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Oxidative Stress in Pulmonary Fibrosis

Eva Otoupalova, Sam Smith, Guangjie Cheng, Victor J. Thannickal

10.1002/cphy.c190017

Source: Volume 10, Issue 2, April 2020

Published online: March 2020

Full Article on Wiley Online Library



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.

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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.
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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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Article Title: Oxidative Stress in Pulmonary Fibrosis
 

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