–1312. |
| 21 . | Stühlinger MC, Stanger O. Asymmetric dimethyl-L-arginine (ADMA): a possible link between homocyst(e)ine and endothelial dysfunction. Curr Drug Metab 2005;6:3–14. |
| 22 . | Konrádová V, Copová C, Suková B, Houstĕk J. Ultrastructure of the bronchial epithelium in three children with asthma. Pediatr Pulmonol 1985;1:182–187. |
| 23 . | Mabalirajan U, Dinda AK, Kumar S, Roshan R, Gupta P, Sharma SK, Ghosh B. Mitochondrial structural changes and dysfunction are associated with experimental allergic asthma. J Immunol 2008;181:3540–3548. |
| 24 . | Aguilera-Aguirre L, Bacsi A, Saavedra-Molina A, Kurosky A, Sur S, Boldogh I. Mitochondrial dysfunction increases allergic airway inflammation. J Immunol 2009;183:5379–5387. |
| 25 . | Pattnaik B, Bodas M, Bhatraju NK, Ahmad T, Pant R, Guleria R, Ghosh B, Agrawal A. IL-4 promotes asymmetric dimethylarginine accumulation, oxo-nitrative stress, and hypoxic response-induced mitochondrial loss in airway epithelial cells. J Allergy Clin Immunol 2016;138:130–141.e9. |
| 26 . | Ahmad T, Mabalirajan U, Ghosh B, Agrawal A. Altered asymmetric dimethyl arginine metabolism in allergically inflamed mouse lungs. Am J Respir Cell Mol Biol 2010;42:3–8. |
| 27 . | Ahmad T, Kumar M, Mabalirajan U, Pattnaik B, Aggarwal S, Singh R, Singh S, Mukerji M, Ghosh B, Agrawal A. Hypoxia response in asthma: differential modulation on inflammation and epithelial injury. Am J Respir Cell Mol Biol 2012;47:1–10. |
| 28 . | Mabalirajan U, Ahmad T, Leishangthem GD, Dinda AK, Agrawal A, Ghosh B. L-arginine reduces mitochondrial dysfunction and airway injury in murine allergic airway inflammation. Int Immunopharmacol 2010;10:1514–1519. |
| 29 . | Mabalirajan U, Ahmad T, Leishangthem GD, Joseph DA, Dinda AK, Agrawal A, Ghosh B. Beneficial effects of high dose of L-arginine on airway hyperresponsiveness and airway inflammation in a murine model of asthma. J Allergy Clin Immunol 2010;125:626–635. |
| 30 . | Holguin F. Arginine and nitric oxide pathways in obesity-associated asthma. J Allergy (Cairo) 2013;2013:714595. |
| 31 . | Holguin F, Comhair SAA, Hazen SL, Powers RW, Khatri SS, Bleecker ER, Busse WW, Calhoun WJ, Castro M, Fitzpatrick AM, et al. An association between L-arginine/asymmetric dimethyl arginine balance, obesity, and the age of asthma onset phenotype. Am J Respir Crit Care Med 2013;187:153–159. |
| 32 . | Xu W, Ghosh S, Comhair SAA, Asosingh K, Janocha AJ, Mavrakis DA, Bennett CD, Gruca LL, Graham BB, Queisser KA, et al. Increased mitochondrial arginine metabolism supports bioenergetics in asthma. J Clin Invest 2016;126:2465–2481. |
| 33 . | Girodet PO, Allard B, Thumerel M, Begueret H, Dupin I, Ousova O, Lassalle R, Maurat E, Ozier A, Trian T, et al. Bronchial smooth muscle remodeling in nonsevere asthma. Am J Respir Crit Care Med 2016;193:627–633. |
| 34 . | Raby BA, Klanderman B, Murphy A, Mazza S, Camargo CA Jr, Silverman EK, Weiss ST. A common mitochondrial haplogroup is associated with elevated total serum IgE levels. J Allergy Clin Immunol 2007;120:351–358. |
| 35 . | Revez JA, Matheson MC, Hui J, Baltic S, James A, Upham JW, Dharmage S, Thompson PJ, Martin NG, Hopper JL, et al.; Australian Asthma Genetics Consortium (AAGC) collaborators. Identification of STOML2 as a putative novel asthma risk gene associated with IL6R. Allergy 2016;71:1020–1030. |
| 36 . | Flaquer A, Heinzmann A, Rospleszcz S, Mailaparambil B, Dietrich H, Strauch K, Grychtol R. Association study of mitochondrial genetic polymorphisms in asthmatic children. Mitochondrion 2014;14:49–53. |
| 37 . | Raygan F, Rezavandi Z, Dadkhah Tehrani S, Farrokhian A, Asemi Z. The effects of coenzyme Q10 administration on glucose homeostasis parameters, lipid profiles, biomarkers of inflammation and oxidative stress in patients with metabolic syndrome. Eur J Nutr 2016;55:2357–2364. |
| 38 . | Gazdik F, Gvozdjakova A, Horvathova M, Weissova S, Kucharska J, Pijak MR, Gazdikova K. Levels of coenzyme Q10 in asthmatics. Bratisl Lek Listy (Tlacene Vyd) 2002;103:353–356. |
| 39 . | Gvozdjáková A, Kucharská J, Bartkovjaková M, Gazdíková K, Gazdík FE. Coenzyme Q10 supplementation reduces corticosteroids dosage in patients with bronchial asthma. Biofactors 2005;25:235–240. |
| 40 . | Mendes FAR, Gonçalves RC, Nunes MPT, Saraiva-Romanholo BM, Cukier A, Stelmach R, Jacob-Filho W, Martins MA, Carvalho CRF. Effects of aerobic training on psychosocial morbidity and symptoms in patients with asthma: a randomized clinical trial. Chest 2010;138:331–337. |
| 41 . | Sideleva O, Black K, Dixon AE. Effects of obesity and weight loss on airway physiology and inflammation in asthma. Pulm Pharmacol Ther 2013;26:455–458. |
| 42 . | Hur KY, Lee MS. New mechanisms of metformin action: focusing on mitochondria and the gut. J Diabetes Investig 2015;6:600–609. |
| 43 . | Park CS, Bang BR, Kwon HS, Moon KA, Kim TB, Lee KY, Moon HB, Cho YS. Metformin reduces airway inflammation and remodeling via activation of AMP-activated protein kinase. Biochem Pharmacol 2012;84:1660–1670. |
| 44 . | Calixto MC, Lintomen L, André DM, Leiria LO, Ferreira D, Lellis-Santos C, Anhê GF, Bordin S, Landgraf RG, Antunes E. Metformin attenuates the exacerbation of the allergic eosinophilic inflammation in high fat-diet–induced obesity in mice. PLoS One 2013;8:e76786. |
| 45 . | Fujimura KE, Lynch SV. Microbiota in allergy and asthma and the emerging relationship with the gut microbiome. Cell Host Microbe 2015;17:592–602. |
| 46 . | Cho I, Blaser MJ. The human microbiome: at the interface of health and disease. Nat Rev Genet 2012;13:260–270. |
| 47 . | Riiser A. The human microbiome, asthma, and allergy. Allergy Asthma Clin Immunol 2015;11:35. |
| 48 . | Islam MN, Das SR, Emin MT, Wei M, Sun L, Westphalen K, Rowlands DJ, Quadri SK, Bhattacharya S, Bhattacharya J. Mitochondrial transfer from bone-marrow–derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med 2012;18:759–765. |
| 49 . | Ahmad T, Mukherjee S, Pattnaik B, Kumar M, Singh S, Kumar M, Rehman R, Tiwari BK, Jha KA, Barhanpurkar AP, et al. Miro1 regulates intercellular mitochondrial transport & enhances mesenchymal stem cell rescue efficacy. EMBO J 2014;33:994–1010. |
| 50 . | Matsushita K. Mesenchymal stem cells and metabolic syndrome: current understanding and potential clinical implications. Stem Cells Int 2016;2016: 2892840. |
Author Contributions: N.K.B. contributed towards writing the review, revising the content, and making the schematic diagrams. A.A. contributed towards writing and revision of the content, and final approval of the submitted manuscript.
Author disclosures are available with the text of this article at www.atsjournals.org.
