Comprehensive Physiology Wiley Online Library

Oxidative Stress in Pulmonary Fibrosis

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Abstract

Oxidative stress has been linked to various disease states as well as physiological aging. The lungs are uniquely exposed to a highly oxidizing environment and have evolved several mechanisms to attenuate oxidative stress. Idiopathic pulmonary fibrosis (IPF) is a progressive age‐related disorder that leads to architectural remodeling, impaired gas exchange, respiratory failure, and death. In this article, we discuss cellular sources of oxidant production, and antioxidant defenses, both enzymatic and nonenzymatic. We outline the current understanding of the pathogenesis of IPF and how oxidative stress contributes to fibrosis. Further, we link oxidative stress to the biology of aging that involves DNA damage responses, loss of proteostasis, and mitochondrial dysfunction. We discuss the recent findings on the role of reactive oxygen species (ROS) in specific fibrotic processes such as macrophage polarization and immunosenescence, alveolar epithelial cell apoptosis and senescence, myofibroblast differentiation and senescence, and alterations in the acellular extracellular matrix. Finally, we provide an overview of the current preclinical studies and clinical trials targeting oxidative stress in fibrosis and potential new strategies for future therapeutic interventions. © 2020 American Physiological Society. Compr Physiol 10:509‐547, 2020.

Figure 1. Figure 1. Intracellular sources of reactive oxygen species/reactive nitrogen species. Mitochondrial electron transport chain (ETC) is a major source of intracellular reactive oxygen species (ROS). Endoplasmic reticulum (ER) is also a significant producer of ROS during normal protein folding as well as under conditions of ER stress and unfolded protein response. Peroxisomes are source of H2O2 that is subsequently utilized by the enzyme catalase for substrate oxidation. NADPH oxidases (NOXes) and dual oxidases (DUOXes) are multicomponent enzymes that produce O2 and H2O2. While NOX4 is constitutively active, other NOXes require several cytosolic subunits such as Rac1, p40phox, p67phox, and p47phox for activation. The activation of DUOXes and NOX5 is calcium dependent. NO⋅ is produced by nitric oxide synthetase (NOS) isoforms. NO⋅ production is limited by the availability of molecular oxygen, l‐arginine, and cofactor tetrahydrobiopterin (BH4). Arginase utilizes arginine for ornithine synthesis in urea cycle and thus decreases its availability for NO⋅ synthesis. Under conditions of arginine deficiency, NOS uncouples and produces O2.
Figure 2. Figure 2. Cellular detoxification mechanisms. Glutathione peroxidase (GPx) utilizes GSH to detoxify peroxides and leads to the formation of oxidized glutathione (GSSG) as a by‐product. GSSG is reduced back to GSH by glutathione reductase. Peroxiredoxins (PRx) also participate in peroxide detoxification. Thioredoxins (Trx) are part of cellular antioxidant system that reduces disulfide bridges in target proteins. Glutathione‐S‐transferases (GST) and glutaredoxins (Glrx) participate in protein glutathionylation and deglutathionylation, respectively. Heme oxygenase (HO) and peroxisomal catalase further aid in the detoxification of intracellular ROS. Superoxide dismutase (SOD) catalyzes dismutation of O2 to H2O2 in mitochondria (Mn‐SOD), cytosol, nucleus, and mitochondrial intermembrane space (Cu,Zn‐SOD) and extracellularly (EC‐SOD). Oxidative stress triggers nuclear translocation of transcription factor Nrf2 and activation of antioxidant response element (ARE) or target antioxidant genes, coordinating antioxidant responses.
Figure 3. Figure 3. Cellular sources of reactive oxygen species/reactive nitrogen species in lung. Macrophages and neutrophils generate reactive oxygen species (ROS) during oxidative burst through NADPH oxidase 2 (NOX2) activation in response to pathogens. NOX4 contributes to constitutive ROS production in various cells. Additionally, macrophages and neutrophils are major source of nitric oxide (NO⋅) through neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS). ONOO forms inside phagosomes and facilitates bacterial killing. Ciliated bronchial epithelial cells (BECs) express dual oxidase 1 and 2 (DUOX1 and DUOX2). Alveolar epithelial cells type 2 (AEC2) express DUOX1; however, DUOX2, NOX1, and NOX4 might be expressed under pathological conditions. Fibroblasts mainly produce H2O2 through NOX4 induction. NOX2, 4, and 5 and xanthine oxidase (XO) are the main sources of ROS in lung endothelium, while endothelial nitric oxide synthase (eNOS) is the main producer of NO⋅. NOX1, 2, 4, and 5 and XO also contribute to ROS production in vascular smooth muscle. Furthermore, mitochondrial reactive oxygen species (mtROS) and endoplasmic reticulum stress likely contribute to oxidative damage in several cell types in the lung.
Figure 4. Figure 4. Fibrosis immunopathogenesis. Pro‐inflammatory macrophage phenotype polarizes from naïve macrophages after priming by interferon‐γ (IFN‐γ) upon stimulation by lipopolysaccharide (LPS) and tumor necrosis factor α (TNF‐α). Pro‐inflammatory macrophages mediate initial inflammatory phase of the immune response, and are characterized by production of high levels of reactive oxygen species (ROS), pro‐inflammatory cytokines, and stimulation of Th‐1 cytotoxic response. Pro‐fibrotic macrophage phenotype is mediated by transforming growth factor β1 (TGF‐β1) and interleukins (IL) IL‐10, IL‐4, and IL‐13. Mitochondrial ROS and endoplasmic reticulum stress might contribute to pro‐fibrotic phenotype of macrophages. Pro‐fibrotic macrophages have low cytotoxic properties and mediate fibrotic phase of injury response through production of pro‐fibrotic mediators TGF‐β1, platelet‐derived growth factor (PDGF), CCL‐18, and tissue inhibitor of metalloproteinase (TIMP).
Figure 5. Figure 5. Epithelium in the pathogenesis of pulmonary fibrosis. Genetic predisposition and aging contribute to susceptibility of alveolar epithelial cells (AECs) to injury, toxins, and oxidative stress. Epithelial cell apoptosis and senescence contribute to fibrosis by impeding reepithelialization, secretion of pro‐fibrotic cytokines, and senescence‐associated secretory phenotype (SASP). Transforming growth factor β1 (TGF‐β1), mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and NADPH oxidase 4 (NOX4) upregulation stimulate AEC apoptosis. TGF‐β1 and downregulation of sirtuin 1 (SIRT1) participate in regulation of AEC senescence. TGF‐β1 also mediates epithelial‐mesenchymal transition.
Figure 6. Figure 6. Mesenchyme in pathogenesis of pulmonary fibrosis. Fibroblast activation, fibroblast‐to‐myofibroblast differentiation, and increased extracellular matrix (ECM) deposition are central to progression of pulmonary fibrosis. Transforming growth factor β1 (TGF‐β1), mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and inadequate peroxisome function all stimulate fibroblast‐to‐myofibroblast differentiation. TGF‐β1 is secreted by macrophages and alveolar epithelial cells (AECs) as part of inactive complex associated with latency‐associated peptide (LAP) and latent TGF‐β‐binding protein (LTBP) and can be activated by mechanical forces, low pH, matrix metalloproteinases (MMPs), integrins, and oxidative stress. TGF‐β1 mediates myofibroblast differentiation through NOX4 upregulation and H2O2 production. H2O2 from activated myofibroblasts contributes to oxidative ECM fragmentation and dityrosine cross‐linking. CCN1 enhances TGF‐β1 signaling, while sirtuin 3 (SIRT3) attenuates it. Nrf2/NOX4 imbalance leads to myofibroblast senescence and apoptosis resistance, resulting in fibrosis persistence.
Figure 7. Figure 7. Therapeutic targets in pulmonary fibrosis. Senescence, immune responses, mitochondrial dysfunction, and dysregulated proteostasis are new targets in pulmonary fibrosis treatment. Reactive oxygen species (ROS) scavengers and drugs targeting redox imbalance might be other viable strategies. Abbreviations: PAI‐1, plasminogen activator 1; SASP, senescence‐associated secretory phenotype; MMPs, matrix metalloproteinasis; 4‐PBA, 4‐phenyl butyric acid; MSCs, mesenchymal stem cells; NOX4, NADPH oxidase 4; SOD, superoxide dismutase; SIRT, sirtuin; IL, interleukin.


Figure 1. Intracellular sources of reactive oxygen species/reactive nitrogen species. Mitochondrial electron transport chain (ETC) is a major source of intracellular reactive oxygen species (ROS). Endoplasmic reticulum (ER) is also a significant producer of ROS during normal protein folding as well as under conditions of ER stress and unfolded protein response. Peroxisomes are source of H2O2 that is subsequently utilized by the enzyme catalase for substrate oxidation. NADPH oxidases (NOXes) and dual oxidases (DUOXes) are multicomponent enzymes that produce O2 and H2O2. While NOX4 is constitutively active, other NOXes require several cytosolic subunits such as Rac1, p40phox, p67phox, and p47phox for activation. The activation of DUOXes and NOX5 is calcium dependent. NO⋅ is produced by nitric oxide synthetase (NOS) isoforms. NO⋅ production is limited by the availability of molecular oxygen, l‐arginine, and cofactor tetrahydrobiopterin (BH4). Arginase utilizes arginine for ornithine synthesis in urea cycle and thus decreases its availability for NO⋅ synthesis. Under conditions of arginine deficiency, NOS uncouples and produces O2.


Figure 2. Cellular detoxification mechanisms. Glutathione peroxidase (GPx) utilizes GSH to detoxify peroxides and leads to the formation of oxidized glutathione (GSSG) as a by‐product. GSSG is reduced back to GSH by glutathione reductase. Peroxiredoxins (PRx) also participate in peroxide detoxification. Thioredoxins (Trx) are part of cellular antioxidant system that reduces disulfide bridges in target proteins. Glutathione‐S‐transferases (GST) and glutaredoxins (Glrx) participate in protein glutathionylation and deglutathionylation, respectively. Heme oxygenase (HO) and peroxisomal catalase further aid in the detoxification of intracellular ROS. Superoxide dismutase (SOD) catalyzes dismutation of O2 to H2O2 in mitochondria (Mn‐SOD), cytosol, nucleus, and mitochondrial intermembrane space (Cu,Zn‐SOD) and extracellularly (EC‐SOD). Oxidative stress triggers nuclear translocation of transcription factor Nrf2 and activation of antioxidant response element (ARE) or target antioxidant genes, coordinating antioxidant responses.


Figure 3. Cellular sources of reactive oxygen species/reactive nitrogen species in lung. Macrophages and neutrophils generate reactive oxygen species (ROS) during oxidative burst through NADPH oxidase 2 (NOX2) activation in response to pathogens. NOX4 contributes to constitutive ROS production in various cells. Additionally, macrophages and neutrophils are major source of nitric oxide (NO⋅) through neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS). ONOO forms inside phagosomes and facilitates bacterial killing. Ciliated bronchial epithelial cells (BECs) express dual oxidase 1 and 2 (DUOX1 and DUOX2). Alveolar epithelial cells type 2 (AEC2) express DUOX1; however, DUOX2, NOX1, and NOX4 might be expressed under pathological conditions. Fibroblasts mainly produce H2O2 through NOX4 induction. NOX2, 4, and 5 and xanthine oxidase (XO) are the main sources of ROS in lung endothelium, while endothelial nitric oxide synthase (eNOS) is the main producer of NO⋅. NOX1, 2, 4, and 5 and XO also contribute to ROS production in vascular smooth muscle. Furthermore, mitochondrial reactive oxygen species (mtROS) and endoplasmic reticulum stress likely contribute to oxidative damage in several cell types in the lung.


Figure 4. Fibrosis immunopathogenesis. Pro‐inflammatory macrophage phenotype polarizes from naïve macrophages after priming by interferon‐γ (IFN‐γ) upon stimulation by lipopolysaccharide (LPS) and tumor necrosis factor α (TNF‐α). Pro‐inflammatory macrophages mediate initial inflammatory phase of the immune response, and are characterized by production of high levels of reactive oxygen species (ROS), pro‐inflammatory cytokines, and stimulation of Th‐1 cytotoxic response. Pro‐fibrotic macrophage phenotype is mediated by transforming growth factor β1 (TGF‐β1) and interleukins (IL) IL‐10, IL‐4, and IL‐13. Mitochondrial ROS and endoplasmic reticulum stress might contribute to pro‐fibrotic phenotype of macrophages. Pro‐fibrotic macrophages have low cytotoxic properties and mediate fibrotic phase of injury response through production of pro‐fibrotic mediators TGF‐β1, platelet‐derived growth factor (PDGF), CCL‐18, and tissue inhibitor of metalloproteinase (TIMP).


Figure 5. Epithelium in the pathogenesis of pulmonary fibrosis. Genetic predisposition and aging contribute to susceptibility of alveolar epithelial cells (AECs) to injury, toxins, and oxidative stress. Epithelial cell apoptosis and senescence contribute to fibrosis by impeding reepithelialization, secretion of pro‐fibrotic cytokines, and senescence‐associated secretory phenotype (SASP). Transforming growth factor β1 (TGF‐β1), mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and NADPH oxidase 4 (NOX4) upregulation stimulate AEC apoptosis. TGF‐β1 and downregulation of sirtuin 1 (SIRT1) participate in regulation of AEC senescence. TGF‐β1 also mediates epithelial‐mesenchymal transition.


Figure 6. Mesenchyme in pathogenesis of pulmonary fibrosis. Fibroblast activation, fibroblast‐to‐myofibroblast differentiation, and increased extracellular matrix (ECM) deposition are central to progression of pulmonary fibrosis. Transforming growth factor β1 (TGF‐β1), mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and inadequate peroxisome function all stimulate fibroblast‐to‐myofibroblast differentiation. TGF‐β1 is secreted by macrophages and alveolar epithelial cells (AECs) as part of inactive complex associated with latency‐associated peptide (LAP) and latent TGF‐β‐binding protein (LTBP) and can be activated by mechanical forces, low pH, matrix metalloproteinases (MMPs), integrins, and oxidative stress. TGF‐β1 mediates myofibroblast differentiation through NOX4 upregulation and H2O2 production. H2O2 from activated myofibroblasts contributes to oxidative ECM fragmentation and dityrosine cross‐linking. CCN1 enhances TGF‐β1 signaling, while sirtuin 3 (SIRT3) attenuates it. Nrf2/NOX4 imbalance leads to myofibroblast senescence and apoptosis resistance, resulting in fibrosis persistence.


Figure 7. Therapeutic targets in pulmonary fibrosis. Senescence, immune responses, mitochondrial dysfunction, and dysregulated proteostasis are new targets in pulmonary fibrosis treatment. Reactive oxygen species (ROS) scavengers and drugs targeting redox imbalance might be other viable strategies. Abbreviations: PAI‐1, plasminogen activator 1; SASP, senescence‐associated secretory phenotype; MMPs, matrix metalloproteinasis; 4‐PBA, 4‐phenyl butyric acid; MSCs, mesenchymal stem cells; NOX4, NADPH oxidase 4; SOD, superoxide dismutase; SIRT, sirtuin; IL, interleukin.
References
 1.Abdelmohsen K, Gorospe M. Noncoding RNA control of cellular senescence. Wiley Interdiscip Rev RNA 6: 615‐629, 2015.
 2.Aesif SW, Anathy V, Kuipers I, Guala AS, Reiss JN, Ho YS, Janssen‐Heininger YM. Ablation of glutaredoxin‐1 attenuates lipopolysaccharide‐induced lung inflammation and alveolar macrophage activation. Am J Respir Cell Mol Biol 44: 491‐499, 2011.
 3.Akamata K, Wei J, Bhattacharyya M, Cheresh P, Bonner MY, Arbiser JL, Raparia K, Gupta MP, Kamp DW, Varga J. SIRT3 is attenuated in systemic sclerosis skin and lungs, and its pharmacologic activation mitigates organ fibrosis. Oncotarget 7: 69321‐69336, 2016.
 4.Alder JK, Barkauskas CE, Limjunyawong N, Stanley SE, Kembou F, Tuder RM, Hogan BL, Mitzner W, Armanios M. Telomere dysfunction causes alveolar stem cell failure. Proc Natl Acad Sci U S A 112: 5099‐5104, 2015.
 5.Alder JK, Chen JJ, Lancaster L, Danoff S, Su SC, Cogan JD, Vulto I, Xie M, Qi X, Tuder RM, Phillips JA 3rd, Lansdorp PM, Loyd JE, Armanios MY. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc Natl Acad Sci U S A 105: 13051‐13056, 2008.
 6.Alderton WK, Cooper CE, Knowles RG. Nitric oxide synthases: Structure, function and inhibition. Biochem J 357: 593‐615, 2001.
 7.Alfadda AA, Sallam RM. Reactive oxygen species in health and disease. J Biomed Biotechnol 2012: 936486, 2012.
 8.Allen JT, Spiteri MA. Growth factors in idiopathic pulmonary fibrosis: Relative roles. Respir Res 3: 13, 2002.
 9.Allen RG, Keogh BP, Gerhard GS, Pignolo R, Horton J, Cristofalo VJ. Expression and regulation of superoxide dismutase activity in human skin fibroblasts from donors of different ages. J Cell Physiol 165: 576‐587, 1995.
 10.Allen RJ, Porte J, Braybrooke R, Flores C, Fingerlin TE, Oldham JM, Guillen‐Guio B, Ma SF, Okamoto T, John AE, Obeidat M, Yang IV, Henry A, Hubbard RB, Navaratnam V, Saini G, Thompson N, Booth HL, Hart SP, Hill MR, Hirani N, Maher TM, McAnulty RJ, Millar AB, Molyneaux PL, Parfrey H, Rassl DM, Whyte MKB, Fahy WA, Marshall RP, Oballa E, Bosse Y, Nickle DC, Sin DD, Timens W, Shrine N, Sayers I, Hall IP, Noth I, Schwartz DA, Tobin MD, Wain LV, Jenkins RG. Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: A genome‐wide association study. Lancet Respir Med 5: 869‐880, 2017.
 11.Almolki A, Taille C, Martin GF, Jose PJ, Zedda C, Conti M, Megret J, Henin D, Aubier M, Boczkowski J. Heme oxygenase attenuates allergen‐induced airway inflammation and hyperreactivity in guinea pigs. Am J Physiol Lung Cell Mol Physiol 287: L26‐L34, 2004.
 12.Alvarez D, Cardenes N, Sellares J, Bueno M, Corey C, Hanumanthu VS, Peng Y, D'Cunha H, Sembrat J, Nouraie M, Shanker S, Caufield C, Shiva S, Armanios M, Mora AL, Rojas M. IPF lung fibroblasts have a senescent phenotype. Am J Physiol Lung Cell Mol Physiol 313: L1164‐L1173, 2017.
 13.Amara N, Goven D, Prost F, Muloway R, Crestani B, Boczkowski J. NOX4/NADPH oxidase expression is increased in pulmonary fibroblasts from patients with idiopathic pulmonary fibrosis and mediates TGFbeta1‐induced fibroblast differentiation into myofibroblasts. Thorax 65: 733‐738, 2010.
 14.Ameziane‐El‐Hassani R, Morand S, Boucher JL, Frapart YM, Apostolou D, Agnandji D, Gnidehou S, Ohayon R, Noel‐Hudson MS, Francon J, Lalaoui K, Virion A, Dupuy C. Dual oxidase‐2 has an intrinsic Ca2+‐dependent H2O2‐generating activity. J Biol Chem 280: 30046‐30054, 2005.
 15.Anathy V, Aesif SW, Guala AS, Havermans M, Reynaert NL, Ho YS, Budd RC, Janssen‐Heininger YM. Redox amplification of apoptosis by caspase‐dependent cleavage of glutaredoxin 1 and S‐glutathionylation of Fas. J Cell Biol 184: 241‐252, 2009.
 16.Anathy V, Lahue KG, Chapman DG, Chia SB, Casey DT, Aboushousha R, van der Velden JLJ, Elko E, Hoffman SM, McMillan DH, Jones JT, Nolin JD, Abdalla S, Schneider R, Seward DJ, Roberson EC, Liptak MD, Cousins ME, Butnor KJ, Taatjes DJ, Budd RC, Irvin CG, Ho YS, Hakem R, Brown KK, Matsui R, Bachschmid MM, Gomez JL, Kaminski N, van der Vliet A, Janssen‐Heininger YMW. Reducing protein oxidation reverses lung fibrosis. Nat Med 24: 1128‐1135, 2018.
 17.Aoshiba K, Yasui S, Tamaoki J, Nagai A. The Fas/Fas‐ligand system is not required for bleomycin‐induced pulmonary fibrosis in mice. Am J Respir Crit Care Med 162: 695‐700, 2000.
 18.Aquino‐Galvez A, Gonzalez‐Avila G, Perez‐Rodriguez M, Partida‐Rodriguez O, Nieves‐Ramirez M, Pina‐Ramirez I, Ramirez‐Martinez G, Castillejos‐Lopez M, Checa M, Ruiz V, Urrea F, Sommer B, Zuniga J, Selman M. Analysis of heat shock protein 70 gene polymorphisms Mexican patients with idiopathic pulmonary fibrosis. BMC Pulm Med 15: 129, 2015.
 19.Araya J, Kojima J, Takasaka N, Ito S, Fujii S, Hara H, Yanagisawa H, Kobayashi K, Tsurushige C, Kawaishi M, Kamiya N, Hirano J, Odaka M, Morikawa T, Nishimura SL, Kawabata Y, Hano H, Nakayama K, Kuwano K. Insufficient autophagy in idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 304: L56‐L69, 2013.
 20.Armanios M. Telomeres and age‐related disease: How telomere biology informs clinical paradigms. J Clin Invest 123: 996‐1002, 2013.
 21.Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, Lawson WE, Xie M, Vulto I, Phillips JA 3rd, Lansdorp PM, Greider CW, Loyd JE. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med 356: 1317‐1326, 2007.
 22.Arsalane K, Dubois CM, Muanza T, Begin R, Boudreau F, Asselin C, Cantin AM. Transforming growth factor‐beta1 is a potent inhibitor of glutathione synthesis in the lung epithelial cell line A549: Transcriptional effect on the GSH rate‐limiting enzyme gamma‐glutamylcysteine synthetase. Am J Respir Cell Mol Biol 17: 599‐607, 1997.
 23.Atzori L, Chua F, Dunsmore SE, Willis D, Barbarisi M, McAnulty RJ, Laurent GJ. Attenuation of bleomycin induced pulmonary fibrosis in mice using the heme oxygenase inhibitor Zn‐deuteroporphyrin IX‐2,4‐bisethylene glycol. Thorax 59: 217‐223, 2004.
 24.Avissar N, Finkelstein JN, Horowitz S, Willey JC, Coy E, Frampton MW, Watkins RH, Khullar P, Xu YL, Cohen HJ. Extracellular glutathione peroxidase in human lung epithelial lining fluid and in lung cells. Am J Phys 270: L173‐L182, 1996.
 25.Baek HA, Kim DS, Park HS, Jang KY, Kang MJ, Lee DG, Moon WS, Chae HJ, Chung MJ. Involvement of endoplasmic reticulum stress in myofibroblastic differentiation of lung fibroblasts. Am J Respir Cell Mol Biol 46: 731‐739, 2012.
 26.Bai G, Hock TD, Logsdon N, Zhou Y, Thannickal VJ. A far‐upstream AP‐1/Smad binding box regulates human NOX4 promoter activation by transforming growth factor‐beta. Gene 540: 62‐67, 2014.
 27.Baig MS, Zaichick SV, Mao M, de Abreu AL, Bakhshi FR, Hart PC, Saqib U, Deng J, Chatterjee S, Block ML, Vogel SM, Malik AB, Consolaro ME, Christman JW, Minshall RD, Gantner BN, Bonini MG. NOS1‐derived nitric oxide promotes NF‐kappaB transcriptional activity through inhibition of suppressor of cytokine signaling‐1. J Exp Med 212: 1725‐1738, 2015.
 28.Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM. Clearance of p16Ink4a‐positive senescent cells delays ageing‐associated disorders. Nature 479: 232‐236, 2011.
 29.Bakin AV, Stourman NV, Sekhar KR, Rinehart C, Yan X, Meredith MJ, Arteaga CL, Freeman ML. Smad3‐ATF3 signaling mediates TGF‐beta suppression of genes encoding Phase II detoxifying proteins. Free Radic Biol Med 38: 375‐387, 2005.
 30.Balch WE, Morimoto RI, Dillin A, Kelly JW. Adapting proteostasis for disease intervention. Science 319: 916‐919, 2008.
 31.Baldwin SR, Simon RH, Grum CM, Ketai LH, Boxer LA, Devall LJ. Oxidant activity in expired breath of patients with adult respiratory distress syndrome. Lancet 1: 11‐14, 1986.
 32.Ballinger CA, Mendis‐Handagama C, Kalmar JR, Arnold RR, Kinkade JM Jr. Changes in the localization of catalase during differentiation of neutrophilic granulocytes. Blood 83: 2654‐2668, 1994.
 33.Ballinger MN, Newstead MW, Zeng X, Bhan U, Mo XM, Kunkel SL, Moore BB, Flavell R, Christman JW, Standiford TJ. IRAK‐M promotes alternative macrophage activation and fibroproliferation in bleomycin‐induced lung injury. J Immunol 194: 1894‐1904, 2015.
 34.Bando M, Hosono T, Mato N, Nakaya T, Yamasawa H, Ohno S, Sugiyama Y. Long‐term efficacy of inhaled N‐acetylcysteine in patients with idiopathic pulmonary fibrosis. Intern Med 49: 2289‐2296, 2010.
 35.Banfi B, Molnar G, Maturana A, Steger K, Hegedus B, Demaurex N, Krause KH. A Ca(2+)‐activated NADPH oxidase in testis, spleen, and lymph nodes. J Biol Chem 276: 37594‐37601, 2001.
 36.Banfi B, Tirone F, Durussel I, Knisz J, Moskwa P, Molnar GZ, Krause KH, Cox JA. Mechanism of Ca2+ activation of the NADPH oxidase 5 (NOX5). J Biol Chem 279: 18583‐18591, 2004.
 37.Bao S, Wang Y, Sweeney P, Chaudhuri A, Doseff AI, Marsh CB, Knoell DL. Keratinocyte growth factor induces Akt kinase activity and inhibits Fas‐mediated apoptosis in A549 lung epithelial cells. Am J Physiol Lung Cell Mol Physiol 288: L36‐L42, 2005.
 38.Barcellos‐Hoff MH, Dix TA. Redox‐mediated activation of latent transforming growth factor‐beta 1. Mol Endocrinol 10: 1077‐1083, 1996.
 39.Bartel DP. MicroRNAs: Target recognition and regulatory functions. Cell 136: 215‐233, 2009.
 40.Baumann O, Walz B. Endoplasmic reticulum of animal cells and its organization into structural and functional domains. Int Rev Cytol 205: 149‐214, 2001.
 41.Baumgartner KB, Samet JM, Coultas DB, Stidley CA, Hunt WC, Colby TV, Waldron JA. Occupational and environmental risk factors for idiopathic pulmonary fibrosis: A multicenter case‐control study. Collaborating Centers. Am J Epidemiol 152: 307‐315, 2000.
 42.Baumgartner KB, Samet JM, Stidley CA, Colby TV, Waldron JA. Cigarette smoking: A risk factor for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 155: 242‐248, 1997.
 43.Beach TA, Johnston CJ, Groves AM, Williams JP, Finkelstein JN. Radiation induced pulmonary fibrosis as a model of progressive fibrosis: Contributions of DNA damage, inflammatory response and cellular senescence genes. Exp Lung Res 43: 134‐149, 2017.
 44.Beausejour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P, Campisi J. Reversal of human cellular senescence: Roles of the p53 and p16 pathways. EMBO J 22: 4212‐4222, 2003.
 45.Bedard K, Krause KH. The NOX family of ROS‐generating NADPH oxidases: Physiology and pathophysiology. Physiol Rev 87: 245‐313, 2007.
 46.Beeh KM, Beier J, Haas IC, Kornmann O, Micke P, Buhl R. Glutathione deficiency of the lower respiratory tract in patients with idiopathic pulmonary fibrosis. Eur Respir J 19: 1119‐1123, 2002.
 47.BelAiba RS, Djordjevic T, Petry A, Diemer K, Bonello S, Banfi B, Hess J, Pogrebniak A, Bickel C, Gorlach A. NOX5 variants are functionally active in endothelial cells. Free Radic Biol Med 42: 446‐459, 2007.
 48.Bell JT, Tsai PC, Yang TP, Pidsley R, Nisbet J, Glass D, Mangino M, Zhai G, Zhang F, Valdes A, Shin SY, Dempster EL, Murray RM, Grundberg E, Hedman AK, Nica A, Small KS, Mu TC, Dermitzakis ET, McCarthy MI, Mill J, Spector TD, Deloukas P. Epigenome‐wide scans identify differentially methylated regions for age and age‐related phenotypes in a healthy ageing population. PLoS Genet 8: e1002629, 2012.
 49.Bellocq A, Azoulay E, Marullo S, Flahault A, Fouqueray B, Philippe C, Cadranel J, Baud L. Reactive oxygen and nitrogen intermediates increase transforming growth factor‐beta1 release from human epithelial alveolar cells through two different mechanisms. Am J Respir Cell Mol Biol 21: 128‐136, 1999.
 50.Berend N. Inhibition of bleomycin lung toxicity by N‐acetyl cysteine in the rat. Pathology 17: 108‐110, 1985.
 51.Berggren M, Gallegos A, Gasdaska JR, Gasdaska PY, Warneke J, Powis G. Thioredoxin and thioredoxin reductase gene expression in human tumors and cell lines, and the effects of serum stimulation and hypoxia. Anticancer Res 16: 3459‐3466, 1996.
 52.Bernard K, Hecker L, Luckhardt TR, Cheng G, Thannickal VJ. NADPH oxidases in lung health and disease. Antioxid Redox Signal 20: 2838‐2853, 2014.
 53.Bernard K, Logsdon NJ, Miguel V, Benavides GA, Zhang J, Carter AB, Darley‐Usmar VM, Thannickal VJ. NADPH oxidase 4 (Nox4) suppresses mitochondrial biogenesis and bioenergetics in lung fibroblasts via a nuclear factor erythroid‐derived 2‐like 2 (Nrf2)‐dependent pathway. J Biol Chem 292: 3029‐3038, 2017.
 54.Bhandary YP, Shetty SK, Marudamuthu AS, Ji HL, Neuenschwander PF, Boggaram V, Morris GF, Fu J, Idell S, Shetty S. Regulation of lung injury and fibrosis by p53‐mediated changes in urokinase and plasminogen activator inhibitor‐1. Am J Pathol 183: 131‐143, 2013.
 55.Bild W, Ciobica A, Padurariu M, Bild V. The interdependence of the reactive species of oxygen, nitrogen, and carbon. J Physiol Biochem 69: 147‐154, 2013.
 56.Bindu S, Pillai VB, Kanwal A, Samant S, Mutlu GM, Verdin E, Dulin N, Gupta MP. SIRT3 blocks myofibroblast differentiation and pulmonary fibrosis by preventing mitochondrial DNA damage. Am J Physiol Lung Cell Mol Physiol 312: L68‐L78, 2017.
 57.Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O. Oxidative stress and antioxidant defense. World Allergy Organ J 5: 9‐19, 2012.
 58.Black D, Lyman S, Qian T, Lemasters JJ, Rippe RA, Nitta T, Kim JS, Behrns KE. Transforming growth factor beta mediates hepatocyte apoptosis through Smad3 generation of reactive oxygen species. Biochimie 89: 1464‐1473, 2007.
 59.Board PG, Menon D. Glutathione transferases, regulators of cellular metabolism and physiology. Biochim Biophys Acta 1830: 3267‐3288, 2013.
 60.Bondy SC, Naderi S. Contribution of hepatic cytochrome P450 systems to the generation of reactive oxygen species. Biochem Pharmacol 48: 155‐159, 1994.
 61.Bowler RP, Nicks M, Tran K, Tanner G, Chang LY, Young SK, Worthen GS. Extracellular superoxide dismutase attenuates lipopolysaccharide‐induced neutrophilic inflammation. Am J Respir Cell Mol Biol 31: 432‐439, 2004.
 62.Bowler RP, Nicks M, Warnick K, Crapo JD. Role of extracellular superoxide dismutase in bleomycin‐induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 282: L719‐L726, 2002.
 63.Brady TC, Chang LY, Day BJ, Crapo JD. Extracellular superoxide dismutase is upregulated with inducible nitric oxide synthase after NF‐kappa B activation. Am J Phys 273: L1002‐L1006, 1997.
 64.Bratic A, Larsson NG. The role of mitochondria in aging. J Clin Invest 123: 951‐957, 2013.
 65.Bravo R, Parra V, Gatica D, Rodriguez AE, Torrealba N, Paredes F, Wang ZV, Zorzano A, Hill JA, Jaimovich E, Quest AF, Lavandero S. Endoplasmic reticulum and the unfolded protein response: Dynamics and metabolic integration. Int Rev Cell Mol Biol 301: 215‐290, 2013.
 66.Brigelius‐Flohe R, Maiorino M. Glutathione peroxidases. Biochim Biophys Acta 1830: 3289‐3303, 2013.
 67.Briones AM, Tabet F, Callera GE, Montezano AC, Yogi A, He Y, Quinn MT, Salaices M, Touyz RM. Differential regulation of Nox1, Nox2 and Nox4 in vascular smooth muscle cells from WKY and SHR. J Am Soc Hypertens 5: 137‐153, 2011.
 68.Brune B, Dehne N, Grossmann N, Jung M, Namgaladze D, Schmid T, von Knethen A, Weigert A. Redox control of inflammation in macrophages. Antioxid Redox Signal 19: 595‐637, 2013.
 69.Bu H, Wedel S, Cavinato M, Jansen‐Durr P. MicroRNA regulation of oxidative stress‐induced cellular senescence. Oxidative Med Cell Longev 2017: 2398696, 2017.
 70.Budinger GR, Mutlu GM, Eisenbart J, Fuller AC, Bellmeyer AA, Baker CM, Wilson M, Ridge K, Barrett TA, Lee VY, Chandel NS. Proapoptotic Bid is required for pulmonary fibrosis. Proc Natl Acad Sci USA 103: 4604‐4609, 2006.
 71.Budinger GR, Mutlu GM, Urich D, Soberanes S, Buccellato LJ, Hawkins K, Chiarella SE, Radigan KA, Eisenbart J, Agrawal H, Berkelhamer S, Hekimi S, Zhang J, Perlman H, Schumacker PT, Jain M, Chandel NS. Epithelial cell death is an important contributor to oxidant‐mediated acute lung injury. Am J Respir Crit Care Med 183: 1043‐1054, 2011.
 72.Bueno M, Lai YC, Romero Y, Brands J, St Croix CM, Kamga C, Corey C, Herazo‐Maya JD, Sembrat J, Lee JS, Duncan SR, Rojas M, Shiva S, Chu CT, Mora AL. PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis. J Clin Invest 125: 521‐538, 2015.
 73.Buhling F, Wille A, Rocken C, Wiesner O, Baier A, Meinecke I, Welte T, Pap T. Altered expression of membrane‐bound and soluble CD95/Fas contributes to the resistance of fibrotic lung fibroblasts to FasL induced apoptosis. Respir Res 6: 37, 2005.
 74.Burman A, Kropski JA, Calvi CL, Serezani AP, Pascoalino BD, Han W, Sherrill T, Gleaves L, Lawson WE, Young LR, Blackwell TS, Tanjore H. Localized hypoxia links ER stress to lung fibrosis through induction of C/EBP homologous protein. JCI Insight 3, 2018.
 75.Byon CH, Heath JM, Chen Y. Redox signaling in cardiovascular pathophysiology: A focus on hydrogen peroxide and vascular smooth muscle cells. Redox Biol 9: 244‐253, 2016.
 76.Byrne AJ, Mathie SA, Gregory LG, Lloyd CM. Pulmonary macrophages: Key players in the innate defence of the airways. Thorax 70: 1189‐1196, 2015.
 77.Cabrera S, Gaxiola M, Arreola JL, Ramirez R, Jara P, D'Armiento J, Richards T, Selman M, Pardo A. Overexpression of MMP9 in macrophages attenuates pulmonary fibrosis induced by bleomycin. Int J Biochem Cell Biol 39: 2324‐2338, 2007.
 78.Calabrese G, Morgan B, Riemer J. Mitochondrial glutathione: Regulation and functions. Antioxid Redox Signal 27: 1162‐1177, 2017.
 79.Calhoun C, Shivshankar P, Saker M, Sloane LB, Livi CB, Sharp ZD, Orihuela CJ, Adnot S, White ES, Richardson A, Le Saux CJ. Senescent cells contribute to the physiological remodeling of aged lungs. J Gerontol A Biol Sci Med Sci 71: 153‐160, 2016.
 80.Camhi SL, Alam J, Otterbein L, Sylvester SL, Choi AM. Induction of heme oxygenase‐1 gene expression by lipopolysaccharide is mediated by AP‐1 activation. Am J Respir Cell Mol Biol 13: 387‐398, 1995.
 81.Campisi J. The biology of replicative senescence. Eur J Cancer 33: 703‐709, 1997.
 82.Canestaro WJ, Forrester SH, Raghu G, Ho L, Devine BE. Drug treatment of idiopathic pulmonary fibrosis: Systematic review and network meta‐analysis. Chest 149: 756‐766, 2016.
 83.Cantin AM, Hubbard RC, Crystal RG. Glutathione deficiency in the epithelial lining fluid of the lower respiratory tract in idiopathic pulmonary fibrosis. Am Rev Respir Dis 139: 370‐372, 1989.
 84.Cantin AM, North SL, Fells GA, Hubbard RC, Crystal RG. Oxidant‐mediated epithelial cell injury in idiopathic pulmonary fibrosis. J Clin Invest 79: 1665‐1673, 1987.
 85.Cao SS, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease. Antioxid Redox Signal 21: 396‐413, 2014.
 86.Carlsson LM, Jonsson J, Edlund T, Marklund SL. Mice lacking extracellular superoxide dismutase are more sensitive to hyperoxia. Proc Natl Acad Sci U S A 92: 6264‐6268, 1995.
 87.Carmona‐Cuenca I, Roncero C, Sancho P, Caja L, Fausto N, Fernandez M, Fabregat I. Upregulation of the NADPH oxidase NOX4 by TGF‐beta in hepatocytes is required for its pro‐apoptotic activity. J Hepatol 49: 965‐976, 2008.
 88.Carnesecchi S, Deffert C, Donati Y, Basset O, Hinz B, Preynat‐Seauve O, Guichard C, Arbiser JL, Banfi B, Pache JC, Barazzone‐Argiroffo C, Krause KH. A key role for NOX4 in epithelial cell death during development of lung fibrosis. Antioxid Redox Signal 15: 607‐619, 2011.
 89.Carnesecchi S, Deffert C, Pagano A, Garrido‐Urbani S, Metrailler‐Ruchonnet I, Schappi M, Donati Y, Matthay MA, Krause KH, Barazzone Argiroffo C. NADPH oxidase‐1 plays a crucial role in hyperoxia‐induced acute lung injury in mice. Am J Respir Crit Care Med 180: 972‐981, 2009.
 90.Carrillo MC, Nokubo M, Kitani K, Satoh K, Sato K. Age‐related alterations of enzyme activities and subunits of hepatic glutathione S‐transferases in male and female Fischer‐344 rats. Biochim Biophys Acta 1077: 325‐331, 1991.
 91.Case AJ, Li S, Basu U, Tian J, Zimmerman MC. Mitochondrial‐localized NADPH oxidase 4 is a source of superoxide in angiotensin II‐stimulated neurons. Am J Physiol Heart Circ Physiol 305: H19‐H28, 2013.
 92.Castro L, Freeman BA. Reactive oxygen species in human health and disease. Nutrition 17: 161, 163‐165, 2001.
 93.Cedergren J, Follin P, Forslund T, Lindmark M, Sundqvist T, Skogh T. Inducible nitric oxide synthase (NOS II) is constitutive in human neutrophils. APMIS 111: 963‐968, 2003.
 94.Chan K, Kan YW. Nrf2 is essential for protection against acute pulmonary injury in mice. Proc Natl Acad Sci U S A 96: 12731‐12736, 1999.
 95.Chanda D, Otoupalova E, Hough KP, Locy ML, Bernard K, Deshane JS, Sanderson RD, Mobley JA, Thannickal VJ. Fibronectin on the surface of extracellular vesicles mediates fibroblast invasion. Am J Respir Cell Mol Biol 60: 279‐288, 2019.
 96.Chandrasekaran A, Idelchik M, Melendez JA. Redox control of senescence and age‐related disease. Redox Biol 11: 91‐102, 2017.
 97.Chapman HA. Epithelial‐mesenchymal interactions in pulmonary fibrosis. Annu Rev Physiol 73: 413‐435, 2011.
 98.Chen K, Pittman RN, Popel AS. Nitric oxide in the vasculature: Where does it come from and where does it go? A quantitative perspective. Antioxid Redox Signal 10: 1185‐1198, 2008.
 99.Chen PM, Wu TC, Wang YC, Cheng YW, Sheu GT, Chen CY, Lee H. Activation of NF‐kappaB by SOD2 promotes the aggressiveness of lung adenocarcinoma by modulating NKX2‐1‐mediated IKKbeta expression. Carcinogenesis 34: 2655‐2663, 2013.
 100.Chen S, Novick P, Ferro‐Novick S. ER structure and function. Curr Opin Cell Biol 25: 428‐433, 2013.
 101.Chen X, Shi C, Meng X, Zhang K, Li X, Wang C, Xiang Z, Hu K, Han X. Inhibition of Wnt/beta‐catenin signaling suppresses bleomycin‐induced pulmonary fibrosis by attenuating the expression of TGF‐beta1 and FGF‐2. Exp Mol Pathol 101: 22‐30, 2016.
 102.Chen Y, Azad MB, Gibson SB. Superoxide is the major reactive oxygen species regulating autophagy. Cell Death Differ 16: 1040‐1052, 2009.
 103.Chen Y, Luo G, Yuan J, Wang Y, Yang X, Wang X, Li G, Liu Z, Zhong N. Vitamin C mitigates oxidative stress and tumor necrosis factor‐alpha in severe community‐acquired pneumonia and LPS‐induced macrophages. Mediat Inflamm 2014: 426740, 2014.
 104.Chen Z, Oberley TD, Ho Y, Chua CC, Siu B, Hamdy RC, Epstein CJ, Chua BH. Overexpression of CuZnSOD in coronary vascular cells attenuates myocardial ischemia/reperfusion injury. Free Radic Biol Med 29: 589‐596, 2000.
 105.Chen Z, S DSO, Zimnicka AM, Jiang Y, Sharma T, Chen S, Lazarov O, Bonini MG, Haus JM, Minshall RD. Reciprocal regulation of eNOS and caveolin‐1 functions in endothelial cells. Mol Biol Cell 29: 1190‐1202, 2018.
 106.Cheng G, Cao Z, Xu X, van Meir EG, Lambeth JD. Homologs of gp91phox: Cloning and tissue expression of Nox3, Nox4, and Nox5. Gene 269: 131‐140, 2001.
 107.Cheng G, Ritsick D, Lambeth JD. Nox3 regulation by NOXO1, p47phox, and p67phox. J Biol Chem 279: 34250‐34255, 2004.
 108.Cheresh P, Morales‐Nebreda L, Kim SJ, Yeldandi A, Williams DB, Cheng Y, Mutlu GM, Budinger GR, Ridge K, Schumacker PT, Bohr VA, Kamp DW. Asbestos‐induced pulmonary fibrosis is augmented in 8‐oxoguanine DNA glycosylase knockout mice. Am J Respir Cell Mol Biol 52: 25‐36, 2015.
 109.Childs BG, Durik M, Baker DJ, van Deursen JM. Cellular senescence in aging and age‐related disease: From mechanisms to therapy. Nat Med 21: 1424‐1435, 2015.
 110.Chilosi M, Doglioni C, Murer B, Poletti V. Epithelial stem cell exhaustion in the pathogenesis of idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffuse Lung Dis 27: 7‐18, 2010.
 111.Chin MP, Bakris GL, Block GA, Chertow GM, Goldsberry A, Inker LA, Heerspink HJL, O'Grady M, Pergola PE, Wanner C, Warnock DG, Meyer CJ. Bardoxolone methyl improves kidney function in patients with chronic kidney disease stage 4 and type 2 diabetes: Post‐Hoc analyses from bardoxolone methyl evaluation in patients with chronic kidney disease and type 2 diabetes study. Am J Nephrol 47: 40‐47, 2018.
 112.Choi MH, Lee IK, Kim GW, Kim BU, Han YH, Yu DY, Park HS, Kim KY, Lee JS, Choi C, Bae YS, Lee BI, Rhee SG, Kang SW. Regulation of PDGF signalling and vascular remodelling by peroxiredoxin II. Nature 435: 347‐353, 2005.
 113.Christou H, Morita T, Hsieh CM, Koike H, Arkonac B, Perrella MA, Kourembanas S. Prevention of hypoxia‐induced pulmonary hypertension by enhancement of endogenous heme oxygenase‐1 in the rat. Circ Res 86: 1224‐1229, 2000.
 114.Clempus RE, Sorescu D, Dikalova AE, Pounkova L, Jo P, Sorescu GP, Schmidt HH, Lassegue B, Griendling KK. Nox4 is required for maintenance of the differentiated vascular smooth muscle cell phenotype. Arterioscler Thromb Vasc Biol 27: 42‐48, 2007.
 115.Coker RK, Laurent GJ, Jeffery PK, du Bois RM, Black CM, McAnulty RJ. Localisation of transforming growth factor beta1 and beta3 mRNA transcripts in normal and fibrotic human lung. Thorax 56: 549‐556, 2001.
 116.Commoner B, Townsend J, Pake GE. Free radicals in biological materials. Nature 174: 689‐691, 1954.
 117.Correll KA, Edeen KE, Redente EF, Zemans RL, Edelman BL, Danhorn T, Curran‐Everett D, Mikels‐Vigdal A, Mason RJ. TGF beta inhibits HGF, FGF7, and FGF10 expression in normal and IPF lung fibroblasts. Physiol Rep 6: e13794, 2018.
 118.Coward WR, Watts K, Feghali‐Bostwick CA, Knox A, Pang L. Defective histone acetylation is responsible for the diminished expression of cyclooxygenase 2 in idiopathic pulmonary fibrosis. Mol Cell Biol 29: 4325‐4339, 2009.
 119.Craig VJ, Zhang L, Hagood JS, Owen CA. Matrix metalloproteinases as therapeutic targets for idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol 53: 585‐600, 2015.
 120.Cronkhite JT, Xing C, Raghu G, Chin KM, Torres F, Rosenblatt RL, Garcia CK. Telomere shortening in familial and sporadic pulmonary fibrosis. Am J Respir Crit Care Med 178: 729‐737, 2008.
 121.Cui H, Ge J, Xie N, Banerjee S, Zhou Y, Antony VB, Thannickal VJ, Liu G. miR‐34a inhibits lung fibrosis by inducing lung fibroblast senescence. Am J Respir Cell Mol Biol 56: 168‐178, 2017.
 122.Cui H, Ge J, Xie N, Banerjee S, Zhou Y, Liu RM, Thannickal VJ, Liu G. miR‐34a promotes fibrosis in aged lungs by inducing alveolarepithelial dysfunctions. Am J Physiol Lung Cell Mol Physiol 312: L415‐l424, 2017.
 123.Cullinan SB, Diehl JA. Coordination of ER and oxidative stress signaling: The PERK/Nrf2 signaling pathway. Int J Biochem Cell Biol 38: 317‐332, 2006.
 124.Cyr AR, Domann FE. The redox basis of epigenetic modifications: From mechanisms to functional consequences. Antioxid Redox Signal 15: 551‐589, 2011.
 125.d'Adda di Fagagna F, Reaper PM, Clay‐Farrace L, Fiegler H, Carr P, Von Zglinicki T, Saretzki G, Carter NP, Jackson SP. A DNA damage checkpoint response in telomere‐initiated senescence. Nature 426: 194‐198, 2003.
 126.de Zeeuw D, Akizawa T, Audhya P, Bakris GL, Chin M, Christ‐Schmidt H, Goldsberry A, Houser M, Krauth M, Lambers Heerspink HJ, McMurray JJ, Meyer CJ, Parving HH, Remuzzi G, Toto RD, Vaziri ND, Wanner C, Wittes J, Wrolstad D, Chertow GM, Investigators BT. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med 369: 2492‐2503, 2013.
 127.Deisseroth A, Dounce AL. Catalase: Physical and chemical properties, mechanism of catalysis, and physiological role. Physiol Rev 50: 319‐375, 1970.
 128.Delbrel E, Soumare A, Naguez A, Label R, Bernard O, Bruhat A, Fafournoux P, Tremblais G, Marchant D, Gille T, Bernaudin JF, Callard P, Kambouchner M, Martinod E, Valeyre D, Uzunhan Y, Planes C, Boncoeur E. HIF‐1alpha triggers ER stress and CHOP‐mediated apoptosis in alveolar epithelial cells, a key event in pulmonary fibrosis. Sci Rep 8: 17939, 2018.
 129.Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, Mitchell JR, Laberge RM, Vijg J, Van Steeg H, Dolle ME, Hoeijmakers JH, de Bruin A, Hara E, Campisi J. An essential role for senescent cells in optimal wound healing through secretion of PDGF‐AA. Dev Cell 31: 722‐733, 2014.
 130.Demedts M, Behr J, Buhl R, Costabel U, Dekhuijzen R, Jansen HM, MacNee W, Thomeer M, Wallaert B, Laurent F, Nicholson AG, Verbeken EK, Verschakelen J, Flower CD, Capron F, Petruzzelli S, De Vuyst P, van den Bosch JM, Rodriguez‐Becerra E, Corvasce G, Lankhorst I, Sardina M, Montanari M, Group IS. High‐dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 353: 2229‐2242, 2005.
 131.Dennery PA. Signaling function of heme oxygenase proteins. Antioxid Redox Signal 20: 1743‐1753, 2014.
 132.Desai LP, Zhou Y, Estrada AV, Ding Q, Cheng G, Collawn JF, Thannickal VJ. Negative regulation of NADPH oxidase 4 by hydrogen peroxide‐inducible clone 5 (Hic‐5) protein. J Biol Chem 289: 18270‐18278, 2014.
 133.Dikalov SI, Nazarewicz RR, Bikineyeva A, Hilenski L, Lassegue B, Griendling KK, Harrison DG, Dikalova AE. Nox2‐induced production of mitochondrial superoxide in angiotensin II‐mediated endothelial oxidative stress and hypertension. Antioxid Redox Signal 20: 281‐294, 2014.
 134.DiLoreto R, Murphy CT. The cell biology of aging. Mol Biol Cell 26: 4524‐4531, 2015.
 135.Dohi M, Hasegawa T, Yamamoto K, Marshall BC. Hepatocyte growth factor attenuates collagen accumulation in a murine model of pulmonary fibrosis. Am J Respir Crit Care Med 162: 2302‐2307, 2000.
 136.Dong X, Li X, Li M, Chen M, Fan Q, Wei W. Inhibitory effects of thalidomide on bleomycin‐induced pulmonary fibrosis in rats via regulation of thioredoxin reductase and inflammations. Am J Transl Res 9: 4390‐4401, 2017.
 137.Dougall WC, Nick HS. Manganese superoxide dismutase: A hepatic acute phase protein regulated by interleukin‐6 and glucocorticoids. Endocrinology 129: 2376‐2384, 1991.
 138.Doyle K, Fitzpatrick FA. Redox signaling, alkylation (carbonylation) of conserved cysteines inactivates class I histone deacetylases 1, 2, and 3 and antagonizes their transcriptional repressor function. J Biol Chem 285: 17417‐17424, 2010.
 139.Drane P, Bravard A, Bouvard V, May E. Reciprocal down‐regulation of p53 and SOD2 gene expression‐implication in p53 mediated apoptosis. Oncogene 20: 430‐439, 2001.
 140.Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S, Wu S, Lang R, Iredale JP. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 115: 56‐65, 2005.
 141.Dunlop EA, Tee AR. mTOR and autophagy: A dynamic relationship governed by nutrients and energy. Semin Cell Dev Biol 36: 121‐129, 2014.
 142.Duval C, Negre‐Salvayre A, Dogilo A, Salvayre R, Penicaud L, Casteilla L. Increased reactive oxygen species production with antisense oligonucleotides directed against uncoupling protein 2 in murine endothelial cells. Biochem Cell Biol 80: 757‐764, 2002.
 143.El‐Agamey A, Lowe GM, McGarvey DJ, Mortensen A, Phillip DM, Truscott TG, Young AJ. Carotenoid radical chemistry and antioxidant/pro‐oxidant properties. Arch Biochem Biophys 430: 37‐48, 2004.
 144.El‐Benna J, Dang PM, Gougerot‐Pocidalo MA. Priming of the neutrophil NADPH oxidase activation: Role of p47phox phosphorylation and NOX2 mobilization to the plasma membrane. Semin Immunopathol 30: 279‐289, 2008.
 145.Emerit J, Michelson AM. Free radicals in medicine and biology. Sem Hop 58: 2670‐2675, 1982.
 146.Epperly MW, Travis EL, Sikora C, Greenberger JS. Manganese [correction of Magnesium] superoxide dismutase (MnSOD) plasmid/liposome pulmonary radioprotective gene therapy: Modulation of irradiation‐induced mRNA for IL‐I, TNF‐alpha, and TGF‐beta correlates with delay of organizing alveolitis/fibrosis. Biol Blood Marrow Transplant 5: 204‐214, 1999.
 147.Epperly MW, Travis EL, Whitsett JA, Raineri I, Epstein CJ, Greenberger JS. Overexpression of manganese superoxide dismutase (MnSOD) in whole lung or alveolar type II cells of MnSOD transgenic mice does not provide intrinsic lung irradiation protection. Int J Cancer 96: 11‐21, 2001.
 148.Espeel M, Van Limbergen G. Immunocytochemical localization of peroxisomal proteins in human liver and kidney. J Inherit Metab Dis 18 (Suppl 1): 135‐154, 1995.
 149.Fattman CL, Chang LY, Termin TA, Petersen L, Enghild JJ, Oury TD. Enhanced bleomycin‐induced pulmonary damage in mice lacking extracellular superoxide dismutase. Free Radic Biol Med 35: 763‐771, 2003.
 150.Fattman CL, Schaefer LM, Oury TD. Extracellular superoxide dismutase in biology and medicine. Free Radic Biol Med 35: 236‐256, 2003.
 151.Filomeni G, De Zio D, Cecconi F. Oxidative stress and autophagy: The clash between damage and metabolic needs. Cell Death Differ 22: 377‐388, 2015.
 152.Fink BD, Reszka KJ, Herlein JA, Mathahs MM, Sivitz WI. Respiratory uncoupling by UCP1 and UCP2 and superoxide generation in endothelial cell mitochondria. Am J Physiol Endocrinol Metab 288: E71‐E79, 2005.
 153.Fischer H. Mechanisms and function of DUOX in epithelia of the lung. Antioxid Redox Signal 11: 2453‐2465, 2009.
 154.Fischer H, Gonzales LK, Kolla V, Schwarzer C, Miot F, Illek B, Ballard PL. Developmental regulation of DUOX1 expression and function in human fetal lung epithelial cells. Am J Physiol Lung Cell Mol Physiol 292: L1506‐L1514, 2007.
 155.Fontana L, Partridge L, Longo VD. Extending healthy life span—from yeast to humans. Science 328: 321‐326, 2010.
 156.Forman HJ, Zhang H, Rinna A. Glutathione: Overview of its protective roles, measurement, and biosynthesis. Mol Asp Med 30: 1‐12, 2009.
 157.Forteza R, Salathe M, Miot F, Forteza R, Conner GE. Regulated hydrogen peroxide production by Duox in human airway epithelial cells. Am J Respir Cell Mol Biol 32: 462‐469, 2005.
 158.Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age‐associated diseases. J Gerontol A Biol Sci Med Sci 69 (Suppl 1): S4‐S9, 2014.
 159.Frasca D, Blomberg BB. Inflammaging decreases adaptive and innate immune responses in mice and humans. Biogerontology 17: 7‐19, 2016.
 160.Fredenburgh LE, Perrella MA, Mitsialis SA. The role of heme oxygenase‐1 in pulmonary disease. Am J Respir Cell Mol Biol 36: 158‐165, 2007.
 161.Freeman BA, Crapo JD. Biology of disease: Free radicals and tissue injury. Lab Investig 47: 412‐426, 1982.
 162.Fukai T, Ushio‐Fukai M. Superoxide dismutases: Role in redox signaling, vascular function, and diseases. Antioxid Redox Signal 15: 1583‐1606, 2011.
 163.Gabasa M, Royo D, Molina‐Molina M, Roca‐Ferrer J, Pujols L, Picado C, Xaubet A, Pereda J. Lung myofibroblasts are characterized by down‐regulated cyclooxygenase‐2 and its main metabolite, prostaglandin E2. PLoS One 8: e65445, 2013.
 164.Gaetani GF, Galiano S, Canepa L, Ferraris AM, Kirkman HN. Catalase and glutathione peroxidase are equally active in detoxification of hydrogen peroxide in human erythrocytes. Blood 73: 334‐339, 1989.
 165.Gan G, Hu R, Dai A, Tan S, Ouyang Q, Fu D, Jiang D. The role of endoplasmic reticulum stress in emphysema results from cigarette smoke exposure. Cell Physiol Biochem 28: 725‐732, 2011.
 166.Gao F, Koenitzer JR, Tobolewski JM, Jiang D, Liang J, Noble PW, Oury TD. Extracellular superoxide dismutase inhibits inflammation by preventing oxidative fragmentation of hyaluronan. J Biol Chem 283: 6058‐6066, 2008.
 167.Gautam N, Das S, Kar Mahapatra S, Chakraborty SP, Kundu PK, Roy S. Age associated oxidative damage in lymphocytes. Oxidative Med Cell Longev 3: 275‐282, 2010.
 168.Gharib SA, Johnston LK, Huizar I, Birkland TP, Hanson J, Wang Y, Parks WC, Manicone AM. MMP28 promotes macrophage polarization toward M2 cells and augments pulmonary fibrosis. J Leukoc Biol 95: 9‐18, 2014.
 169.Ghatak S, Hascall VC, Markwald RR, Feghali‐Bostwick C, Artlett CM, Gooz M, Bogatkevich GS, Atanelishvili I, Silver RM, Wood J, Thannickal VJ, Misra S. Transforming growth factor beta1 (TGFbeta1)‐induced CD44V6‐NOX4 signaling in pathogenesis of idiopathic pulmonary fibrosis. J Biol Chem 292: 10490‐10519, 2017.
 170.Ghosh MK, Arun R, Chattopadhyay DJ, Chatterjee IB. Cytochrome P450‐mediated oxidative damage of nuclear membrane proteins and its prevention by vitamin C. Indian J Biochem Biophys 40: 309‐314, 2003.
 171.Giorgi C, Marchi S, Simoes ICM, Ren Z, Morciano G, Perrone M, Patalas‐Krawczyk P, Borchard S, Jedrak P, Pierzynowska K, Szymanski J, Wang DQ, Portincasa P, Wegrzyn G, Zischka H, Dobrzyn P, Bonora M, Duszynski J, Rimessi A, Karkucinska‐Wieckowska A, Dobrzyn A, Szabadkai G, Zavan B, Oliveira PJ, Sardao VA, Pinton P, Wieckowski MR. Mitochondria and reactive oxygen species in aging and age‐related diseases. Int Rev Cell Mol Biol 340: 209‐344, 2018.
 172.Giorgio M, Migliaccio E, Orsini F, Paolucci D, Moroni M, Contursi C, Pelliccia G, Luzi L, Minucci S, Marcaccio M, Pinton P, Rizzuto R, Bernardi P, Paolucci F, Pelicci PG. Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell 122: 221‐233, 2005.
 173.Giustarini D, Rossi R, Milzani A, Colombo R, Dalle‐Donne I. S‐glutathionylation: From redox regulation of protein functions to human diseases. J Cell Mol Med 8: 201‐212, 2004.
 174.Gordon S. Alternative activation of macrophages. Nat Rev Immunol 3: 23‐35, 2003.
 175.Gordon S, Martinez FO. Alternative activation of macrophages: Mechanism and functions. Immunity 32: 593‐604, 2010.
 176.Gorowiec MR, Borthwick LA, Parker SM, Kirby JA, Saretzki GC, Fisher AJ. Free radical generation induces epithelial‐to‐mesenchymal transition in lung epithelium via a TGF‐beta1‐dependent mechanism. Free Radic Biol Med 52: 1024‐1032, 2012.
 177.Goyal MM, Basak A. Human catalase: Looking for complete identity. Protein Cell 1: 888‐897, 2010.
 178.Goyal P, Weissmann N, Grimminger F, Hegel C, Bader L, Rose F, Fink L, Ghofrani HA, Schermuly RT, Schmidt HH, Seeger W, Hanze J. Upregulation of NAD(P)H oxidase 1 in hypoxia activates hypoxia‐inducible factor 1 via increase in reactive oxygen species. Free Radic Biol Med 36: 1279‐1288, 2004.
 179.Graham KA, Kulawiec M, Owens KM, Li X, Desouki MM, Chandra D, Singh KK. NADPH oxidase 4 is an oncoprotein localized to mitochondria. Cancer Biol Ther 10: 223‐231, 2010.
 180.Green DE, Kang BY, Murphy TC, Hart CM. Peroxisome proliferator‐activated receptor gamma (PPARgamma) regulates thrombospondin‐1 and Nox4 expression in hypoxia‐induced human pulmonary artery smooth muscle cell proliferation. Pulm Circ 2: 483‐491, 2012.
 181.Green DE, Murphy TC, Kang BY, Kleinhenz JM, Szyndralewiez C, Page P, Sutliff RL, Hart CM. The Nox4 inhibitor GKT137831 attenuates hypoxia‐induced pulmonary vascular cell proliferation. Am J Respir Cell Mol Biol 47: 718‐726, 2012.
 182.Gregory AD, Kliment CR, Metz HE, Kim KH, Kargl J, Agostini BA, Crum LT, Oczypok EA, Oury TA, Houghton AM. Neutrophil elastase promotes myofibroblast differentiation in lung fibrosis. J Leukoc Biol 98: 143‐152, 2015.
 183.Griendling KK, Sorescu D, Ushio‐Fukai M. NAD(P)H oxidase: Role in cardiovascular biology and disease. Circ Res 86: 494‐501, 2000.
 184.Griess B, Tom E, Domann F, Teoh‐Fitzgerald M. Extracellular superoxide dismutase and its role in cancer. Free Radic Biol Med 112: 464‐479, 2017.
 185.Griffiths HR, Gao D, Pararasa C. Redox regulation in metabolic programming and inflammation. Redox Biol 12: 50‐57, 2017.
 186.Groner Y, Elroy‐Stein O, Avraham KB, Schickler M, Knobler H, Minc‐Golomb D, Bar‐Peled O, Yarom R, Rotshenker S. Cell damage by excess CuZnSOD and Down's syndrome. Biomed Pharmacother 48: 231‐240, 1994.
 187.Guignabert C, Phan C, Seferian A, Huertas A, Tu L, Thuillet R, Sattler C, Le Hiress M, Tamura Y, Jutant EM, Chaumais MC, Bouchet S, Maneglier B, Molimard M, Rousselot P, Sitbon O, Simonneau G, Montani D, Humbert M. Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension. J Clin Invest 126: 3207‐3218, 2016.
 188.Guillaumet‐Adkins A, Yanez Y, Peris‐Diaz MD, Calabria I, Palanca‐Ballester C, Sandoval J. Epigenetics and oxidative stress in aging. Oxidative Med Cell Longev 2017: 9175806, 2017.
 189.Guo W, Saito S, Sanchez CG, Zhuang Y, Gongora Rosero RE, Shan B, Luo F, Lasky JA. TGF‐beta1 stimulates HDAC4 nucleus‐to‐cytoplasm translocation and NADPH oxidase 4‐derived reactive oxygen species in normal human lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 312: L936‐L944, 2017.
 190.Guo X, Li T, Xu Y, Xu X, Zhu Z, Zhang Y, Xu J, Xu K, Cheng H, Zhang X, Ke Y. Increased levels of Gab1 and Gab2 adaptor proteins skew interleukin‐4 (IL‐4) signaling toward M2 macrophage‐driven pulmonary fibrosis in mice. J Biol Chem 292: 14003‐14015, 2017.
 191.Guzik TJ, Chen W, Gongora MC, Guzik B, Lob HE, Mangalat D, Hoch N, Dikalov S, Rudzinski P, Kapelak B, Sadowski J, Harrison DG. Calcium‐dependent NOX5 nicotinamide adenine dinucleotide phosphate oxidase contributes to vascular oxidative stress in human coronary artery disease. J Am Coll Cardiol 52: 1803‐1809, 2008.
 192.Hagen TM, Brown LA, Jones DP. Protection against paraquat‐induced injury by exogenous GSH in pulmonary alveolar type II cells. Biochem Pharmacol 35: 4537‐4542, 1986.
 193.Hagimoto N, Kuwano K, Inoshima I, Yoshimi M, Nakamura N, Fujita M, Maeyama T, Hara N. TGF‐beta 1 as an enhancer of Fas‐mediated apoptosis of lung epithelial cells. J Immunol 168: 6470‐6478, 2002.
 194.Hagimoto N, Kuwano K, Miyazaki H, Kunitake R, Fujita M, Kawasaki M, Kaneko Y, Hara N. Induction of apoptosis and pulmonary fibrosis in mice in response to ligation of Fas antigen. Am J Respir Cell Mol Biol 17: 272‐278, 1997.
 195.Hagimoto N, Kuwano K, Nomoto Y, Kunitake R, Hara N. Apoptosis and expression of Fas/Fas ligand mRNA in bleomycin‐induced pulmonary fibrosis in mice. Am J Respir Cell Mol Biol 16: 91‐101, 1997.
 196.Hagiwara SI, Ishii Y, Kitamura S. Aerosolized administration of N‐acetylcysteine attenuates lung fibrosis induced by bleomycin in mice. Am J Respir Crit Care Med 162: 225‐231, 2000.
 197.Hagood JS, Prabhakaran P, Kumbla P, Salazar L, MacEwen MW, Barker TH, Ortiz LA, Schoeb T, Siegal GP, Alexander CB, Pardo A, Selman M. Loss of fibroblast Thy‐1 expression correlates with lung fibrogenesis. Am J Pathol 167: 365‐379, 2005.
 198.Haigis MC, Guarente LP. Mammalian sirtuins—emerging roles in physiology, aging, and calorie restriction. Genes Dev 20: 2913‐2921, 2006.
 199.Halliwell B, Gutteridge JM. Oxygen free radicals and iron in relation to biology and medicine: Some problems and concepts. Arch Biochem Biophys 246: 501‐514, 1986.
 200.Hanschmann EM, Godoy JR, Berndt C, Hudemann C, Lillig CH. Thioredoxins, glutaredoxins, and peroxiredoxins—molecular mechanisms and health significance: From cofactors to antioxidants to redox signaling. Antioxid Redox Signal 19: 1539‐1605, 2013.
 201.Harel S, Mayaki D, Sanchez V, Hussain SNA. NOX2, NOX4, and mitochondrial‐derived reactive oxygen species contribute to angiopoietin‐1 signaling and angiogenic responses in endothelial cells. Vasc Pharmacol 92: 22‐32, 2017.
 202.Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature 345: 458‐460, 1990.
 203.Harman D. Aging: A theory based on free radical and radiation chemistry. J Gerontol 11: 298‐300, 1956.
 204.Harper RW, Xu C, Eiserich JP, Chen Y, Kao CY, Thai P, Setiadi H, Wu R. Differential regulation of dual NADPH oxidases/peroxidases, Duox1 and Duox2, by Th1 and Th2 cytokines in respiratory tract epithelium. FEBS Lett 579: 4911‐4917, 2005.
 205.Harrison P, Bradley L, Bomford A. Mechanism of regulation of HGF/SF gene expression in fibroblasts by TGF‐beta1. Biochem Biophys Res Commun 271: 203‐211, 2000.
 206.Hashimoto D, Chow A, Noizat C, Teo P, Beasley MB, Leboeuf M, Becker CD, See P, Price J, Lucas D, Greter M, Mortha A, Boyer SW, Forsberg EC, Tanaka M, van Rooijen N, Garcia‐Sastre A, Stanley ER, Ginhoux F, Frenette PS, Merad M. Tissue‐resident macrophages self‐maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38: 792‐804, 2013.
 207.Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res 25: 585‐621, 1961.
 208.He C, Larson‐Casey JL, Davis D, Hanumanthu VS, Longhini ALF, Thannickal VJ, Gu L, Carter AB. NOX4 modulates macrophage phenotype and mitochondrial biogenesis in asbestosis. JCI Insight: 4, 2019.
 209.He C, Larson‐Casey JL, Gu L, Ryan AJ, Murthy S, Carter ABC. Zn‐superoxide dismutase‐mediated redox regulation of Jumonji domain containing 3 modulates macrophage polarization and pulmonary fibrosis. Am J Respir Cell Mol Biol 55: 58‐71, 2016.
 210.He C, Murthy S, McCormick ML, Spitz DR, Ryan AJ, Carter AB. Mitochondrial Cu,Zn‐superoxide dismutase mediates pulmonary fibrosis by augmenting H2O2 generation. J Biol Chem 286: 15597‐15607, 2011.
 211.He C, Ryan AJ, Murthy S, Carter AB. Accelerated development of pulmonary fibrosis via Cu,Zn‐superoxide dismutase‐induced alternative activation of macrophages. J Biol Chem 288: 20745‐20757, 2013.
 212.Hecker L. Mechanisms and consequences of oxidative stress in lung disease: Therapeutic implications for an aging populace. Am J Physiol Lung Cell Mol Physiol 314: L642‐L653, 2018.
 213.Hecker L, Logsdon NJ, Kurundkar D, Kurundkar A, Bernard K, Hock T, Meldrum E, Sanders YY, Thannickal VJ. Reversal of persistent fibrosis in aging by targeting Nox4‐Nrf2 redox imbalance. Sci Transl Med 6: 231ra247, 2014.
 214.Hecker L, Vittal R, Jones T, Jagirdar R, Luckhardt TR, Horowitz JC, Pennathur S, Martinez FJ, Thannickal VJ. NADPH oxidase‐4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nat Med 15: 1077‐1081, 2009.
 215.Helling BA, Yang IV. Epigenetics in lung fibrosis: From pathobiology to treatment perspective. Curr Opin Pulm Med 21: 454‐462, 2015.
 216.Hemann MT, Strong MA, Hao LY, Greider CW. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107: 67‐77, 2001.
 217.Hengartner MO. The biochemistry of apoptosis. Nature 407: 770‐776, 2000.
 218.Herranz N, Gallage S, Mellone M, Wuestefeld T, Klotz S, Hanley CJ, Raguz S, Acosta JC, Innes AJ, Banito A, Georgilis A, Montoya A, Wolter K, Dharmalingam G, Faull P, Carroll T, Martinez‐Barbera JP, Cutillas P, Reisinger F, Heikenwalder M, Miller RA, Withers D, Zender L, Thomas GJ, Gil J. mTOR regulates MAPKAPK2 translation to control the senescence‐associated secretory phenotype. Nat Cell Biol 17: 1205‐1217, 2015.
 219.Herrera I, Cisneros J, Maldonado M, Ramirez R, Ortiz‐Quintero B, Anso E, Chandel NS, Selman M, Pardo A. Matrix metalloproteinase (MMP)‐1 induces lung alveolar epithelial cell migration and proliferation, protects from apoptosis, and represses mitochondrial oxygen consumption. J Biol Chem 288: 25964‐25975, 2013.
 220.Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton‐Piallat ML, Gabbiani G. The myofibroblast: One function, multiple origins. Am J Pathol 170: 1807‐1816, 2007.
 221.Hogaboam CM, Murray L, Martinez FJ. Epigenetic mechanisms through which Toll‐like receptor‐9 drives idiopathic pulmonary fibrosis progression. Proc Am Thorac Soc 9: 172‐176, 2012.
 222.Hopkins RB, Burke N, Fell C, Dion G, Kolb M. Epidemiology and survival of idiopathic pulmonary fibrosis from national data in Canada. Eur Respir J 48: 187‐195, 2016.
 223.Horowitz JC, Rogers DS, Sharma V, Vittal R, White ES, Cui Z, Thannickal VJ. Combinatorial activation of FAK and AKT by transforming growth factor‐beta1 confers an anoikis‐resistant phenotype to myofibroblasts. Cell Signal 19: 761‐771, 2007.
 224.Horowitz JC, Thannickal VJ. Idiopathic pulmonary fibrosis: New concepts in pathogenesis and implications for drug therapy. Treat Respir Med 5: 325‐342, 2006.
 225.Hoshino T, Nakamura H, Okamoto M, Kato S, Araya S, Nomiyama K, Oizumi K, Young HA, Aizawa H, Yodoi J. Redox‐active protein thioredoxin prevents proinflammatory cytokine‐ or bleomycin‐induced lung injury. Am J Respir Crit Care Med 168: 1075‐1083, 2003.
 226.Hou J, Ma T, Cao H, Chen Y, Wang C, Chen X, Xiang Z, Han X. TNF‐alpha‐induced NF‐kappaB activation promotes myofibroblast differentiation of LR‐MSCs and exacerbates bleomycin‐induced pulmonary fibrosis. J Cell Physiol 233: 2409‐2419, 2018.
 227.Hou J, Shi J, Chen L, Lv Z, Chen X, Cao H, Xiang Z, Han X. M2 macrophages promote myofibroblast differentiation of LR‐MSCs and are associated with pulmonary fibrogenesis. Cell Commun Signal 16: 89, 2018.
 228.Hoyne GF, Elliott H, Mutsaers SE, Prele CM. Idiopathic pulmonary fibrosis and a role for autoimmunity. Immunol Cell Biol 95: 577‐583, 2017.
 229.Hsu HS, Liu CC, Lin JH, Hsu TW, Hsu JW, Su K, Hung SC. Involvement of ER stress, PI3K/AKT activation, and lung fibroblast proliferation in bleomycin‐induced pulmonary fibrosis. Sci Rep 7: 14272, 2017.
 230.Hu B, Gharaee‐Kermani M, Wu Z, Phan SH. Epigenetic regulation of myofibroblast differentiation by DNA methylation. Am J Pathol 177: 21‐28, 2010.
 231.Huang LS, Jiang P, Feghali‐Bostwick C, Reddy SP, Garcia JGN, Natarajan V. Lysocardiolipin acyltransferase regulates TGF‐beta mediated lung fibroblast differentiation. Free Radic Biol Med 112: 162‐173, 2017.
 232.Huang SK, Scruggs AM, Donaghy J, Horowitz JC, Zaslona Z, Przybranowski S, White ES, Peters‐Golden M. Histone modifications are responsible for decreased Fas expression and apoptosis resistance in fibrotic lung fibroblasts. Cell Death Dis 4: e621, 2013.
 233.Huang WT, Vayalil PK, Miyata T, Hagood J, Liu RM. Therapeutic value of small molecule inhibitor to plasminogen activator inhibitor‐1 for lung fibrosis. Am J Respir Cell Mol Biol 46: 87‐95, 2012.
 234.Huang X, Yang N, Fiore VF, Barker TH, Sun Y, Morris SW, Ding Q, Thannickal VJ, Zhou Y. Matrix stiffness‐induced myofibroblast differentiation is mediated by intrinsic mechanotransduction. Am J Respir Cell Mol Biol 47: 340‐348, 2012.
 235.Hunninghake GM, Hatabu H, Okajima Y, Gao W, Dupuis J, Latourelle JC, Nishino M, Araki T, Zazueta OE, Kurugol S, Ross JC, San Jose Estepar R, Murphy E, Steele MP, Loyd JE, Schwarz MI, Fingerlin TE, Rosas IO, Washko GR, O'Connor GT, Schwartz DA. MUC5B promoter polymorphism and interstitial lung abnormalities. N Engl J Med 368: 2192‐2200, 2013.
 236.Hutchinson J, Fogarty A, Hubbard R, McKeever T. Global incidence and mortality of idiopathic pulmonary fibrosis: A systematic review. Eur Respir J 46: 795‐806, 2015.
 237.Idiopathic Pulmonary Fibrosis Clinical Research Network, Martinez FJ, de Andrade JA, Anstrom KJ, King TE Jr, Raghu G. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 370: 2093‐2101, 2014.
 238.Im J, Hergert P, Nho RS. Reduced FoxO3a expression causes low autophagy in idiopathic pulmonary fibrosis fibroblasts on collagen matrices. Am J Physiol Lung Cell Mol Physiol 309: L552‐L561, 2015.
 239.Inoue N, Ramasamy S, Fukai T, Nerem RM, Harrison DG. Shear stress modulates expression of Cu/Zn superoxide dismutase in human aortic endothelial cells. Circ Res 79: 32‐37, 1996.
 240.Iyer SS, Ramirez AM, Ritzenthaler JD, Torres‐Gonzalez E, Roser‐Page S, Mora AL, Brigham KL, Jones DP, Roman J, Rojas M. Oxidation of extracellular cysteine/cystine redox state in bleomycin‐induced lung fibrosis. Am J Physiol Lung Cell Mol Physiol 296: L37‐L45, 2009.
 241.Jablonski RP, Kim SJ, Cheresh P, Williams DB, Morales‐Nebreda L, Cheng Y, Yeldandi A, Bhorade S, Pardo A, Selman M, Ridge K, Gius D, Budinger GRS, Kamp DW. SIRT3 deficiency promotes lung fibrosis by augmenting alveolar epithelial cell mitochondrial DNA damage and apoptosis. FASEB J 31: 2520‐2532, 2017.
 242.Jain M, Rivera S, Monclus EA, Synenki L, Zirk A, Eisenbart J, Feghali‐Bostwick C, Mutlu GM, Budinger GR, Chandel NS. Mitochondrial reactive oxygen species regulate transforming growth factor‐beta signaling. J Biol Chem 288: 770‐777, 2013.
 243.Jaiswal AK. Nrf2 signaling in coordinated activation of antioxidant gene expression. Free Radic Biol Med 36: 1199‐1207, 2004.
 244.Janssen‐Heininger YM, Mossman BT, Heintz NH, Forman HJ, Kalyanaraman B, Finkel T, Stamler JS, Rhee SG, van der Vliet A. Redox‐based regulation of signal transduction: Principles, pitfalls, and promises. Free Radic Biol Med 45: 1‐17, 2008.
 245.Jardine H, MacNee W, Donaldson K, Rahman I. Molecular mechanism of transforming growth factor (TGF)‐beta1‐induced glutathione depletion in alveolar epithelial cells. Involvement of AP‐1/ARE and Fra‐1. J Biol Chem 277: 21158‐21166, 2002.
 246.Jarman ER, Khambata VS, Yun Ye L, Cheung K, Thomas M, Duggan N, Jarai G. A translational preclinical model of interstitial pulmonary fibrosis and pulmonary hypertension: Mechanistic pathways driving disease pathophysiology. Physiol Rep 2, 2014.
 247.Ji WJ, Ma YQ, Zhou X, Zhang YD, Lu RY, Sun HY, Guo ZZ, Zhang Z, Li YM, Wei LQ. Temporal and spatial characterization of mononuclear phagocytes in circulating, lung alveolar and interstitial compartments in a mouse model of bleomycin‐induced pulmonary injury. J Immunol Methods 403: 7‐16, 2014.
 248.Jiang C, Liu G, Luckhardt T, Antony V, Zhou Y, Carter AB, Thannickal VJ, Liu RM. Serpine 1 induces alveolar type II cell senescence through activating p53‐p21‐Rb pathway in fibrotic lung disease. Aging Cell 16: 1114‐1124, 2017.
 249.Jiang D, Liang J, Fan J, Yu S, Chen S, Luo Y, Prestwich GD, Mascarenhas MM, Garg HG, Quinn DA, Homer RJ, Goldstein DR, Bucala R, Lee PJ, Medzhitov R, Noble PW. Regulation of lung injury and repair by Toll‐like receptors and hyaluronan. Nat Med 11: 1173‐1179, 2005.
 250.Jiang F, Roberts SJ, Datla S, Dusting GJ. NO modulates NADPH oxidase function via heme oxygenase‐1 in human endothelial cells. Hypertension 48: 950‐957, 2006.
 251.Joshi S, Singh AR, Wong SS, Zulcic M, Jiang M, Pardo A, Selman M, Hagood JS, Durden DL. Rac2 is required for alternative macrophage activation and bleomycin induced pulmonary fibrosis; a macrophage autonomous phenotype. PLoS One 12: e0182851, 2017.
 252.Justice JN, Nambiar AM, Tchkonia T, LeBrasseur NK, Pascual R, Hashmi SK, Prata L, Masternak MM, Kritchevsky SB, Musi N, Kirkland JL. Senolytics in idiopathic pulmonary fibrosis: Results from a first‐in‐human, open‐label, pilot study. EBioMedicine 40: 554‐563, 2019.
 253.Kadota T, Fujita Y, Yoshioka Y, Araya J, Kuwano K, Ochiya T. Emerging role of extracellular vesicles as a senescence‐associated secretory phenotype: Insights into the pathophysiology of lung diseases. Mol Asp Med 60: 92‐103, 2018.
 254.Kamio K, Azuma A, Ohta K, Sugiyama Y, Nukiwa T, Kudoh S, Mizushima T. Double‐blind controlled trial of lecithinized superoxide dismutase in patients with idiopathic interstitial pneumonia ‐ short term evaluation of safety and tolerability. BMC Pulm Med 14: 86, 2014.
 255.Kamp DW, Panduri V, Weitzman SA, Chandel N. Asbestos‐induced alveolar epithelial cell apoptosis: Role of mitochondrial dysfunction caused by iron‐derived free radicals. Mol Cell Biochem 234‐235: 153‐160, 2002.
 256.Kang H. Role of MicroRNAs in TGF‐beta Signaling Pathway‐Mediated Pulmonary Fibrosis. Int J Mol Sci 18, 2017.
 257.Katsuyama M, Matsuno K, Yabe‐Nishimura C. Physiological roles of NOX/NADPH oxidase, the superoxide‐generating enzyme. J Clin Biochem Nutr 50: 9‐22, 2012.
 258.Kaufman RJ. Stress signaling from the lumen of the endoplasmic reticulum: Coordination of gene transcriptional and translational controls. Genes Dev 13: 1211‐1233, 1999.
 259.Kaur SJ, McKeown SR, Rashid S. Mutant SOD1 mediated pathogenesis of amyotrophic lateral sclerosis. Gene 577: 109‐118, 2016.
 260.Kawahara TL, Michishita E, Adler AS, Damian M, Berber E, Lin M, McCord RA, Ongaigui KC, Boxer LD, Chang HY, Chua KF. SIRT6 links histone H3 lysine 9 deacetylation to NF‐kappaB‐dependent gene expression and organismal life span. Cell 136: 62‐74, 2009.
 261.Kawamura K, Ichikado K, Yasuda Y, Anan K, Suga M. Azithromycin for idiopathic acute exacerbation of idiopathic pulmonary fibrosis: A retrospective single‐center study. BMC Pulm Med 17: 94, 2017.
 262.Kelm M. Nitric oxide metabolism and breakdown. Biochim Biophys Acta 1411: 273‐289, 1999.
 263.Khanfer R, Carroll D, Lord JM, Phillips AC. Reduced neutrophil superoxide production among healthy older adults in response to acute psychological stress. Int J Psychophysiol 86: 238‐244, 2012.
 264.Kikuchi N, Ishii Y, Morishima Y, Yageta Y, Haraguchi N, Yamadori T, Masuko H, Sakamoto T, Yanagawa T, Warabi E, Ishii T, Hizawa N. Aggravation of bleomycin‐induced pulmonary inflammation and fibrosis in mice lacking peroxiredoxin I. Am J Respir Cell Mol Biol 45: 600‐609, 2011.
 265.Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, Sheppard D, Chapman HA. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A 103: 13180‐13185, 2006.
 266.Kim MJ, Ryu JC, Kwon Y, Lee S, Bae YS, Yoon JH, Ryu JH. Dual oxidase 2 in lung epithelia is essential for hyperoxia‐induced acute lung injury in mice. Antioxid Redox Signal 21: 1803‐1818, 2014.
 267.Kim SJ, Cheresh P, Jablonski RP, Morales‐Nebreda L, Cheng Y, Hogan E, Yeldandi A, Chi M, Piseaux R, Ridge K, Michael Hart C, Chandel N, Scott Budinger GR, Kamp DW. Mitochondrial catalase overexpressed transgenic mice are protected against lung fibrosis in part via preventing alveolar epithelial cell mitochondrial DNA damage. Free Radic Biol Med 101: 482‐490, 2016.
 268.Kim SJ, Cheresh P, Jablonski RP, Williams DB, Kamp DW. The role of mitochondrial DNA in mediating alveolar epithelial cell apoptosis and pulmonary fibrosis. Int J Mol Sci 16: 21486‐21519, 2015.
 269.Kim Y, Kim BH, Lee H, Jeon B, Lee YS, Kwon MJ, Kim TY. Regulation of skin inflammation and angiogenesis by EC‐SOD via HIF‐1alpha and NF‐kappaB pathways. Free Radic Biol Med 51: 1985‐1995, 2011.
 270.Kim YC, Masutani H, Yamaguchi Y, Itoh K, Yamamoto M, Yodoi J. Hemin‐induced activation of the thioredoxin gene by Nrf2. A differential regulation of the antioxidant responsive element by a switch of its binding factors. J Biol Chem 276: 18399‐18406, 2001.
 271.Kim YM, Kim SJ, Tatsunami R, Yamamura H, Fukai T, Ushio‐Fukai M. ROS‐induced ROS release orchestrated by Nox4, Nox2, and mitochondria in VEGF signaling and angiogenesis. Am J Physiol Cell Physiol 312: C749‐C764, 2017.
 272.King TE Jr, Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet 378: 1949‐1961, 2011.
 273.Kinnula VL, Fattman CL, Tan RJ, Oury TD. Oxidative stress in pulmonary fibrosis: A possible role for redox modulatory therapy. Am J Respir Crit Care Med 172: 417‐422, 2005.
 274.Kinnula VL, Hodgson UA, Lakari EK, Tan RJ, Sormunen RT, Soini YM, Kakko SJ, Laitinen TH, Oury TD, Paakko PK. Extracellular superoxide dismutase has a highly specific localization in idiopathic pulmonary fibrosis/usual interstitial pneumonia. Histopathology 49: 66‐74, 2006.
 275.Kinnula VL, Lehtonen S, Kaarteenaho‐Wiik R, Lakari E, Paakko P, Kang SW, Rhee SG, Soini Y. Cell specific expression of peroxiredoxins in human lung and pulmonary sarcoidosis. Thorax 57: 157‐164, 2002.
 276.Klein D, Steens J, Wiesemann A, Schulz F, Kaschani F, Rock K, Yamaguchi M, Wirsdorfer F, Kaiser M, Fischer JW, Stuschke M, Jendrossek V. Mesenchymal stem cell therapy protects lungs from radiation‐induced endothelial cell loss by restoring superoxide dismutase 1 expression. Antioxid Redox Signal 26: 563‐582, 2017.
 277.Kliment CR, Tobolewski JM, Manni ML, Tan RJ, Enghild J, Oury TD. Extracellular superoxide dismutase protects against matrix degradation of heparan sulfate in the lung. Antioxid Redox Signal 10: 261‐268, 2008.
 278.Klinger JR, Kadowitz PJ. The nitric oxide pathway in pulmonary vascular disease. Am J Cardiol 120: S71‐S79, 2017.
 279.Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science 290: 1717‐1721, 2000.
 280.Kobayashi K, Araya J, Minagawa S, Hara H, Saito N, Kadota T, Sato N, Yoshida M, Tsubouchi K, Kurita Y, Ito S, Fujita Y, Takasaka N, Utsumi H, Yanagisawa H, Hashimoto M, Wakui H, Kojima J, Shimizu K, Numata T, Kawaishi M, Kaneko Y, Asano H, Yamashita M, Odaka M, Morikawa T, Nakayama K, Kuwano K. Involvement of PARK2‐mediated mitophagy in idiopathic pulmonary fibrosis pathogenesis. J Immunol 197: 504‐516, 2016.
 281.Kobayashi T, Kim H, Liu X, Sugiura H, Kohyama T, Fang Q, Wen FQ, Abe S, Wang X, Atkinson JJ, Shipley JM, Senior RM, Rennard SI. Matrix metalloproteinase‐9 activates TGF‐beta and stimulates fibroblast contraction of collagen gels. Am J Physiol Lung Cell Mol Physiol 306: L1006‐L1015, 2014.
 282.Kobayashi T, Liu X, Kim HJ, Kohyama T, Wen FQ, Abe S, Fang Q, Zhu YK, Spurzem JR, Bitterman P, Rennard SI. TGF‐beta1 and serum both stimulate contraction but differentially affect apoptosis in 3D collagen gels. Respir Res 6: 141, 2005.
 283.Kolahian S, Fernandez IE, Eickelberg O, Hartl D. Immune mechanisms in pulmonary fibrosis. Am J Respir Cell Mol Biol 55: 309‐322, 2016.
 284.Kondo T, Reaume AG, Huang TT, Carlson E, Murakami K, Chen SF, Hoffman EK, Scott RW, Epstein CJ, Chan PH. Reduction of CuZn‐superoxide dismutase activity exacerbates neuronal cell injury and edema formation after transient focal cerebral ischemia. J Neurosci 17: 4180‐4189, 1997.
 285.Korfei M, Ruppert C, Mahavadi P, Henneke I, Markart P, Koch M, Lang G, Fink L, Bohle RM, Seeger W, Weaver TE, Guenther A. Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 178: 838‐846, 2008.
 286.Korovila I, Hugo M, Castro JP, Weber D, Hohn A, Grune T, Jung T. Proteostasis, oxidative stress and aging. Redox Biol 13: 550‐567, 2017.
 287.Kosmider B, Messier EM, Chu HW, Mason RJ. Human alveolar epithelial cell injury induced by cigarette smoke. PLoS One 6: e26059, 2011.
 288.Kottmann RM, Trawick E, Judge JL, Wahl LA, Epa AP, Owens KM, Thatcher TH, Phipps RP, Sime PJ. Pharmacologic inhibition of lactate production prevents myofibroblast differentiation. Am J Physiol Lung Cell Mol Physiol 309: L1305‐L1312, 2015.
 289.Kreuz S, Fischle W. Oxidative stress signaling to chromatin in health and disease. Epigenomics 8: 843‐862, 2016.
 290.Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C, Yee H, Zender L, Lowe SW. Senescence of activated stellate cells limits liver fibrosis. Cell 134: 657‐667, 2008.
 291.Kropski JA, Blackwell TS, Loyd JE. The genetic basis of idiopathic pulmonary fibrosis. Eur Respir J 45: 1717‐1727, 2015.
 292.Kulasekaran P, Scavone CA, Rogers DS, Arenberg DA, Thannickal VJ, Horowitz JC. Endothelin‐1 and transforming growth factor‐beta1 independently induce fibroblast resistance to apoptosis via AKT activation. Am J Respir Cell Mol Biol 41: 484‐493, 2009.
 293.Kurita Y, Araya J, Minagawa S, Hara H, Ichikawa A, Saito N, Kadota T, Tsubouchi K, Sato N, Yoshida M, Kobayashi K, Ito S, Fujita Y, Utsumi H, Yanagisawa H, Hashimoto M, Wakui H, Yoshii Y, Ishikawa T, Numata T, Kaneko Y, Asano H, Yamashita M, Odaka M, Morikawa T, Nakayama K, Kuwano K. Pirfenidone inhibits myofibroblast differentiation and lung fibrosis development during insufficient mitophagy. Respir Res 18: 114, 2017.
 294.Kuroda J, Nakagawa K, Yamasaki T, Nakamura K, Takeya R, Kuribayashi F, Imajoh‐Ohmi S, Igarashi K, Shibata Y, Sueishi K, Sumimoto H. The superoxide‐producing NAD(P)H oxidase Nox4 in the nucleus of human vascular endothelial cells. Genes Cells 10: 1139‐1151, 2005.
 295.Kurosaki F, Uchibori R, Sehara Y, Saga Y, Urabe M, Mizukami H, Hagiwara K, Kume A. AAV6‐mediated IL‐10 expression in the lung ameliorates bleomycin‐induced pulmonary fibrosis in mice. Hum Gene Ther 29: 1242‐1251, 2018.
 296.Kurundkar A, Thannickal VJ. Redox mechanisms in age‐related lung fibrosis. Redox Biol 9: 67‐76, 2016.
 297.Kurundkar AR, Kurundkar D, Rangarajan S, Locy ML, Zhou Y, Liu RM, Zmijewski J, Thannickal VJ. The matricellular protein CCN1 enhances TGF‐beta1/SMAD3‐dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury. FASEB J 30: 2135‐2150, 2016.
 298.Kurz DJ, Decary S, Hong Y, Erusalimsky JD. Senescence‐associated (beta)‐galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J Cell Sci 113 (Pt 20): 3613‐3622, 2000.
 299.Kuwano K, Hagimoto N, Kawasaki M, Yatomi T, Nakamura N, Nagata S, Suda T, Kunitake R, Maeyama T, Miyazaki H, Hara N. Essential roles of the Fas‐Fas ligand pathway in the development of pulmonary fibrosis. J Clin Invest 104: 13‐19, 1999.
 300.Kuwano K, Kunitake R, Maeyama T, Hagimoto N, Kawasaki M, Matsuba T, Yoshimi M, Inoshima I, Yoshida K, Hara N. Attenuation of bleomycin‐induced pneumopathy in mice by a caspase inhibitor. Am J Physiol Lung Cell Mol Physiol 280: L316‐L325, 2001.
 301.Kuwano K, Miyazaki H, Hagimoto N, Kawasaki M, Fujita M, Kunitake R, Kaneko Y, Hara N. The involvement of Fas‐Fas ligand pathway in fibrosing lung diseases. Am J Respir Cell Mol Biol 20: 53‐60, 1999.
 302.Kuwano K, Nomoto Y, Kunitake R, Hagimoto N, Matsuba T, Nakanishi Y, Hara N. Detection of adenovirus E1A DNA in pulmonary fibrosis using nested polymerase chain reaction. Eur Respir J 10: 1445‐1449, 1997.
 303.Kwong CH, Malech HL, Rotrosen D, Leto TL. Regulation of the human neutrophil NADPH oxidase by rho‐related G‐proteins. Biochemistry 32: 5711‐5717, 1993.
 304.Laberge RM, Sun Y, Orjalo AV, Patil CK, Freund A, Zhou L, Curran SC, Davalos AR, Wilson‐Edell KA, Liu S, Limbad C, Demaria M, Li P, Hubbard GB, Ikeno Y, Javors M, Desprez PY, Benz CC, Kapahi P, Nelson PS, Campisi J. MTOR regulates the pro‐tumorigenic senescence‐associated secretory phenotype by promoting IL1A translation. Nat Cell Biol 17: 1049‐1061, 2015.
 305.Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM, Mitch WE, Harrison DG. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest 111: 1201‐1209, 2003.
 306.Lappi‐Blanco E, Soini Y, Paakko P. Apoptotic activity is increased in the newly formed fibromyxoid connective tissue in bronchiolitis obliterans organizing pneumonia. Lung 177: 367‐376, 1999.
 307.Larios JM, Budhiraja R, Fanburg BL, Thannickal VJ. Oxidative protein cross‐linking reactions involving L‐tyrosine in transforming growth factor‐beta1‐stimulated fibroblasts. J Biol Chem 276: 17437‐17441, 2001.
 308.Larson‐Casey JL, Deshane JS, Ryan AJ, Thannickal VJ, Carter AB. Macrophage Akt1 kinase‐mediated mitophagy modulates apoptosis resistance and pulmonary fibrosis. Immunity 44: 582‐596, 2016.
 309.Laskin DL, Kimura T, Sakakibara S, Riley DJ, Berg RA. Chemotactic activity of collagen‐like polypeptides for human peripheral blood neutrophils. J Leukoc Biol 39: 255‐266, 1986.
 310.Lassegue B, Sorescu D, Szocs K, Yin Q, Akers M, Zhang Y, Grant SL, Lambeth JD, Griendling KK. Novel gp91(phox) homologues in vascular smooth muscle cells: nox1 mediates angiotensin II‐induced superoxide formation and redox‐sensitive signaling pathways. Circ Res 88: 888‐894, 2001.
 311.Lawrence J, Nho R. The role of the mammalian target of rapamycin (mTOR) in pulmonary fibrosis. Int J Mol Sci 19, 2018.
 312.Lawson WE, Crossno PF, Polosukhin VV, Roldan J, Cheng DS, Lane KB, Blackwell TR, Xu C, Markin C, Ware LB, Miller GG, Loyd JE, Blackwell TS. Endoplasmic reticulum stress in alveolar epithelial cells is prominent in IPF: Association with altered surfactant protein processing and herpesvirus infection. Am J Physiol Lung Cell Mol Physiol 294: L1119‐L1126, 2008.
 313.Lee PJ, Alam J, Sylvester SL, Inamdar N, Otterbein L, Choi AM. Regulation of heme oxygenase‐1 expression in vivo and in vitro in hyperoxic lung injury. Am J Respir Cell Mol Biol 14: 556‐568, 1996.
 314.Legakis JE, Koepke JI, Jedeszko C, Barlaskar F, Terlecky LJ, Edwards HJ, Walton PA, Terlecky SR. Peroxisome senescence in human fibroblasts. Mol Biol Cell 13: 4243‐4255, 2002.
 315.Lehmann M, Korfei M, Mutze K, Klee S, Skronska‐Wasek W, Alsafadi HN, Ota C, Costa R, Schiller HB, Lindner M, Wagner DE, Gunther A, Konigshoff M. Senolytic drugs target alveolar epithelial cell function and attenuate experimental lung fibrosis ex vivo. Eur Respir J 50, 2017.
 316.Leto TL, Morand S, Hurt D, Ueyama T. Targeting and regulation of reactive oxygen species generation by Nox family NADPH oxidases. Antioxid Redox Signal 11: 2607‐2619, 2009.
 317.Ley B, Collard HR, King TE Jr. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 183: 431‐440, 2011.
 318.Li G, Scull C, Ozcan L, Tabas I. NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis. J Cell Biol 191: 1113‐1125, 2010.
 319.Li S, Tabar SS, Malec V, Eul BG, Klepetko W, Weissmann N, Grimminger F, Seeger W, Rose F, Hanze J. NOX4 regulates ROS levels under normoxic and hypoxic conditions, triggers proliferation, and inhibits apoptosis in pulmonary artery adventitial fibroblasts. Antioxid Redox Signal 10: 1687‐1698, 2008.
 320.Li Z, Shi K, Guan L, Cao T, Jiang Q, Yang Y, Xu C. ROS leads to MnSOD upregulation through ERK2 translocation and p53 activation in selenite‐induced apoptosis of NB4 cells. FEBS Lett 584: 2291‐2297, 2010.
 321.Lillig CH, Berndt C, Vergnolle O, Lonn ME, Hudemann C, Bill E, Holmgren A. Characterization of human glutaredoxin 2 as iron‐sulfur protein: A possible role as redox sensor. Proc Natl Acad Sci U S A 102: 8168‐8173, 2005.
 322.Lim H, Park H, Kim HP. Effects of flavonoids on senescence‐associated secretory phenotype formation from bleomycin‐induced senescence in BJ fibroblasts. Biochem Pharmacol 96: 337‐348, 2015.
 323.Lin JH, Walter P, Yen TS. Endoplasmic reticulum stress in disease pathogenesis. Annu Rev Pathol 3: 399‐425, 2008.
 324.Liu F, Mih JD, Shea BS, Kho AT, Sharif AS, Tager AM, Tschumperlin DJ. Feedback amplification of fibrosis through matrix stiffening and COX‐2 suppression. J Cell Biol 190: 693‐706, 2010.
 325.Liu M, Xu H, Zhang L, Zhang C, Yang L, Ma E, Liu L, Li Y. Salvianolic acid B inhibits myofibroblast transdifferentiation in experimental pulmonary fibrosis via the up‐regulation of Nrf2. Biochem Biophys Res Commun 495: 325‐331, 2018.
 326.Liu RM, Desai LP. Reciprocal regulation of TGF‐beta and reactive oxygen species: A perverse cycle for fibrosis. Redox Biol 6: 565‐577, 2015.
 327.Liu RM, Gaston Pravia KA. Oxidative stress and glutathione in TGF‐beta‐mediated fibrogenesis. Free Radic Biol Med 48: 1‐15, 2010.
 328.Liu T, Ullenbruch M, Young Choi Y, Yu H, Ding L, Xaubet A, Pereda J, Feghali‐Bostwick CA, Bitterman PB, Henke CA, Pardo A, Selman M, Phan SH. Telomerase and telomere length in pulmonary fibrosis. Am J Respir Cell Mol Biol 49: 260‐268, 2013.
 329.Liu Y, Lu F, Kang L, Wang Z, Wang Y. Pirfenidone attenuates bleomycin‐induced pulmonary fibrosis in mice by regulating Nrf2/Bach1 equilibrium. BMC Pulm Med 17: 63, 2017.
 330.Lofgren S, Fernando MR, Xing KY, Wang Y, Kuszynski CA, Ho YS, Lou MF. Effect of thioltransferase (glutaredoxin) deletion on cellular sensitivity to oxidative stress and cell proliferation in lens epithelial cells of thioltransferase knockout mouse. Invest Ophthalmol Vis Sci 49: 4497‐4505, 2008.
 331.Lopez‐Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell 153: 1194‐1217, 2013.
 332.Loukides S, Bouros D, Papatheodorou G, Panagou P, Siafakas NM. The relationships among hydrogen peroxide in expired breath condensate, airway inflammation, and asthma severity. Chest 121: 338‐346, 2002.
 333.Lowery EM, Brubaker AL, Kuhlmann E, Kovacs EJ. The aging lung. Clin Interv Aging 8: 1489‐1496, 2013.
 334.Lu HL, Huang XY, Luo YF, Tan WP, Chen PF, Guo YB. Activation of M1 macrophages plays a critical role in the initiation of acute lung injury. Biosci Rep 38: pii: BSR20171555, 2018.
 335.Lu J, Zhang H, Chen X, Zou Y, Li J, Wang L, Wu M, Zang J, Yu Y, Zhuang W, Xia Q, Wang J. A small molecule activator of SIRT3 promotes deacetylation and activation of manganese superoxide dismutase. Free Radic Biol Med 112: 287‐297, 2017.
 336.Lu SC. Regulation of glutathione synthesis. Curr Top Cell Regul 36: 95‐116, 2000.
 337.Lu SC. Glutathione synthesis. Biochim Biophys Acta 1830: 3143‐3153, 2013.
 338.Lumsden RV, Worrell JC, Boylan D, Walsh SM, Cramton J, Counihan I, O'Beirne S, Medina MF, Gauldie J, Fabre A, Donnelly SC, Kane R, Keane MP. Modulation of pulmonary fibrosis by IL‐13Ralpha2. Am J Physiol Lung Cell Mol Physiol 308: L710‐L718, 2015.
 339.Lundberg JO, Gladwin MT, Weitzberg E. Strategies to increase nitric oxide signalling in cardiovascular disease. Nat Rev Drug Discov 14: 623‐641, 2015.
 340.Lushchak VI. Glutathione homeostasis and functions: Potential targets for medical interventions. J Amino Acids 2012: 736837, 2012.
 341.Lushchak VI. Free radicals, reactive oxygen species, oxidative stress and its classification. Chem Biol Interact 224: 164‐175, 2014.
 342.Lv XX, Wang XX, Li K, Wang ZY, Li Z, Lv Q, Fu XM, Hu ZW. Rupatadine protects against pulmonary fibrosis by attenuating PAF‐mediated senescence in rodents. PLoS One 8: e68631, 2013.
 343.Maarsingh H, Pera T, Meurs H. Arginase and pulmonary diseases. Naunyn Schmiedeberg's Arch Pharmacol 378: 171‐184, 2008.
 344.MacMicking J, Xie QW, Nathan C. Nitric oxide and macrophage function. Annu Rev Immunol 15: 323‐350, 1997.
 345.Maier B, Gluba W, Bernier B, Turner T, Mohammad K, Guise T, Sutherland A, Thorner M, Scrable H. Modulation of mammalian life span by the short isoform of p53. Genes Dev 18: 306‐319, 2004.
 346.Malhotra JD, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress: A vicious cycle or a double‐edged sword? Antioxid Redox Signal 9: 2277‐2293, 2007.
 347.Malouf MA, Hopkins P, Snell G, Glanville AR, Everolimus in IPFSI. An investigator‐driven study of everolimus in surgical lung biopsy confirmed idiopathic pulmonary fibrosis. Respirology 16: 776‐783, 2011.
 348.Maniatis NA, Brovkovych V, Allen SE, John TA, Shajahan AN, Tiruppathi C, Vogel SM, Skidgel RA, Malik AB, Minshall RD. Novel mechanism of endothelial nitric oxide synthase activation mediated by caveolae internalization in endothelial cells. Circ Res 99: 870‐877, 2006.
 349.Manickam N, Patel M, Griendling KK, Gorin Y, Barnes JL. RhoA/Rho kinase mediates TGF‐beta1‐induced kidney myofibroblast activation through Poldip2/Nox4‐derived reactive oxygen species. Am J Physiol Renal Physiol 307: F159‐F171, 2014.
 350.Manoury B, Nenan S, Leclerc O, Guenon I, Boichot E, Planquois JM, Bertrand CP, Lagente V. The absence of reactive oxygen species production protects mice against bleomycin‐induced pulmonary fibrosis. Respir Res 6: 11, 2005.
 351.Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: Tumor‐associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23: 549‐555, 2002.
 352.Markaki M, Tavernarakis N. Metabolic control by target of rapamycin and autophagy during ageing ‐ a mini‐review. Gerontology 59: 340‐348, 2013.
 353.Markart P, Luboeinski T, Korfei M, Schmidt R, Wygrecka M, Mahavadi P, Mayer K, Wilhelm J, Seeger W, Guenther A, Ruppert C. Alveolar oxidative stress is associated with elevated levels of nonenzymatic low‐molecular‐weight antioxidants in patients with different forms of chronic fibrosing interstitial lung diseases. Antioxid Redox Signal 11: 227‐240, 2009.
 354.Martinez G, Duran‐Aniotz C, Cabral‐Miranda F, Vivar JP, Hetz C. Endoplasmic reticulum proteostasis impairment in aging. Aging Cell 16: 615‐623, 2017.
 355.Martinez P, Blasco MA. Telomere‐driven diseases and telomere‐targeting therapies. J Cell Biol 216: 875‐887, 2017.
 356.Martyn KD, Frederick LM, von Loehneysen K, Dinauer MC, Knaus UG. Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases. Cell Signal 18: 69‐82, 2006.
 357.Marzani B, Felzani G, Bellomo RG, Vecchiet J, Marzatico F. Human muscle aging: ROS‐mediated alterations in rectus abdominis and vastus lateralis muscles. Exp Gerontol 40: 959‐965, 2005.
 358.Matos L, Gouveia A, Almeida H. Copper ability to induce premature senescence in human fibroblasts. Age (Dordr) 34: 783‐794, 2012.
 359.McHugh D, Gil J. Senescence and aging: Causes, consequences, and therapeutic avenues. J Cell Biol 217: 65‐77, 2018.
 360.McHugh J, Cheek DJ. Nitric oxide and regulation of vascular tone: Pharmacological and physiological considerations. Am J Crit Care 7: 131‐140; quiz 141‐132, 1998.
 361.McMillan DH, van der Velden JL, Lahue KG, Qian X, Schneider RW, Iberg MS, Nolin JD, Abdalla S, Casey DT, Tew KD, Townsend DM, Henderson CJ, Wolf CR, Butnor KJ, Taatjes DJ, Budd RC, Irvin CG, van der Vliet A, Flemer S, Anathy V, Janssen‐Heininger YM. Attenuation of lung fibrosis in mice with a clinically relevant inhibitor of glutathione‐S‐transferase pi. JCI Insight 1: pii: 85717, 2016.
 362.Meiners S, Eickelberg O, Konigshoff M. Hallmarks of the ageing lung. Eur Respir J 45: 807‐827, 2015.
 363.Mercer PF, Woodcock HV, Eley JD, Plate M, Sulikowski MG, Durrenberger PF, Franklin L, Nanthakumar CB, Man Y, Genovese F, McAnulty RJ, Yang S, Maher TM, Nicholson AG, Blanchard AD, Marshall RP, Lukey PT, Chambers RC. Exploration of a potent PI3 kinase/mTOR inhibitor as a novel anti‐fibrotic agent in IPF. Thorax 71: 701‐711, 2016.
 364.Miao L, St Clair DK. Regulation of superoxide dismutase genes: Implications in disease. Free Radic Biol Med 47: 344‐356, 2009.
 365.Michaeloudes C, Sukkar MB, Khorasani NM, Bhavsar PK, Chung KF. TGF‐beta regulates Nox4, MnSOD and catalase expression, and IL‐6 release in airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 300: L295‐L304, 2011.
 366.Michishita E, McCord RA, Berber E, Kioi M, Padilla‐Nash H, Damian M, Cheung P, Kusumoto R, Kawahara TL, Barrett JC, Chang HY, Bohr VA, Ried T, Gozani O, Chua KF. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 452: 492‐496, 2008.
 367.Mieyal JJ, Gallogly MM, Qanungo S, Sabens EA, Shelton MD. Molecular mechanisms and clinical implications of reversible protein S‐glutathionylation. Antioxid Redox Signal 10: 1941‐1988, 2008.
 368.Minagawa S, Araya J, Numata T, Nojiri S, Hara H, Yumino Y, Kawaishi M, Odaka M, Morikawa T, Nishimura SL, Nakayama K, Kuwano K. Accelerated epithelial cell senescence in IPF and the inhibitory role of SIRT6 in TGF‐beta‐induced senescence of human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 300: L391‐L401, 2011.
 369.Misharin AV, Morales‐Nebreda L, Reyfman PA, Cuda CM, Walter JM, McQuattie‐Pimentel AC, Chen CI, Anekalla KR, Joshi N, Williams KJN, Abdala‐Valencia H, Yacoub TJ, Chi M, Chiu S, Gonzalez‐Gonzalez FJ, Gates K, Lam AP, Nicholson TT, Homan PJ, Soberanes S, Dominguez S, Morgan VK, Saber R, Shaffer A, Hinchcliff M, Marshall SA, Bharat A, Berdnikovs S, Bhorade SM, Bartom ET, Morimoto RI, Balch WE, Sznajder JI, Chandel NS, Mutlu GM, Jain M, Gottardi CJ, Singer BD, Ridge KM, Bagheri N, Shilatifard A, Budinger GRS, Perlman H. Monocyte‐derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J Exp Med 214: 2387‐2404, 2017.
 370.Mittal M, Roth M, Konig P, Hofmann S, Dony E, Goyal P, Selbitz AC, Schermuly RT, Ghofrani HA, Kwapiszewska G, Kummer W, Klepetko W, Hoda MA, Fink L, Hanze J, Seeger W, Grimminger F, Schmidt HH, Weissmann N. Hypoxia‐dependent regulation of nonphagocytic NADPH oxidase subunit NOX4 in the pulmonary vasculature. Circ Res 101: 258‐267, 2007.
 371.Miyoshi K, Yanagi S, Kawahara K, Nishio M, Tsubouchi H, Imazu Y, Koshida R, Matsumoto N, Taguchi A, Yamashita S, Suzuki A, Nakazato M. Epithelial PTEN controls acute lung injury and fibrosis by regulating alveolar epithelial cell integrity. Am J Respir Crit Care Med 187: 262‐275, 2013.
 372.Mizuno S, Matsumoto K, Li MY, Nakamura T. HGF reduces advancing lung fibrosis in mice: A potential role for MMP‐dependent myofibroblast apoptosis. FASEB J 19: 580‐582, 2005.
 373.Moodley YP, Misso NL, Scaffidi AK, Fogel‐Petrovic M, McAnulty RJ, Laurent GJ, Thompson PJ, Knight DA. Inverse effects of interleukin‐6 on apoptosis of fibroblasts from pulmonary fibrosis and normal lungs. Am J Respir Cell Mol Biol 29: 490‐498, 2003.
 374.Moskwa P, Lorentzen D, Excoffon KJ, Zabner J, McCray PB Jr, Nauseef WM, Dupuy C, Banfi B. A novel host defense system of airways is defective in cystic fibrosis. Am J Respir Crit Care Med 175: 174‐183, 2007.
 375.Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L, Liu P, Mostoslavsky G, Franco S, Murphy MM, Mills KD, Patel P, Hsu JT, Hong AL, Ford E, Cheng HL, Kennedy C, Nunez N, Bronson R, Frendewey D, Auerbach W, Valenzuela D, Karow M, Hottiger MO, Hursting S, Barrett JC, Guarente L, Mulligan R, Demple B, Yancopoulos GD, Alt FW. Genomic instability and aging‐like phenotype in the absence of mammalian SIRT6. Cell 124: 315‐329, 2006.
 376.Muezzinler A, Zaineddin AK, Brenner H. A systematic review of leukocyte telomere length and age in adults. Ageing Res Rev 12: 509‐519, 2013.
 377.Mulugeta S, Nureki S, Beers MF. Lost after translation: Insights from pulmonary surfactant for understanding the role of alveolar epithelial dysfunction and cellular quality control in fibrotic lung disease. Am J Physiol Lung Cell Mol Physiol 309: L507‐L525, 2015.
 378.Mumby S, Upton RL, Chen Y, Stanford SJ, Quinlan GJ, Nicholson AG, Gutteridge JM, Lamb NJ, Evans TW. Lung heme oxygenase‐1 is elevated in acute respiratory distress syndrome. Crit Care Med 32: 1130‐1135, 2004.
 379.Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J, Pittet JF, Kaminski N, Garat C, Matthay MA, Rifkin DB, Sheppard D. The integrin alpha v beta 6 binds and activates latent TGF beta 1: A mechanism for regulating pulmonary inflammation and fibrosis. Cell 96: 319‐328, 1999.
 380.Murata H, Ihara Y, Nakamura H, Yodoi J, Sumikawa K, Kondo T. Glutaredoxin exerts an antiapoptotic effect by regulating the redox state of Akt. J Biol Chem 278: 50226‐50233, 2003.
 381.Murley JS, Kataoka Y, Cao D, Li JJ, Oberley LW, Grdina DJ. Delayed radioprotection by NFkappaB‐mediated induction of Sod2 (MnSOD) in SA‐NH tumor cells after exposure to clinically used thiol‐containing drugs. Radiat Res 162: 536‐546, 2004.
 382.Murray LA, Chen Q, Kramer MS, Hesson DP, Argentieri RL, Peng X, Gulati M, Homer RJ, Russell T, van Rooijen N, Elias JA, Hogaboam CM, Herzog EL. TGF‐beta driven lung fibrosis is macrophage dependent and blocked by Serum amyloid P. Int J Biochem Cell Biol 43: 154‐162, 2011.
 383.Murray PJ. Macrophage polarization. Annu Rev Physiol 79: 541‐566, 2017.
 384.Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11: 723‐737, 2011.
 385.Murthy S, Adamcakova‐Dodd A, Perry SS, Tephly LA, Keller RM, Metwali N, Meyerholz DK, Wang Y, Glogauer M, Thorne PS, Carter AB. Modulation of reactive oxygen species by Rac1 or catalase prevents asbestos‐induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 297: L846‐L855, 2009.
 386.Nakagome K, Dohi M, Okunishi K, Tanaka R, Miyazaki J, Yamamoto K. In vivo IL‐10 gene delivery attenuates bleomycin induced pulmonary fibrosis by inhibiting the production and activation of TGF‐beta in the lung. Thorax 61: 886‐894, 2006.
 387.Nakashima N, Kuwano K, Maeyama T, Hagimoto N, Yoshimi M, Hamada N, Yamada M, Nakanishi Y. The p53‐Mdm2 association in epithelial cells in idiopathic pulmonary fibrosis and non‐specific interstitial pneumonia. J Clin Pathol 58: 583‐589, 2005.
 388.Nakatani Y, Nakamura N, Sano J, Inayama Y, Kawano N, Yamanaka S, Miyagi Y, Nagashima Y, Ohbayashi C, Mizushima M, Manabe T, Kuroda M, Yokoi T, Matsubara O. Interstitial pneumonia in Hermansky‐Pudlak syndrome: Significance of florid foamy swelling/degeneration (giant lamellar body degeneration) of type‐2 pneumocytes. Virchows Arch 437: 304‐313, 2000.
 389.Nelson A, Mendoza T, Hoyle GW, Brody AR, Fermin C, Morris GF. Enhancement of fibrogenesis by the p53 tumor suppressor protein in asbestos‐exposed rodents. Chest 120: 33S‐34S, 2001.
 390.Nelson KK, Subbaram S, Connor KM, Dasgupta J, Ha XF, Meng TC, Tonks NK, Melendez JA. Redox‐dependent matrix metalloproteinase‐1 expression is regulated by JNK through Ets and AP‐1 promoter motifs. J Biol Chem 281: 14100‐14110, 2006.
 391.Nett RJ, Cummings KJ, Cannon B, Cox‐Ganser J, Nathan SD. Dental personnel treated for idiopathic pulmonary fibrosis at a Tertiary Care Center ‐ Virginia, 2000‐2015. MMWR Morb Mortal Wkly Rep 67: 270‐273, 2018.
 392.Nguyen GT, Green ER, Mecsas J. Neutrophils to the ROScue: Mechanisms of NADPH oxidase activation and bacterial resistance. Front Cell Infect Microbiol 7: 373, 2017.
 393.Nguyen T, Nioi P, Pickett CB. The Nrf2‐antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 284: 13291‐13295, 2009.
 394.Nho RS. Alteration of aging‐dependent microRNAs in idiopathic pulmonary fibrosis. Drug Dev Res 76: 343‐353, 2015.
 395.Nho RS, Hergert P. IPF fibroblasts are desensitized to type I collagen matrix‐induced cell death by suppressing low autophagy via aberrant Akt/mTOR kinases. PLoS One 9: e94616, 2014.
 396.Ni S, Wang D, Qiu X, Pang L, Song Z, Guo K. Bone marrow mesenchymal stem cells protect against bleomycin‐induced pulmonary fibrosis in rat by activating Nrf2 signaling. Int J Clin Exp Pathol 8: 7752‐7761, 2015.
 397.Niedbala W, Wei XQ, Piedrafita D, Xu D, Liew FY. Effects of nitric oxide on the induction and differentiation of Th1 cells. Eur J Immunol 29: 2498‐2505, 1999.
 398.Nisbet RE, Bland JM, Kleinhenz DJ, Mitchell PO, Walp ER, Sutliff RL, Hart CM. Rosiglitazone attenuates chronic hypoxia‐induced pulmonary hypertension in a mouse model. Am J Respir Cell Mol Biol 42: 482‐490, 2010.
 399.Nishi K, Oda T, Takabuchi S, Oda S, Fukuda K, Adachi T, Semenza GL, Shingu K, Hirota K. LPS induces hypoxia‐inducible factor 1 activation in macrophage‐differentiated cells in a reactive oxygen species‐dependent manner. Antioxid Redox Signal 10: 983‐995, 2008.
 400.Niu Y, DesMarais TL, Tong Z, Yao Y, Costa M. Oxidative stress alters global histone modification and DNA methylation. Free Radic Biol Med 82: 22‐28, 2015.
 401.Nogueira‐Neto J, Cardoso AS, Monteiro HP, Fonseca FL, Ramos LR, Junqueira VB, Simon KA. Basal neutrophil function in human aging: Implications in endothelial cell adhesion. Cell Biol Int 40: 796‐802, 2016.
 402.Nogueiras R, Habegger KM, Chaudhary N, Finan B, Banks AS, Dietrich MO, Horvath TL, Sinclair DA, Pfluger PT, Tschop MH. Sirtuin 1 and sirtuin 3: Physiological modulators of metabolism. Physiol Rev 92: 1479‐1514, 2012.
 403.Noth I, Zhang Y, Ma SF, Flores C, Barber M, Huang Y, Broderick SM, Wade MS, Hysi P, Scuirba J, Richards TJ, Juan‐Guardela BM, Vij R, Han MK, Martinez FJ, Kossen K, Seiwert SD, Christie JD, Nicolae D, Kaminski N, Garcia JGN. Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: A genome‐wide association study. Lancet Respir Med 1: 309‐317, 2013.
 404.Nozik‐Grayck E, Suliman HB, Piantadosi CA. Extracellular superoxide dismutase. Int J Biochem Cell Biol 37: 2466‐2471, 2005.
 405.Oak SR, Murray L, Herath A, Sleeman M, Anderson I, Joshi AD, Coelho AL, Flaherty KR, Toews GB, Knight D, Martinez FJ, Hogaboam CM. A micro RNA processing defect in rapidly progressing idiopathic pulmonary fibrosis. PLoS One 6: e21253, 2011.
 406.O'Connor JC, Wallace DM, O'Brien CJ, Cotter TG. A novel antioxidant function for the tumor‐suppressor gene p53 in the retinal ganglion cell. Invest Ophthalmol Vis Sci 49: 4237‐4244, 2008.
 407.Odajima N, Betsuyaku T, Nagai K, Moriyama C, Wang DH, Takigawa T, Ogino K, Nishimura M. The role of catalase in pulmonary fibrosis. Respir Res 11: 183, 2010.
 408.Offen D, Ziv I, Sternin H, Melamed E, Hochman A. Prevention of dopamine‐induced cell death by thiol antioxidants: Possible implications for treatment of Parkinson's disease. Exp Neurol 141: 32‐39, 1996.
 409.Oh J, Riek AE, Weng S, Petty M, Kim D, Colonna M, Cella M, Bernal‐Mizrachi C. Endoplasmic reticulum stress controls M2 macrophage differentiation and foam cell formation. J Biol Chem 287: 11629‐11641, 2012.
 410.Oikawa S, Kawanishi S. Site‐specific DNA damage at GGG sequence by oxidative stress may accelerate telomere shortening. FEBS Lett 453: 365‐368, 1999.
 411.Oldham JM, Ma SF, Martinez FJ, Anstrom KJ, Raghu G, Schwartz DA, Valenzi E, Witt L, Lee C, Vij R, Huang Y, Strek ME, Noth I, Investigators IPTOLLIP. MUC5B, and the response to N‐acetylcysteine among individuals with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 192: 1475‐1482, 2015.
 412.Olovnikov IA, Kravchenko JE, Chumakov PM. Homeostatic functions of the p53 tumor suppressor: Regulation of energy metabolism and antioxidant defense. Semin Cancer Biol 19: 32‐41, 2009.
 413.O'Neill JS, Feeney KA. Circadian redox and metabolic oscillations in mammalian systems. Antioxid Redox Signal 20: 2966‐2981, 2014.
 414.Oruqaj G, Karnati S, Vijayan V, Kotarkonda LK, Boateng E, Zhang W, Ruppert C, Gunther A, Shi W, Baumgart‐Vogt E. Compromised peroxisomes in idiopathic pulmonary fibrosis, a vicious cycle inducing a higher fibrotic response via TGF‐beta signaling. Proc Natl Acad Sci U S A 112: E2048‐E2057, 2015.
 415.Osborn‐Heaford HL, Murthy S, Gu L, Larson‐Casey JL, Ryan AJ, Shi L, Glogauer M, Neighbors JD, Hohl R, Carter AB. Targeting the isoprenoid pathway to abrogate progression of pulmonary fibrosis. Free Radic Biol Med 86: 47‐56, 2015.
 416.Ott M, Gogvadze V, Orrenius S, Zhivotovsky B. Mitochondria, oxidative stress and cell death. Apoptosis 12: 913‐922, 2007.
 417.Oury TD, Chang LY, Marklund SL, Day BJ, Crapo JD. Immunocytochemical localization of extracellular superoxide dismutase in human lung. Lab Investig 70: 889‐898, 1994.
 418.Oury TD, Crapo JD, Valnickova Z, Enghild JJ. Human extracellular superoxide dismutase is a tetramer composed of two disulphide‐linked dimers: A simplified, high‐yield purification of extracellular superoxide dismutase. Biochem J 317 (Pt 1): 51‐57, 1996.
 419.Pacht ER, Timerman AP, Lykens MG, Merola AJ. Deficiency of alveolar fluid glutathione in patients with sepsis and the adult respiratory distress syndrome. Chest 100: 1397‐1403, 1991.
 420.Pan J, Li D, Xu Y, Zhang J, Wang Y, Chen M, Lin S, Huang L, Chung EJ, Citrin DE, Wang Y, Hauer‐Jensen M, Zhou D, Meng A. Inhibition of Bcl‐2/xl with ABT‐263 selectively kills senescent type ii pneumocytes and reverses persistent pulmonary fibrosis induced by ionizing radiation in mice. Int J Radiat Oncol Biol Phys 99: 353‐361, 2017.
 421.Panduri V, Weitzman SA, Chandel N, Kamp DW. The mitochondria‐regulated death pathway mediates asbestos‐induced alveolar epithelial cell apoptosis. Am J Respir Cell Mol Biol 28: 241‐248, 2003.
 422.Paneni F, Cosentino F. p66 Shc as the engine of vascular aging. Curr Vasc Pharmacol 10: 697‐699, 2012.
 423.Paolocci G, Folletti I, Toren K, Ekstrom M, Dell'Omo M, Muzi G, Murgia N. Occupational risk factors for idiopathic pulmonary fibrosis in Southern Europe: A case‐control study. BMC Pulm Med 18: 75, 2018.
 424.Pardo A, Selman M. Lung fibroblasts, aging, and idiopathic pulmonary fibrosis. Ann Am Thorac Soc 13 (Suppl 5): S417‐S421, 2016.
 425.Parizada B, Werber MM, Nimrod A. Protective effects of human recombinant MnSOD in adjuvant arthritis and bleomycin‐induced lung fibrosis. Free Radic Res Commun 15: 297‐301, 1991.
 426.Park JH, Zhuang J, Li J, Hwang PM. p53 as guardian of the mitochondrial genome. FEBS Lett 590: 924‐934, 2016.
 427.Parker MW, Rossi D, Peterson M, Smith K, Sikstrom K, White ES, Connett JE, Henke CA, Larsson O, Bitterman PB. Fibrotic extracellular matrix activates a profibrotic positive feedback loop. J Clin Invest 124: 1622‐1635, 2014.
 428.Parzych KR, Klionsky DJ. An overview of autophagy: Morphology, mechanism, and regulation. Antioxid Redox Signal 20: 460‐473, 2014.
 429.Passos JF, Saretzki G, Ahmed S, Nelson G, Richter T, Peters H, Wappler I, Birket MJ, Harold G, Schaeuble K, Birch‐Machin MA, Kirkwood TB, von Zglinicki T. Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere‐dependent senescence. PLoS Biol 5: e110, 2007.
 430.Patel AS, Song JW, Chu SG, Mizumura K, Osorio JC, Shi Y, El‐Chemaly S, Lee CG, Rosas IO, Elias JA, Choi AM, Morse D. Epithelial cell mitochondrial dysfunction and PINK1 are induced by transforming growth factor‐beta1 in pulmonary fibrosis. PLoS One 10: e0121246, 2015.
 431.Pattabiraman G, Palasiewicz K, Galvin JP, Ucker DS. Aging‐associated dysregulation of homeostatic immune response termination (and not initiation). Aging Cell 16: 585‐593, 2017.
 432.Pechkovsky DV, Prasse A, Kollert F, Engel KM, Dentler J, Luttmann W, Friedrich K, Muller‐Quernheim J, Zissel G. Alternatively activated alveolar macrophages in pulmonary fibrosis‐mediator production and intracellular signal transduction. Clin Immunol 137: 89‐101, 2010.
 433.Pedruzzi E, Guichard C, Ollivier V, Driss F, Fay M, Prunet C, Marie JC, Pouzet C, Samadi M, Elbim C, O'Dowd Y, Bens M, Vandewalle A, Gougerot‐Pocidalo MA, Lizard G, Ogier‐Denis E. NAD(P)H oxidase Nox‐4 mediates 7‐ketocholesterol‐induced endoplasmic reticulum stress and apoptosis in human aortic smooth muscle cells. Mol Cell Biol 24: 10703‐10717, 2004.
 434.Peltoniemi M, Kaarteenaho‐Wiik R, Saily M, Sormunen R, Paakko P, Holmgren A, Soini Y, Kinnula VL. Expression of glutaredoxin is highly cell specific in human lung and is decreased by transforming growth factor‐beta in vitro and in interstitial lung diseases in vivo. Hum Pathol 35: 1000‐1007, 2004.
 435.Pendyala S, Gorshkova IA, Usatyuk PV, He D, Pennathur A, Lambeth JD, Thannickal VJ, Natarajan V. Role of Nox4 and Nox2 in hyperoxia‐induced reactive oxygen species generation and migration of human lung endothelial cells. Antioxid Redox Signal 11: 747‐764, 2009.
 436.Perkins A, Nelson KJ, Parsonage D, Poole LB, Karplus PA. Peroxiredoxins: Guardians against oxidative stress and modulators of peroxide signaling. Trends Biochem Sci 40: 435‐445, 2015.
 437.Peskin AV, Turner R, Maghzal GJ, Winterbourn CC, Kettle AJ. Oxidation of methionine to dehydromethionine by reactive halogen species generated by neutrophils. Biochemistry 48: 10175‐10182, 2009.
 438.Petersen SV, Oury TD, Ostergaard L, Valnickova Z, Wegrzyn J, Thogersen IB, Jacobsen C, Bowler RP, Fattman CL, Crapo JD, Enghild JJ. Extracellular superoxide dismutase (EC‐SOD) binds to type i collagen and protects against oxidative fragmentation. J Biol Chem 279: 13705‐13710, 2004.
 439.Petry A, Djordjevic T, Weitnauer M, Kietzmann T, Hess J, Gorlach A. NOX2 and NOX4 mediate proliferative response in endothelial cells. Antioxid Redox Signal 8: 1473‐1484, 2006.
 440.Piao YJ, Seo YH, Hong F, Kim JH, Kim YJ, Kang MH, Kim BS, Jo SA, Jo I, Jue DM, Kang I, Ha J, Kim SS. Nox 2 stimulates muscle differentiation via NF‐kappaB/iNOS pathway. Free Radic Biol Med 38: 989‐1001, 2005.
 441.Pinto M, Moraes CT. Mechanisms linking mtDNA damage and aging. Free Radic Biol Med 85: 250‐258, 2015.
 442.Plataki M, Koutsopoulos AV, Darivianaki K, Delides G, Siafakas NM, Bouros D. Expression of apoptotic and antiapoptotic markers in epithelial cells in idiopathic pulmonary fibrosis. Chest 127: 266‐274, 2005.
 443.Pociask DA, Sime PJ, Brody AR. Asbestos‐derived reactive oxygen species activate TGF‐beta1. Lab Investig 84: 1013‐1023, 2004.
 444.Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B. A model for p53‐induced apoptosis. Nature 389: 300‐305, 1997.
 445.Portnoy J, Pan T, Dinarello CA, Shannon JM, Westcott JY, Zhang L, Mason RJ. Alveolar type II cells inhibit fibroblast proliferation: Role of IL‐1alpha. Am J Physiol Lung Cell Mol Physiol 290: L307‐L316, 2006.
 446.Prasse A, Pechkovsky DV, Toews GB, Jungraithmayr W, Kollert F, Goldmann T, Vollmer E, Muller‐Quernheim J, Zissel G. A vicious circle of alveolar macrophages and fibroblasts perpetuates pulmonary fibrosis via CCL18. Am J Respir Crit Care Med 173: 781‐792, 2006.
 447.Quinlan TR, Li D, Laubach VE, Shesely EG, Zhou N, Johns RA. eNOS‐deficient mice show reduced pulmonary vascular proliferation and remodeling to chronic hypoxia. Am J Physiol Lung Cell Mol Physiol 279: L641‐L650, 2000.
 448.Rabbani ZN, Anscher MS, Folz RJ, Archer E, Huang H, Chen L, Golson ML, Samulski TS, Dewhirst MW, Vujaskovic Z. Overexpression of extracellular superoxide dismutase reduces acute radiation induced lung toxicity. BMC Cancer 5: 59, 2005.
 449.Rabinovich EI, Kapetanaki MG, Steinfeld I, Gibson KF, Pandit KV, Yu G, Yakhini Z, Kaminski N. Global methylation patterns in idiopathic pulmonary fibrosis. PLoS One 7: e33770, 2012.
 450.Rada B, Hably C, Meczner A, Timar C, Lakatos G, Enyedi P, Ligeti E. Role of Nox2 in elimination of microorganisms. Semin Immunopathol 30: 237‐253, 2008.
 451.Rada B, Leto TL. Characterization of hydrogen peroxide production by Duox in bronchial epithelial cells exposed to Pseudomonas aeruginosa. FEBS Lett 584: 917‐922, 2010.
 452.Raes G, De Baetselier P, Noel W, Beschin A, Brombacher F, Hassanzadeh Gh G. Differential expression of FIZZ1 and Ym1 in alternatively versus classically activated macrophages. J Leukoc Biol 71: 597‐602, 2002.
 453.Raghu G, Richeldi L, Crestani B, Wung P, Bejuit R, Esperet C, Antoni C, Soubrane C. SAR156597 in idiopathic pulmonary fibrosis: A phase 2 placebo‐controlled study (DRI11772). Eur Respir J: 52: pii: 1801130, 2018.
 454.Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 174: 810‐816, 2006.
 455.Rahaman SO, Grove LM, Paruchuri S, Southern BD, Abraham S, Niese KA, Scheraga RG, Ghosh S, Thodeti CK, Zhang DX, Moran MM, Schilling WP, Tschumperlin DJ, Olman MA. TRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in mice. J Clin Invest 124: 5225‐5238, 2014.
 456.Rahman I, Bel A, Mulier B, Lawson MF, Harrison DJ, Macnee W, Smith CA. Transcriptional regulation of gamma‐glutamylcysteine synthetase‐heavy subunit by oxidants in human alveolar epithelial cells. Biochem Biophys Res Commun 229: 832‐837, 1996.
 457.Rahman I, MacNee W. Oxidative stress and regulation of glutathione in lung inflammation. Eur Respir J 16: 534‐554, 2000.
 458.Rahman I, Skwarska E, Henry M, Davis M, O'Connor CM, FitzGerald MX, Greening A, MacNee W. Systemic and pulmonary oxidative stress in idiopathic pulmonary fibrosis. Free Radic Biol Med 27: 60‐68, 1999.
 459.Ramirez G, Hagood JS, Sanders Y, Ramirez R, Becerril C, Segura L, Barrera L, Selman M, Pardo A. Absence of Thy‐1 results in TGF‐beta induced MMP‐9 expression and confers a profibrotic phenotype to human lung fibroblasts. Lab Investig 91: 1206‐1218, 2011.
 460.Rangarajan S, Bernard K, Thannickal VJ. Mitochondrial dysfunction in pulmonary fibrosis. Ann Am Thorac Soc 14: S383‐S388, 2017.
 461.Rangarajan S, Bone NB, Zmijewska AA, Jiang S, Park DW, Bernard K, Locy ML, Ravi S, Deshane J, Mannon RB, Abraham E, Darley‐Usmar V, Thannickal VJ, Zmijewski JW. Metformin reverses established lung fibrosis in a bleomycin model. Nat Med 24: 1121‐1127, 2018.
 462.Reynaert NL, Wouters EF, Janssen‐Heininger YM. Modulation of glutaredoxin‐1 expression in a mouse model of allergic airway disease. Am J Respir Cell Mol Biol 36: 147‐151, 2007.
 463.Rhee SG, Chae HZ, Kim K. Peroxiredoxins: A historical overview and speculative preview of novel mechanisms and emerging concepts in cell signaling. Free Radic Biol Med 38: 1543‐1552, 2005.
 464.Rock JR, Barkauskas CE, Cronce MJ, Xue Y, Harris JR, Liang J, Noble PW, Hogan BL. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proc Natl Acad Sci U S A 108: E1475‐E1483, 2011.
 465.Romero Y, Bueno M, Ramirez R, Alvarez D, Sembrat JC, Goncharova EA, Rojas M, Selman M, Mora AL, Pardo A. mTORC1 activation decreases autophagy in aging and idiopathic pulmonary fibrosis and contributes to apoptosis resistance in IPF fibroblasts. Aging Cell 15: 1103‐1112, 2016.
 466.Rosas IO, Richards TJ, Konishi K, Zhang Y, Gibson K, Lokshin AE, Lindell KO, Cisneros J, Macdonald SD, Pardo A, Sciurba F, Dauber J, Selman M, Gochuico BR, Kaminski N. MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis. PLoS Med 5: e93, 2008.
 467.Roum JH, Buhl R, McElvaney NG, Borok Z, Crystal RG. Systemic deficiency of glutathione in cystic fibrosis. J Appl Physiol (1985) 75: 2419‐2424, 1993.
 468.Rufini A, Tucci P, Celardo I, Melino G. Senescence and aging: The critical roles of p53. Oncogene 32: 5129‐5143, 2013.
 469.Rushmore TH, Morton MR, Pickett CB. The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J Biol Chem 266: 11632‐11639, 1991.
 470.Rutkowski DT, Arnold SM, Miller CN, Wu J, Li J, Gunnison KM, Mori K, Sadighi Akha AA, Raden D, Kaufman RJ. Adaptation to ER stress is mediated by differential stabilities of pro‐survival and pro‐apoptotic mRNAs and proteins. PLoS Biol 4: e374, 2006.
 471.Ryu JH, Moua T, Daniels CE, Hartman TE, Yi ES, Utz JP, Limper AH. Idiopathic pulmonary fibrosis: Evolving concepts. Mayo Clin Proc 89: 1130‐1142, 2014.
 472.Sablina AA, Budanov AV, Ilyinskaya GV, Agapova LS, Kravchenko JE, Chumakov PM. The antioxidant function of the p53 tumor suppressor. Nat Med 11: 1306‐1313, 2005.
 473.Saini R, Patel S, Saluja R, Sahasrabuddhe AA, Singh MP, Habib S, Bajpai VK, Dikshit M. Nitric oxide synthase localization in the rat neutrophils: Immunocytochemical, molecular, and biochemical studies. J Leukoc Biol 79: 519‐528, 2006.
 474.Sakiyama H, Fujiwara N, Yoneoka Y, Yoshihara D, Eguchi H, Suzuki KC. Zn‐SOD deficiency induces the accumulation of hepatic collagen. Free Radic Res 50: 666‐677, 2016.
 475.Saleem A, Adhihetty PJ, Hood DA. Role of p53 in mitochondrial biogenesis and apoptosis in skeletal muscle. Physiol Genomics 37: 58‐66, 2009.
 476.Sanders YY, Ambalavanan N, Halloran B, Zhang X, Liu H, Crossman DK, Bray M, Zhang K, Thannickal VJ, Hagood JS. Altered DNA methylation profile in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 186: 525‐535, 2012.
 477.Sanders YY, Cui Z, Le Saux CJ, Horowitz JC, Rangarajan S, Kurundkar A, Antony VB, Thannickal VJ. SMAD‐independent down‐regulation of caveolin‐1 by TGF‐beta: Effects on proliferation and survival of myofibroblasts. PLoS One 10: e0116995, 2015.
 478.Sanders YY, Hagood JS, Liu H, Zhang W, Ambalavanan N, Thannickal VJ. Histone deacetylase inhibition promotes fibroblast apoptosis and ameliorates pulmonary fibrosis in mice. Eur Respir J 43: 1448‐1458, 2014.
 479.Sanders YY, Liu H, Liu G, Thannickal VJ. Epigenetic mechanisms regulate NADPH oxidase‐4 expression in cellular senescence. Free Radic Biol Med 79: 197‐205, 2015.
 480.Sanders YY, Liu H, Scruggs AM, Duncan SR, Huang SK, Thannickal VJ. Epigenetic regulation of caveolin‐1 gene expression in lung fibroblasts. Am J Respir Cell Mol Biol 56: 50‐61, 2017.
 481.Sanders YY, Pardo A, Selman M, Nuovo GJ, Tollefsbol TO, Siegal GP, Hagood JS. Thy‐1 promoter hypermethylation: A novel epigenetic pathogenic mechanism in pulmonary fibrosis. Am J Respir Cell Mol Biol 39: 610‐618, 2008.
 482.Sandler NG, Mentink‐Kane MM, Cheever AW, Wynn TA. Global gene expression profiles during acute pathogen‐induced pulmonary inflammation reveal divergent roles for Th1 and Th2 responses in tissue repair. J Immunol 171: 3655‐3667, 2003.
 483.Santos CX, Tanaka LY, Wosniak J, Laurindo FR. Mechanisms and implications of reactive oxygen species generation during the unfolded protein response: Roles of endoplasmic reticulum oxidoreductases, mitochondrial electron transport, and NADPH oxidase. Antioxid Redox Signal 11: 2409‐2427, 2009.
 484.Sardina JL, Lopez‐Ruano G, Sanchez‐Abarca LI, Perez‐Simon JA, Gaztelumendi A, Trigueros C, Llanillo M, Sanchez‐Yague J, Hernandez‐Hernandez A. p22phox‐dependent NADPH oxidase activity is required for megakaryocytic differentiation. Cell Death Differ 17: 1842‐1854, 2010.
 485.Sato N, Takasaka N, Yoshida M, Tsubouchi K, Minagawa S, Araya J, Saito N, Fujita Y, Kurita Y, Kobayashi K, Ito S, Hara H, Kadota T, Yanagisawa H, Hashimoto M, Utsumi H, Wakui H, Kojima J, Numata T, Kaneko Y, Odaka M, Morikawa T, Nakayama K, Kohrogi H, Kuwano K. Metformin attenuates lung fibrosis development via NOX4 suppression. Respir Res 17: 107, 2016.
 486.Schafer MJ, White TA, Iijima K, Haak AJ, Ligresti G, Atkinson EJ, Oberg AL, Birch J, Salmonowicz H, Zhu Y, Mazula DL, Brooks RW, Fuhrmann‐Stroissnigg H, Pirtskhalava T, Prakash YS, Tchkonia T, Robbins PD, Aubry MC, Passos JF, Kirkland JL, Tschumperlin DJ, Kita H, LeBrasseur NK. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun 8: 14532, 2017.
 487.Schamberger AC, Schiller HB, Fernandez IE, Sterclova M, Heinzelmann K, Hennen E, Hatz R, Behr J, Vasakova M, Mann M, Eickelberg O, Staab‐Weijnitz CA. Glutathione peroxidase 3 localizes to the epithelial lining fluid and the extracellular matrix in interstitial lung disease. Sci Rep 6: 29952, 2016.
 488.Schroeder SA, Swift M, Sandoval C, Langston C. Interstitial lung disease in patients with ataxia‐telangiectasia. Pediatr Pulmonol 39: 537‐543, 2005.
 489.Schuster N, Krieglstein K. Mechanisms of TGF‐beta‐mediated apoptosis. Cell Tissue Res 307: 1‐14, 2002.
 490.Segal AW, West I, Wientjes F, Nugent JH, Chavan AJ, Haley B, Garcia RC, Rosen H, Scrace G. Cytochrome b‐245 is a flavocytochrome containing FAD and the NADPH‐binding site of the microbicidal oxidase of phagocytes. Biochem J 284 (Pt 3): 781‐788, 1992.
 491.Sellares J, Rojas M. Quercetin in idiopathic pulmonary fibrosis: Another brick in the senolytic wall. Am J Respir Cell Mol Biol 60: 3‐4, 2019.
 492.Selman M, King TE, Pardo A, American Thoracic Society, European Respiratory Society, American College of Chest Physicians. Idiopathic pulmonary fibrosis: Prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 134: 136‐151, 2001.
 493.Selman M, Pardo A. Role of epithelial cells in idiopathic pulmonary fibrosis: From innocent targets to serial killers. Proc Am Thorac Soc 3: 364‐372, 2006.
 494.Sener G, Topaloglu N, Sehirli AO, Ercan F, Gedik N. Resveratrol alleviates bleomycin‐induced lung injury in rats. Pulm Pharmacol Ther 20: 642‐649, 2007.
 495.Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88: 593‐602, 1997.
 496.Sevier CS, Kaiser CA. Ero1 and redox homeostasis in the endoplasmic reticulum. Biochim Biophys Acta 1783: 549‐556, 2008.
 497.Shahzeidi S, Sarnstrand B, Jeffery PK, McAnulty RJ, Laurent GJ. Oral N‐acetylcysteine reduces bleomycin‐induced collagen deposition in the lungs of mice. Eur Respir J 4: 845‐852, 1991.
 498.Shih PH, Yen GC. Differential expressions of antioxidant status in aging rats: The role of transcriptional factor Nrf2 and MAPK signaling pathway. Biogerontology 8: 71‐80, 2007.
 499.Shin JA, Chung JS, Cho SH, Kim HJ, Yoo YD. Romo1 expression contributes to oxidative stress‐induced death of lung epithelial cells. Biochem Biophys Res Commun 439: 315‐320, 2013.
 500.Shivshankar P, Brampton C, Miyasato S, Kasper M, Thannickal VJ, Le Saux CJ. Caveolin‐1 deficiency protects from pulmonary fibrosis by modulating epithelial cell senescence in mice. Am J Respir Cell Mol Biol 47: 28‐36, 2012.
 501.Sica A, Erreni M, Allavena P, Porta C. Macrophage polarization in pathology. Cell Mol Life Sci 72: 4111‐4126, 2015.
 502.Sies H, Berndt C, Jones DP. Oxidative stress. Annu Rev Biochem 86: 715‐748, 2017.
 503.Sies H, Cadenas E. Oxidative stress: Damage to intact cells and organs. Philos Trans R Soc Lond Ser B Biol Sci 311: 617‐631, 1985.
 504.Sipkens JA, Hahn N, van den Brand CS, Meischl C, Cillessen SA, Smith DE, Juffermans LJ, Musters RJ, Roos D, Jakobs C, Blom HJ, Smulders YM, Krijnen PA, Stehouwer CD, Rauwerda JA, van Hinsbergh VW, Niessen HW. Homocysteine‐induced apoptosis in endothelial cells coincides with nuclear NOX2 and peri‐nuclear NOX4 activity. Cell Biochem Biophys 67: 341‐352, 2013.
 505.Sisson TH, Mendez M, Choi K, Subbotina N, Courey A, Cunningham A, Dave A, Engelhardt JF, Liu X, White ES, Thannickal VJ, Moore BB, Christensen PJ, Simon RH. Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosis. Am J Respir Crit Care Med 181: 254‐263, 2010.
 506.Siwik DA, Pagano PJ, Colucci WS. Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. Am J Physiol Cell Physiol 280: C53‐C60, 2001.
 507.Smith M, Dalurzo M, Panse P, Parish J, Leslie K. Usual interstitial pneumonia‐pattern fibrosis in surgical lung biopsies. Clinical, radiological and histopathological clues to aetiology. J Clin Pathol 66: 896‐903, 2013.
 508.Somborac‐Bacura A, van der Toorn M, Franciosi L, Slebos DJ, Zanic‐Grubisic T, Bischoff R, van Oosterhout AJ. Cigarette smoke induces endoplasmic reticulum stress response and proteasomal dysfunction in human alveolar epithelial cells. Exp Physiol 98: 316‐325, 2013.
 509.Song JJ, Lee YJ. Differential role of glutaredoxin and thioredoxin in metabolic oxidative stress‐induced activation of apoptosis signal‐regulating kinase 1. Biochem J 373: 845‐853, 2003.
 510.Song JS, Cho HH, Lee BJ, Bae YC, Jung JS. Role of thioredoxin 1 and thioredoxin 2 on proliferation of human adipose tissue‐derived mesenchymal stem cells. Stem Cells Dev 20: 1529‐1537, 2011.
 511.Sosulski ML, Gongora R, Danchuk S, Dong C, Luo F, Sanchez CG. Deregulation of selective autophagy during aging and pulmonary fibrosis: The role of TGFbeta1. Aging Cell 14: 774‐783, 2015.
 512.Starr ME, Ueda J, Yamamoto S, Evers BM, Saito H. The effects of aging on pulmonary oxidative damage, protein nitration, and extracellular superoxide dismutase down‐regulation during systemic inflammation. Free Radic Biol Med 50: 371‐380, 2011.
 513.Stewart JP, Egan JJ, Ross AJ, Kelly BG, Lok SS, Hasleton PS, Woodcock AA. The detection of Epstein‐Barr virus DNA in lung tissue from patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 159: 1336‐1341, 1999.
 514.Stralin P, Marklund SL. Multiple cytokines regulate the expression of extracellular superoxide dismutase in human vascular smooth muscle cells. Atherosclerosis 151: 433‐441, 2000.
 515.Stroes E, Kastelein J, Cosentino F, Erkelens W, Wever R, Koomans H, Luscher T, Rabelink T. Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest 99: 41‐46, 1997.
 516.Sturrock A, Cahill B, Norman K, Huecksteadt TP, Hill K, Sanders K, Karwande SV, Stringham JC, Bull DA, Gleich M, Kennedy TP, Hoidal JR. Transforming growth factor‐beta1 induces Nox4 NAD(P)H oxidase and reactive oxygen species‐dependent proliferation in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 290: L661‐L673, 2006.
 517.Sumimoto H. Structure, regulation and evolution of Nox‐family NADPH oxidases that produce reactive oxygen species. FEBS J 275: 3249‐3277, 2008.
 518.Sun T, Liu J, Zhao de W. Efficacy of N‐acetylcysteine in idiopathic pulmonary fibrosis: A systematic review and meta‐analysis. Medicine (Baltimore) 95: e3629, 2016.
 519.Swamy SM, Rajasekaran NS, Thannickal VJ. Nuclear factor‐erythroid‐2‐related factor 2 in aging and lung fibrosis. Am J Pathol 186: 1712‐1723, 2016.
 520.Takeya R, Ueno N, Kami K, Taura M, Kohjima M, Izaki T, Nunoi H, Sumimoto H. Novel human homologues of p47phox and p67phox participate in activation of superoxide‐producing NADPH oxidases. J Biol Chem 278: 25234‐25246, 2003.
 521.Tamborindeguy MT, Matte BF, Ramos GO, Alves AM, Bernardi L, Lamers ML. NADPH‐oxidase‐derived ROS alters cell migration by modulating adhesions dynamics. Biol Cell 110: 225‐236, 2018.
 522.Tan RJ, Fattman CL, Watkins SC, Oury TD. Redistribution of pulmonary EC‐SOD after exposure to asbestos. J Appl Physiol (1985) 97: 2006‐2013, 2004.
 523.Tanaka K, Ishihara T, Azuma A, Kudoh S, Ebina M, Nukiwa T, Sugiyama Y, Tasaka Y, Namba T, Ishihara T, Sato K, Mizushima Y, Mizushima T. Therapeutic effect of lecithinized superoxide dismutase on bleomycin‐induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 298: L348‐L360, 2010.
 524.Tanaka KI, Azuma A, Miyazaki Y, Sato K, Mizushima T. Effects of lecithinized superoxide dismutase and/or pirfenidone against bleomycin‐induced pulmonary fibrosis. Chest 142: 1011‐1019, 2012.
 525.Tanaka T, Yoshimi M, Maeyama T, Hagimoto N, Kuwano K, Hara N. Resistance to Fas‐mediated apoptosis in human lung fibroblast. Eur Respir J 20: 359‐368, 2002.
 526.Tang H, Gao L, Mao J, He H, Liu J, Cai X, Lin H, Wu T. Salidroside protects against bleomycin‐induced pulmonary fibrosis: Activation of Nrf2‐antioxidant signaling, and inhibition of NF‐kappaB and TGF‐beta1/Smad‐2/‐3 pathways. Cell Stress Chaperones 21: 239‐249, 2016.
 527.Tang YW, Johnson JE, Browning PJ, Cruz‐Gervis RA, Davis A, Graham BS, Brigham KL, Oates JA Jr, Loyd JE, Stecenko AA. Herpesvirus DNA is consistently detected in lungs of patients with idiopathic pulmonary fibrosis. J Clin Microbiol 41: 2633‐2640, 2003.
 528.Tanjore H, Blackwell TS, Lawson WE. Emerging evidence for endoplasmic reticulum stress in the pathogenesis of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 302: L721‐L729, 2012.
 529.Tavana O, Benjamin CL, Puebla‐Osorio N, Sang M, Ullrich SE, Ananthaswamy HN, Zhu C. Absence of p53‐dependent apoptosis leads to UV radiation hypersensitivity, enhanced immunosuppression and cellular senescence. Cell Cycle 9: 3328‐3336, 2010.
 530.Tenhunen R, Marver HS, Schmid R. The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci U S A 61: 748‐755, 1968.
 531.Terada LS, Guidot DM, Leff JA, Willingham IR, Hanley ME, Piermattei D, Repine JE. Hypoxia injures endothelial cells by increasing endogenous xanthine oxidase activity. Proc Natl Acad Sci U S A 89: 3362‐3366, 1992.
 532.Teramoto S, Fukuchi Y, Uejima Y, Shu CY, Orimo H. Superoxide anion formation and glutathione metabolism of blood in patients with idiopathic pulmonary fibrosis. Biochem Mol Med 55: 66‐70, 1995.
 533.Thannickal VJ. Mechanisms of pulmonary fibrosis: Role of activated myofibroblasts and NADPH oxidase. Fibrogenesis Tissue Repair 5: S23, 2012.
 534.Thannickal VJ. Mechanistic links between aging and lung fibrosis. Biogerontology 14: 609‐615, 2013.
 535.Thannickal VJ, Fanburg BL. Activation of an H2O2‐generating NADH oxidase in human lung fibroblasts by transforming growth factor beta 1. J Biol Chem 270: 30334‐30338, 1995.
 536.Thannickal VJ, Fanburg BL. Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol 279: L1005‐L1028, 2000.
 537.Thiery JP, Sleeman JP. Complex networks orchestrate epithelial‐mesenchymal transitions. Nat Rev Mol Cell Biol 7: 131‐142, 2006.
 538.Thomas DD, Espey MG, Ridnour LA, Hofseth LJ, Mancardi D, Harris CC, Wink DA. Hypoxic inducible factor 1alpha, extracellular signal‐regulated kinase, and p53 are regulated by distinct threshold concentrations of nitric oxide. Proc Natl Acad Sci U S A 101: 8894‐8899, 2004.
 539.Thomas DD, Ridnour LA, Isenberg JS, Flores‐Santana W, Switzer CH, Donzelli S, Hussain P, Vecoli C, Paolocci N, Ambs S, Colton CA, Harris CC, Roberts DD, Wink DA. The chemical biology of nitric oxide: Implications in cellular signaling. Free Radic Biol Med 45: 18‐31, 2008.
 540.Tian K, Chen P, Liu Z, Si S, Zhang Q, Mou Y, Han L, Wang Q, Zhou X. Sirtuin 6 inhibits epithelial to mesenchymal transition during idiopathic pulmonary fibrosis via inactivating TGF‐beta1/Smad3 signaling. Oncotarget 8: 61011‐61024, 2017.
 541.Tian Y, Li H, Qiu T, Dai J, Zhang Y, Chen J, Cai H. Loss of PTEN induces lung fibrosis via alveolar epithelial cell senescence depending on NF‐kappaB activation. Aging Cell 18: e12858, 2019.
 542.Tiitto L, Kaarteenaho‐Wiik R, Sormunen R, Holmgren A, Paakko P, Soini Y, Kinnula VL. Expression of the thioredoxin system in interstitial lung disease. J Pathol 201: 363‐370, 2003.
 543.Tobar N, Toyos M, Urra C, Mendez N, Arancibia R, Smith PC, Martinez J. c‐Jun N terminal kinase modulates NOX‐4 derived ROS production and myofibroblasts differentiation in human breast stromal cells. BMC Cancer 14: 640, 2014.
 544.Tolbert NE, Essner E. Microbodies: Peroxisomes and glyoxysomes. J Cell Biol 91: 271s‐283s, 1981.
 545.Tomioka H, Kuwata Y, Imanaka K, Hashimoto K, Ohnishi H, Tada K, Sakamoto H, Iwasaki H. A pilot study of aerosolized N‐acetylcysteine for idiopathic pulmonary fibrosis. Respirology 10: 449‐455, 2005.
 546.Tomos IP, Tzouvelekis A, Aidinis V, Manali ED, Bouros E, Bouros D, Papiris SA. Extracellular matrix remodeling in idiopathic pulmonary fibrosis. It is the ‘bed’ that counts and not ‘the sleepers’. Expert Rev Respir Med 11: 299‐309, 2017.
 547.Traver G, Mont S, Gius D, Lawson WE, Ding GX, Sekhar KR, Freeman ML. Loss of Nrf2 promotes alveolar type 2 cell loss in irradiated, fibrotic lung. Free Radic Biol Med 112: 578‐586, 2017.
 548.Trujillo G, O'Connor EC, Kunkel SL, Hogaboam CM. A novel mechanism for CCR4 in the regulation of macrophage activation in bleomycin‐induced pulmonary fibrosis. Am J Pathol 172: 1209‐1221, 2008.
 549.Tsakiri KD, Cronkhite JT, Kuan PJ, Xing C, Raghu G, Weissler JC, Rosenblatt RL, Shay JW, Garcia CK. Adult‐onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci U S A 104: 7552‐7557, 2007.
 550.Tsan MF. Superoxide dismutase and pulmonary oxygen toxicity: Lessons from transgenic and knockout mice (review). Int J Mol Med 7: 13‐19, 2001.
 551.Tsubouchi K, Araya J, Minagawa S, Hara H, Ichikawa A, Saito N, Kadota T, Sato N, Yoshida M, Kurita Y, Kobayashi K, Ito S, Fujita Y, Utsumi H, Yanagisawa H, Hashimoto M, Wakui H, Yoshii Y, Ishikawa T, Numata T, Kaneko Y, Asano H, Yamashita M, Odaka M, Morikawa T, Nakayama K, Nakanishi Y, Kuwano K. Azithromycin attenuates myofibroblast differentiation and lung fibrosis development through proteasomal degradation of NOX4. Autophagy 13: 1420‐1434, 2017.
 552.Tsuburai T, Suzuki M, Nagashima Y, Suzuki S, Inoue S, Hasiba T, Ueda A, Ikehara K, Matsuse T, Ishigatsubo Y. Adenovirus‐mediated transfer and overexpression of heme oxygenase 1 cDNA in lung prevents bleomycin‐induced pulmonary fibrosis via a Fas‐Fas ligand‐independent pathway. Hum Gene Ther 13: 1945‐1960, 2002.
 553.Ueno M, Maeno T, Nomura M, Aoyagi‐Ikeda K, Matsui H, Hara K, Tanaka T, Iso T, Suga T, Kurabayashi M. Hypoxia‐inducible factor‐1alpha mediates TGF‐beta‐induced PAI‐1 production in alveolar macrophages in pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 300: L740‐L752, 2011.
 554.Ueno N, Takeya R, Miyano K, Kikuchi H, Sumimoto H. The NADPH oxidase Nox3 constitutively produces superoxide in a p22phox‐dependent manner: Its regulation by oxidase organizers and activators. J Biol Chem 280: 23328‐23339, 2005.
 555.Ueyama T, Geiszt M, Leto TL. Involvement of Rac1 in activation of multicomponent Nox1‐ and Nox3‐based NADPH oxidases. Mol Cell Biol 26: 2160‐2174, 2006.
 556.Uhal BD, Joshi I, Hughes WF, Ramos C, Pardo A, Selman M. Alveolar epithelial cell death adjacent to underlying myofibroblasts in advanced fibrotic human lung. Am J Phys 275: L1192‐L1199, 1998.
 557.Van Buul JD, Fernandez‐Borja M, Anthony EC, Hordijk PL. Expression and localization of NOX2 and NOX4 in primary human endothelial cells. Antioxid Redox Signal 7: 308‐317, 2005.
 558.van den Blink B, Dillingh MR, Ginns LC, Morrison LD, Moerland M, Wijsenbeek M, Trehu EG, Bartholmai BJ, Burggraaf J. Recombinant human pentraxin‐2 therapy in patients with idiopathic pulmonary fibrosis: Safety, pharmacokinetics and exploratory efficacy. Eur Respir J 47: 889‐897, 2016.
 559.Van Dyken SJ, Locksley RM. Interleukin‐4‐ and interleukin‐13‐mediated alternatively activated macrophages: Roles in homeostasis and disease. Annu Rev Immunol 31: 317‐343, 2013.
 560.Vancheri C. Gastro‐oesophageal reflux and idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffuse Lung Dis 30 (Suppl 1): 37‐39, 2013.
 561.Varol C, Mildner A, Jung S. Macrophages: Development and tissue specialization. Annu Rev Immunol 33: 643‐675, 2015.
 562.Vassilakis DA, Sourvinos G, Spandidos DA, Siafakas NM, Bouros D. Frequent genetic alterations at the microsatellite level in cytologic sputum samples of patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 162: 1115‐1119, 2000.
 563.Vece TJ, Schecter MG, Gatti RA, Tunuguntla R, Garcia CK, Langston C, Dishop MK, Moore RH, Fan LL. Rapid and progressive pulmonary fibrosis in 2 families with DNA repair deficiencies of undetermined etiology. J Pediatr 160: 700‐702 e703, 2012.
 564.Verfaillie T, Rubio N, Garg AD, Bultynck G, Rizzuto R, Decuypere JP, Piette J, Linehan C, Gupta S, Samali A, Agostinis P. PERK is required at the ER‐mitochondrial contact sites to convey apoptosis after ROS‐based ER stress. Cell Death Differ 19: 1880‐1891, 2012.
 565.Verma R, Kushwah L, Gohel D, Patel M, Marvania T, Balakrishnan S. Evaluating the ameliorative potential of quercetin against the bleomycin‐induced pulmonary fibrosis in wistar rats. Pulm Med 2013: 921724, 2013.
 566.Vincent T, Neve EP, Johnson JR, Kukalev A, Rojo F, Albanell J, Pietras K, Virtanen I, Philipson L, Leopold PL, Crystal RG, de Herreros AG, Moustakas A, Pettersson RF, Fuxe J. A SNAIL1‐SMAD3/4 transcriptional repressor complex promotes TGF‐beta mediated epithelial‐mesenchymal transition. Nat Cell Biol 11: 943‐950, 2009.
 567.Visner GA, Lu F, Zhou H, Latham C, Agarwal A, Zander DS. Graft protective effects of heme oxygenase 1 in mouse tracheal transplant‐related obliterative bronchiolitis. Transplantation 76: 650‐656, 2003.
 568.von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem Sci 27: 339‐344, 2002.
 569.Vousden KH, Lane DP. p53 in health and disease. Nat Rev Mol Cell Biol 8: 275‐283, 2007.
 570.Vuorinen K, Ohlmeier S, Lepparanta O, Salmenkivi K, Myllarniemi M, Kinnula VL. Peroxiredoxin II expression and its association with oxidative stress and cell proliferation in human idiopathic pulmonary fibrosis. J Histochem Cytochem 56: 951‐959, 2008.
 571.Waghray M, Cui Z, Horowitz JC, Subramanian IM, Martinez FJ, Toews GB, Thannickal VJ. Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial cell death by activated myofibroblasts. FASEB J 19: 854‐856, 2005.
 572.Wallach‐Dayan SB, Izbicki G, Cohen PY, Gerstl‐Golan R, Fine A, Breuer R. Bleomycin initiates apoptosis of lung epithelial cells by ROS but not by Fas/FasL pathway. Am J Physiol Lung Cell Mol Physiol 290: L790‐L796, 2006.
 573.Wang HD, Yamaya M, Okinaga S, Jia YX, Kamanaka M, Takahashi H, Guo LY, Ohrui T, Sasaki H. Bilirubin ameliorates bleomycin‐induced pulmonary fibrosis in rats. Am J Respir Crit Care Med 165: 406‐411, 2002.
 574.Wang L, Clutter S, Benincosa J, Fortney J, Gibson LF. Activation of transforming growth factor‐beta1/p38/Smad3 signaling in stromal cells requires reactive oxygen species‐mediated MMP‐2 activity during bone marrow damage. Stem Cells 23: 1122‐1134, 2005.
 575.Wang L, Song Y, Li X, Guo H, Zhang G. Role of thioredoxin nitration in bleomycin‐induced pulmonary fibrosis in rats. Can J Physiol Pharmacol 94: 59‐64, 2016.
 576.Wang T, Arifoglu P, Ronai Z, Tew KD. Glutathione S‐transferase P1‐1 (GSTP1‐1) inhibits c‐Jun N‐terminal kinase (JNK1) signaling through interaction with the C terminus. J Biol Chem 276: 20999‐21003, 2001.
 577.Wang XM, Zhang Y, Kim HP, Zhou Z, Feghali‐Bostwick CA, Liu F, Ifedigbo E, Xu X, Oury TD, Kaminski N, Choi AM. Caveolin‐1: A critical regulator of lung fibrosis in idiopathic pulmonary fibrosis. J Exp Med 203: 2895‐2906, 2006.
 578.Wang Y, Lou MF. The regulation of NADPH oxidase and its association with cell proliferation in human lens epithelial cells. Invest Ophthalmol Vis Sci 50: 2291‐2300, 2009.
 579.Waters DW, Blokland KEC, Pathinayake PS, Burgess JK, Mutsaers SE, Prele CM, Schuliga M, Grainge CL, Knight DA. Fibroblast senescence in the pathology of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 315: L162‐L172, 2018.
 580.Wedgwood S, Lakshminrusimha S, Schumacker PT, Steinhorn RH. Cyclic stretch stimulates mitochondrial reactive oxygen species and Nox4 signaling in pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 309: L196‐L203, 2015.
 581.Wenisch C, Patruta S, Daxbock F, Krause R, Horl W. Effect of age on human neutrophil function. J Leukoc Biol 67: 40‐45, 2000.
 582.Westermann W, Schobl R, Rieber EP, Frank KH. Th2 cells as effectors in postirradiation pulmonary damage preceding fibrosis in the rat. Int J Radiat Biol 75: 629‐638, 1999.
 583.Weyand CM, Goronzy JJ. Aging of the immune system. Mechanisms and therapeutic targets. Ann Am Thorac Soc 13 (Suppl 5): S422‐S428, 2016.
 584.White ES, Lazar MH, Thannickal VJ. Pathogenetic mechanisms in usual interstitial pneumonia/idiopathic pulmonary fibrosis. J Pathol 201: 343‐354, 2003.
 585.Wickens AP. Ageing and the free radical theory. Respir Physiol 128: 379‐391, 2001.
 586.Widlansky ME, Gutterman DD. Regulation of endothelial function by mitochondrial reactive oxygen species. Antioxid Redox Signal 15: 1517‐1530, 2011.
 587.Wijkstrom‐Frei C, El‐Chemaly S, Ali‐Rachedi R, Gerson C, Cobas MA, Forteza R, Salathe M, Conner GE. Lactoperoxidase and human airway host defense. Am J Respir Cell Mol Biol 29: 206‐212, 2003.
 588.Wild AC, Moinova HR, Mulcahy RT. Regulation of gamma‐glutamylcysteine synthetase subunit gene expression by the transcription factor Nrf2. J Biol Chem 274: 33627‐33636, 1999.
 589.Wiley CD, Velarde MC, Lecot P, Liu S, Sarnoski EA, Freund A, Shirakawa K, Lim HW, Davis SS, Ramanathan A, Gerencser AA, Verdin E, Campisi J. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab 23: 303‐314, 2016.
 590.Willis BC, Borok Z. TGF‐beta‐induced EMT: Mechanisms and implications for fibrotic lung disease. Am J Physiol Lung Cell Mol Physiol 293: L525‐L534, 2007.
 591.Wink DA, Hines HB, Cheng RY, Switzer CH, Flores‐Santana W, Vitek MP, Ridnour LA, Colton CA. Nitric oxide and redox mechanisms in the immune response. J Leukoc Biol 89: 873‐891, 2011.
 592.Wink DA, Miranda KM, Espey MG, Pluta RM, Hewett SJ, Colton C, Vitek M, Feelisch M, Grisham MB. Mechanisms of the antioxidant effects of nitric oxide. Antioxid Redox Signal 3: 203‐213, 2001.
 593.Wink DA, Mitchell JB. Chemical biology of nitric oxide: Insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide. Free Radic Biol Med 25: 434‐456, 1998.
 594.Wipff PJ, Rifkin DB, Meister JJ, Hinz B. Myofibroblast contraction activates latent TGF‐beta1 from the extracellular matrix. J Cell Biol 179: 1311‐1323, 2007.
 595.Wolters PJ, Collard HR, Jones KD. Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol 9: 157‐179, 2014.
 596.Wu Q, Allouch A, Paoletti A, Leteur C, Mirjolet C, Martins I, Voisin L, Law F, Dakhli H, Mintet E, Thoreau M, Muradova Z, Gauthier M, Caron O, Milliat F, Ojcius DM, Rosselli F, Solary E, Modjtahedi N, Deutsch E, Perfettini JL. NOX2‐dependent ATM kinase activation dictates pro‐inflammatory macrophage phenotype and improves effectiveness to radiation therapy. Cell Death Differ 24: 1632‐1644, 2017.
 597.Wuyts WA, Willems S, Vos R, Vanaudenaerde BM, De Vleeschauwer SI, Rinaldi M, Vanhooren HM, Geudens N, Verleden SE, Demedts MG, Thomeer M, Verbeken EK, Verleden GM. Azithromycin reduces pulmonary fibrosis in a bleomycin mouse model. Exp Lung Res 36: 602‐614, 2010.
 598.Wynn TA, Barron L. Macrophages: Master regulators of inflammation and fibrosis. Semin Liver Dis 30: 245‐257, 2010.
 599.Xia H, Khalil W, Kahm J, Jessurun J, Kleidon J, Henke CA. Pathologic caveolin‐1 regulation of PTEN in idiopathic pulmonary fibrosis. Am J Pathol 176: 2626‐2637, 2010.
 600.Xu J, Li T, Wu H, Xu T. Role of thioredoxin in lung disease. Pulm Pharmacol Ther 25: 154‐162, 2012.
 601.Xu Y, Tai W, Qu X, Wu W, Li Z, Deng S, Vongphouttha C, Dong Z. Rapamycin protects against paraquat‐induced pulmonary fibrosis: Activation of Nrf2 signaling pathway. Biochem Biophys Res Commun 490: 535‐540, 2017.
 602.Xue C, Johns RA. Endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 333: 1642‐1644, 1995.
 603.Xue J, Schmidt SV, Sander J, Draffehn A, Krebs W, Quester I, De Nardo D, Gohel TD, Emde M, Schmidleithner L, Ganesan H, Nino‐Castro A, Mallmann MR, Labzin L, Theis H, Kraut M, Beyer M, Latz E, Freeman TC, Ulas T, Schultze JL. Transcriptome‐based network analysis reveals a spectrum model of human macrophage activation. Immunity 40: 274‐288, 2014.
 604.Yamashita CM, Dolgonos L, Zemans RL, Young SK, Robertson J, Briones N, Suzuki T, Campbell MN, Gauldie J, Radisky DC, Riches DW, Yu G, Kaminski N, McCulloch CA, Downey GP. Matrix metalloproteinase 3 is a mediator of pulmonary fibrosis. Am J Pathol 179: 1733‐1745, 2011.
 605.Yan B, Ma Z, Shi S, Hu Y, Ma T, Rong G, Yang J. Sulforaphane prevents bleomycin‐induced pulmonary fibrosis in mice by inhibiting oxidative stress via nuclear factor erythroid 2related factor2 activation. Mol Med Rep 15: 4005‐4014, 2017.
 606.Yanai H, Shteinberg A, Porat Z, Budovsky A, Braiman A, Ziesche R, Fraifeld VE. Cellular senescence‐like features of lung fibroblasts derived from idiopathic pulmonary fibrosis patients. Aging (Albany NY) 7: 664‐672, 2015.
 607.Yang IV, Pedersen BS, Rabinovich E, Hennessy CE, Davidson EJ, Murphy E, Guardela BJ, Tedrow JR, Zhang Y, Singh MK, Correll M, Schwarz MI, Geraci M, Sciurba FC, Quackenbush J, Spira A, Kaminski N, Schwartz DA. Relationship of DNA methylation and gene expression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 190: 1263‐1272, 2014.
 608.Yao Y, Wang Y, Zhang Z, He L, Zhu J, Zhang M, He X, Cheng Z, Ao Q, Cao Y, Yang P, Su Y, Zhao J, Zhang S, Yu Q, Ning Q, Xiang X, Xiong W, Wang CY, Xu Y. Chop deficiency protects mice against bleomycin‐induced pulmonary fibrosis by attenuating M2 macrophage production. Mol Ther 24: 915‐925, 2016.
 609.Yona S, Kim KW, Wolf Y, Mildner A, Varol D, Breker M, Strauss‐Ayali D, Viukov S, Guilliams M, Misharin A, Hume DA, Perlman H, Malissen B, Zelzer E, Jung S. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38: 79‐91, 2013.
 610.Yoo HY, Chang MS, Rho HM. The activation of the rat copper/zinc superoxide dismutase gene by hydrogen peroxide through the hydrogen peroxide‐responsive element and by paraquat and heat shock through the same heat shock element. J Biol Chem 274: 23887‐23892, 1999.
 611.Yoo JH, Erzurum SC, Hay JG, Lemarchand P, Crystal RG. Vulnerability of the human airway epithelium to hyperoxia. Constitutive expression of the catalase gene in human bronchial epithelial cells despite oxidant stress. J Clin Invest 93: 297‐302, 1994.
 612.Yoon YS, Lee JH, Hwang SC, Choi KS, Yoon G. TGF beta1 induces prolonged mitochondrial ROS generation through decreased complex IV activity with senescent arrest in Mv1Lu cells. Oncogene 24: 1895‐1903, 2005.
 613.Young LR, Gulleman PM, Bridges JP, Weaver TE, Deutsch GH, Blackwell TS, McCormack FX. The alveolar epithelium determines susceptibility to lung fibrosis in Hermansky‐Pudlak syndrome. Am J Respir Crit Care Med 186: 1014‐1024, 2012.
 614.Yu DM, Jung SH, An HT, Lee S, Hong J, Park JS, Lee H, Lee H, Bahn MS, Lee HC, Han NK, Ko J, Lee JS, Ko YG. Caveolin‐1 deficiency induces premature senescence with mitochondrial dysfunction. Aging Cell 16: 773‐784, 2017.
 615.Yu G, Kovkarova‐Naumovski E, Jara P, Parwani A, Kass D, Ruiz V, Lopez‐Otin C, Rosas IO, Gibson KF, Cabrera S, Ramirez R, Yousem SA, Richards TJ, Chensny LJ, Selman M, Kaminski N, Pardo A. Matrix metalloproteinase‐19 is a key regulator of lung fibrosis in mice and humans. Am J Respir Crit Care Med 186: 752‐762, 2012.
 616.Zank DC, Bueno M, Mora AL, Rojas M. Idiopathic pulmonary fibrosis: Aging, mitochondrial dysfunction, and cellular bioenergetics. Front Med (Lausanne) 5: 10, 2018.
 617.Zelko IN, Folz RJ. Myeloid zinc finger (MZF)‐like, Kruppel‐like and Ets families of transcription factors determine the cell‐specific expression of mouse extracellular superoxide dismutase. Biochem J 369: 375‐386, 2003.
 618.Zelko IN, Stepp MW, Vorst AL, Folz RJ. Histone acetylation regulates the cell‐specific and interferon‐gamma‐inducible expression of extracellular superoxide dismutase in human pulmonary arteries. Am J Respir Cell Mol Biol 45: 953‐961, 2011.
 619.Zhang DX, Gutterman DD. Mitochondrial reactive oxygen species‐mediated signaling in endothelial cells. Am J Physiol Heart Circ Physiol 292: H2023‐2031, 2007.
 620.Zhang H, Davies KJA, Forman HJ. Oxidative stress response and Nrf2 signaling in aging. Free Radic Biol Med 88: 314‐336, 2015.
 621.Zhang HY, Phan SH. Inhibition of myofibroblast apoptosis by transforming growth factor beta(1). Am J Respir Cell Mol Biol 21: 658‐665, 1999.
 622.Zhang J, Ye ZW, Singh S, Townsend DM, Tew KD. An evolving understanding of the S‐glutathionylation cycle in pathways of redox regulation. Free Radic Biol Med 120: 204‐216, 2018.
 623.Zhang L, Wang Y, Wu G, Xiong W, Gu W, Wang CY. Macrophages: Friend or foe in idiopathic pulmonary fibrosis? Respir Res 19: 170, 2018.
 624.Zhang Y, Choksi S, Chen K, Pobezinskaya Y, Linnoila I, Liu ZG. ROS play a critical role in the differentiation of alternatively activated macrophages and the occurrence of tumor‐associated macrophages. Cell Res 23: 898‐914, 2013.
 625.Zhao H, Qin HY, Cao LF, Chen YH, Tan ZX, Zhang C, Xu DX. Phenylbutyric acid inhibits epithelial‐mesenchymal transition during bleomycin‐induced lung fibrosis. Toxicol Lett 232: 213‐220, 2015.
 626.Zhao H, Wu QQ, Cao LF, Qing HY, Zhang C, Chen YH, Wang H, Liu RY, Xu DX. Melatonin inhibits endoplasmic reticulum stress and epithelial‐mesenchymal transition during bleomycin‐induced pulmonary fibrosis in mice. PLoS One 9: e97266, 2014.
 627.Zhao Y, Vanhoutte PM, Leung SW. Vascular nitric oxide: Beyond eNOS. J Pharmacol Sci 129: 83‐94, 2015.
 628.Zhong L, Holmgren A. Mammalian thioredoxin reductases as hydroperoxide reductases. Methods Enzymol 347: 236‐243, 2002.
 629.Zhou H, Lu F, Latham C, Zander DS, Visner GA. Heme oxygenase‐1 expression in human lungs with cystic fibrosis and cytoprotective effects against Pseudomonas aeruginosa in vitro. Am J Respir Crit Care Med 170: 633‐640, 2004.
 630.Zhu L, Fu X, Chen X, Han X, Dong P. M2 macrophages induce EMT through the TGF‐beta/Smad2 signaling pathway. Cell Biol Int 41: 960‐968, 2017.
 631.Ziegenhagen MW, Zabel P, Zissel G, Schlaak M, Muller‐Quernheim J. Serum level of interleukin 8 is elevated in idiopathic pulmonary fibrosis and indicates disease activity. Am J Respir Crit Care Med 157: 762‐768, 1998.

Teaching Material

Eva Otoupalova, Sam Smith, Guangjie Cheng, and Victor J. Thannickal. Oxidative Stress in Pulmonary Fibrosis. Compr Physiol 10 : 2020, 509-547.

Didactic Synopsis

Major Teaching Points:

* Free radicals contain one or more unpaired electrons. They include reactive oxygen species (ROS) and reactive nitrogen species (RNS).

    a. ROS include superoxide anion (O2•-), hydroxyl radical (HO) and the non-radical species, hydrogen peroxide (H2O2).
    b. RNS are reactive derivatives of nitrogen that include nitric oxide (NO), NO2, N2O3 and peroxynitrite (ONOO-).

* Generation of ROS in cells may be derived from several sources, including mitochondrial electron transport chain (ETC), endoplasmic reticulum, NOX/DUOX enzymes and peroxisomes. Lung epithelial cells, fibroblasts, immune cells, endothelial cells and vascular smooth muscle cells contribute to ROS/RNS production in the lung.

* IPF is a progressive, terminal lung disease associated with aging. IPF may represent an accelerated aging phenotype associated with oxidative stress that predisposes/contributes to DNA damage, epigenetic alterations, cellular senescence, dysregulated proteostasis and mitochondrial dysfunction.

* The lung has several mechanisms for detoxification of ROS. Non-specific (non-enzymatic) mechanisms involve small molecule antioxidants such as glutathione, while specific detoxification systems involve specialized enzymatic systems. Several of these enzymatic systems regulate glutathione metabolism and include glutathione-S-transferases, glutathione peroxidases and glutaredoxins. Superoxide dismutase, catalase, peroxiredoxins and thioredoxins represent other ROS-metabolizing enzymes. There is evidence of diminished antioxidant responses in IPF.

* Macrophages polarization is dynamic and regulated during injury-repair processes. M1-like phenotypes are primarily observed during the initial phase of tissue injury, while M2-like phenotypes are observed during the reparative phase. Oxidative stress might contribute to macrophage polarization. Aging of the immune system impairs host defenses and induces chronic low-grade inflammation and increases susceptibility to epithelial damage.

* Increased susceptibility to apoptosis in alveolar epithelial cells has been observed in IPF. Oxidative stress, ER stress and mitochondrial dysfunction have been shown to contribute to epithelial cell apoptosis in various fibrosis models.

* Myofibroblast differentiation, senescence and apoptosis resistance are hallmarks of fibrosis progression. TGF-β1 is a major pro-fibrotic mediator that stimulates myofibroblast differentiation and NOX4-dependent ROS production. The imbalance of oxidant production and antioxidant defenses contributes to myofibroblast senescence.

* Extracellular matrix (ECM) plays important role in fibrosis. Oxidative damage to ECM proteins might lead to their fragmentation and/or stabilization that dysregulates resolution of inflammation and fibrosis.

Didactic Legends

The following legends to the figures that appear throughout the article are written to be useful for teaching.

Figure 1. Teaching Points: Intracellular sources of reactive oxygen species/reactive nitrogen species. Mitochondrial electron transport chain (ETC) is a major source of intracellular reactive oxygen species (ROS). Endoplasmatic reticulum (ER) is also significant producer of ROS during normal protein folding as well as under conditions of ER stress and unfolded protein response. Peroxisomes are source of H2O2 that is subsequently utilized by the enzyme catalase for substrate oxidation. NADPH oxidases (NOXes) and dual oxidases (DUOXes) are multicomponent enzymes that produce O2•- and H2O2. While NOX4 is constitutively active, other NOXes require several cytosolic subunits such as Rac1, p40phox, p67phox and p47phox for activation. The activation of DUOXes and NOX5 is calcium dependent. NO is produced by nitric oxide synthetase (NOS) isoforms. NO production is limited by availability of molecular oxygen, L-arginine and cofactor tetrahydrobiopterin (BH4). Arginase utilizes arginine for ornithine synthesis in urea cycle and thus decreases its availability for NO synthesis. Under conditions of arginine deficiency, NOS uncouples and produces O2*.

Figure 2. Teaching Points: Cellular detoxification mechanisms. Glutathione peroxidase (GPx) utilizes GSH to detoxify peroxides and leads to formation of oxidized glutathione (GSSG) as byproduct. GSSG is reduced back to GSH by glutathione reductase. Peroxiredoxins (PRx) also participate in peroxide detoxification. Thioredoxines (Trx) are part of cellular antioxidant system that reduces disulfide bridges in target proteins. Glutathione-S-transferases (GST) and glutaredoxins (Glrx) participate in protein glutathionylation and de-glutathionylation, respectively. Heme oxygenase (HO) as well as peroxismal catalase further aid in detoxification of intracellular ROS. Superoxide dismutase (SOD) catalyses dismutation of O2•- to H2O2 in mitochondria (Mn-SOD), cytosol, nucleus and mitochondrial intermembrane space (Cu,Zn-SOD) and extracellularly (EC-SOD). Oxidative stress triggers nuclear translocation of transcription factor Nrf2 and activation of antioxidant response element (ARE) or target antioxidant genes, coordinating antioxidant responses.

Figure 3. Teaching Points: Cellular sources of reactive oxygen species/reactive nitrogen species in lung. Macrophages and neutrophils generate reactive oxygen species (ROS) during oxidative burst through NADPH oxidase 2 (NOX2) activation in response to pathogens. NOX4 contributes to constitutive ROS production in these cells. Additionally, macrophages and neutrophils are major source of nitric oxide (NO) through neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS). ONOO- forms inside phagosomes and facilitates bacterial killing. Ciliated bronchial epithelial cells (BEC) express dual oxidase 1 and 2 (DUOX1 and DUOX2). Alveolar epithelial cells type 2 (AEC2) express DUOX1, however DUOX2, NOX1 and NOX4 might be expressed under pathological conditions. Fibroblasts mainly produce H2O2 through NOX4 induction. NOX2,4 and 5 and xanthine oxidase (XO) are main sources of ROS in lung endothelium, while endothelial nitric oxide synthase (eNOS) is main producer of NO. NOX 1,2,4 and 5 and XO also contribute to ROS production in vascular smooth muscle. Furthermore, mitochondrial ROS (mtROS) and endoplasmatic reticulum stress likely contribute to oxidative damage in several cell types in the lung.

Figure 4. Teaching Points: Fibrosis immunopathogenesis. Pro-inflammatory macrophage phenotype polarizes from naïve macrophages after priming by interferon-γ (IFN-γ) upon stimulation by lipopolysacharide (LPS) and tumor-necrosis factor α (TNF-α). Pro-inflammatory macrophages mediate initial inflammatory phase of the immune response, and are characterized by production of high levels of reactive oxygen species (ROS), pro-inflammatory cytokines and stimulation of Th-1 cytotoxic response. Pro-fibrotic macrophage phenotype is mediated by transforming growth factor β1 (TGF-β1) and interleukins (IL) IL-10, IL-4 and IL13. Mitochondrial ROS and endoplasmatic reticulum stress might contribute to pro-fibrotic phenotype of macrophages. Pro-fibrotic macrophages have low cytotoxic properties and mediate fibrotic phase of injury response through production of pro-fibrotic mediators TGF-β1, platelet-derived growth factor (PDGF), CCL-18 and tissue inhibitor of metalloproteinase (TIMP).

Figure 5. Teaching Points: Epithelium in pathogenesis of pulmonary fibrosis.  Genetic predisposition and ageing contribute to susceptibility of alveolar epithelial cells (AECs) to injury, toxins and oxidative stress. Epithelial cell apoptosis and senescence contribute to fibrosis by impeding reepithelization, secretion of pro-fibrotic cytokines and senescence-associated secretory phenotype (SASP). Transforming growth factor β1 (TGF-β1), mitochondrial dysfunction, endoplasmatic reticulum (ER) stress and NADPH oxidase 4 (NOX4) upregulation stimulate AEC apoptosis. TGF-β1 and downregulation of sirtuin 1 (SIRT1) participate in regulation of AEC senescence. TGF-β1 also mediates epithelial-mesenchymal transition.

Figure 6. Teaching Points: Mesenchyme in pathogenesis of pulmonary fibrosis. Fibroblast activation, fibroblast-to-myofibroblast differentiation and increased extracellular matrix (ECM) deposition is central to progression of pulmonary fibrosis. Transforming growth factor β1 (TGF-β1), mitochondrial dysfunction, endoplasmatic reticulum (ER) stress and inadequate peroxisome function all stimulate fibroblast to myofibroblast differentiation. TGF-β1 is secreted by macrophages and alveolar epithelial cells (AECs) as part of inactive complex associated with latency associated peptide (LAP) and latent TGF-β-binding protein (LTBP) and can be activated by mechanical forces, low pH, matrix metalloproteinases (MMPs), integrins and oxidative stress. TGF-β1 mediates myofibroblast differentiation through NOX4 upregulation and H2O2 production. H2O2 from activated myofibroblasts contributes to oxidative ECM fragmentation and dityrosine crosslinking. CCN1 enhances TGF-β1 signaling, while sirtuin 3 (SIRT3) attenuates it. Nrf2/NOX4 imbalance leads to myofibroblast senescence and apoptosis resistance, resulting in fibrosis persistence.

 

Figure 7. Teaching Points: Therapeutic targets in pulmonary fibrosis. Senescence, immune responses, mitochondrial dysfunction and dysregulated proteostasis are new targets in pulmonary fibrosis treatment. Reactive oxygen species (ROS) scavengers and drugs targeting redox imbalance might be other viable strategies. Abbreviations: Plasminogen activator 1 (PAI-1); senescence-associated secretory phenotype (SASP); matrix metalloproteinasis (MMPs); 4-phenyl butyric acid (4-PBA); mesenchymal stem cells (MSCs); NADPH oxidase 4 (NOX4); superoxide dismutase (SOD); sirtuin (SIRT); interleukin (IL).


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How to Cite

Eva Otoupalova, Sam Smith, Guangjie Cheng, Victor J. Thannickal. Oxidative Stress in Pulmonary Fibrosis. Compr Physiol 2020, 10: 509-547. doi: 10.1002/cphy.c190017