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Review
. 2022 Jan 21:12:794997.
doi: 10.3389/fphar.2021.794997. eCollection 2021.

Targeting Oxidative Stress as a Therapeutic Approach for Idiopathic Pulmonary Fibrosis

Cristina Estornut  1 , Javier Milara  1   2   3 , María Amparo Bayarri  1 , Nada Belhadj  1 , Julio Cortijo  1   2   3   4
Affiliations
Review

Targeting Oxidative Stress as a Therapeutic Approach for Idiopathic Pulmonary Fibrosis

Cristina Estornut et al. Front Pharmacol. .

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease characterized by an abnormal reepithelialisation, an excessive tissue remodelling and a progressive fibrosis within the alveolar wall that are not due to infection or cancer. Oxidative stress has been proposed as a key molecular process in pulmonary fibrosis development and different components of the redox system are altered in the cellular actors participating in lung fibrosis. To this respect, several activators of the antioxidant machinery and inhibitors of the oxidant species and pathways have been assayed in preclinical in vitro and in vivo models and in different clinical trials. This review discusses the role of oxidative stress in the development and progression of IPF and its underlying mechanisms as well as the evidence of oxidative stress in human IPF. Finally, we analyze the mechanism of action, the efficacy and the current status of different drugs developed to inhibit the oxidative stress as anti-fibrotic therapy in IPF.

Keywords: IPF—idiopathic pulmonary fibrosis; ROS—reactive oxygen species; antioxidant therapy; fibrosis; oxidative stress.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Simplified diagram of the principal molecular mechanisms of the NOX inhibitors Diphenyleneiodonium (DPI), VAS2870, GKT137831 and GKT136901 (GKTs), Apocynin (APO) and Metformin (MET). αSMA: alpha smooth muscle actin; IL-1β: interleuquina 1beta; IL-6: interleuquina 6; iNOS: inducible nitrogen oxide synthase; NFκβ: nuclear factor kappa beta; NOX1,2,4: NADPH oxidases; ROS/RNS: reactive oxygen species/reactive nitrogen species; TGF-β1: transforming growth factor beta 1; TNFα: tumoral necrosis factor alpha Created with Biorender.com.
FIGURE 2
FIGURE 2
Simplified diagram of the principal molecular mechanisms of the antioxidant enhancers n-acetyl cysteine (NAC), Quercetin (QUER) and Salvianolic acid B (SAL B). αSMA: alpha smooth muscle actin; ARE: antioxidant responsive element; CAT: catalase; CYS: cysteine; GCLC: glutamate cysteine ligase catalytic subunit; GCLM: glutamate cysteine ligase modifier subunit; GLUT: glutamate; GPX: glutathione peroxidase; GSH: glutathione; HO-1: heme oxygenase 1; IL-1β: interleuquina 1beta; IL-6: interleuquina 6; iNOS: inducible nitrogen oxide synthase; NFκβ: nuclear factor kappa beta; NOX1,2,4: NADPH oxidases; NQO1: NAD(P)H:quinone oxidoreductase 1; NRF2: nuclear factor erythroid 2-related factor 2; ROS/RNS: reactive oxygen species/reactive nitrogen species; TGF-β1: transforming growth factor beta 1; TNFα: tumoral necrosis factor alpha; SIRT: sirtuine 1; SOD: supeoxide dismutase Created with Biorender.com.
FIGURE 3
FIGURE 3
Simplified diagram of the principal molecular mechanisms of the antioxidant enhancers Epigallocatechin (EGCG), Tanshinone IIA (TAN IIA), Crocin (CRO) and Echinochrome A (ECH A). αSMA: alpha smooth muscle actin; ARE: antioxidant responsive element; CAT: catalase; CYS: cysteine; GCLC: glutamate cysteine ligase catalytic subunit; GCLM: glutamate cysteine ligase modifier subunit; GLUT: glutamate; GPX: glutathione peroxidase; GSH: glutathione; HO-1: heme oxygenase 1; IL-1β: interleuquina 1beta; IL-6: interleuquina 6; iNOS: inducible nitrogen oxide synthase; NFκβ: nuclear factor kappa beta; NOX1,2,4: NADPH oxidases; NQO1: NAD(P)H:quinone oxidoreductase 1; NRF2: nuclear factor erythroid 2-related factor 2; ROS/RNS: reactive oxygen species/reactive nitrogen species; TGF-β1: transforming growth factor beta 1; TNFα: tumoral necrosis factor alpha; SIRT: sirtuine 1; SOD: supeoxide dismutase Created with Biorender.com.
FIGURE 4
FIGURE 4
Simplified diagram of the principal molecular mechanisms of the antioxidant enhancers Resveratrol (RES), Sulforaphane (SFN), Melatonin (MEL) and Curcumin (CUR). αSMA: alpha smooth muscle actin; AMPK: AMP-activated protein kinase; ARE: antioxidant responsive element CAT: catalase; CYS: cysteine; GCLC: glutamate cysteine ligase catalytic subunit; GCLM: glutamate cysteine ligase modifier subunit; GLUT: glutamate; GPX: glutathione peroxidase; GSH: glutathione; HO-1: heme oxygenase 1; IL-1β: interleuquina 1beta; IL-6: interleuquina 6; iNOS: inducible nitrogen oxide synthase; NFκβ: nuclear factor kappa beta; NOX1,2,4: NADPH oxidases; NQO1: NAD(P)H:quinone oxidoreductase 1; NRF2: nuclear factor erythroid 2-related factor 2; ROS/RNS: reactive oxygen species/reactive nitrogen species; TGF-β1: transforming growth factor beta 1; TNFα: tumoral necrosis factor alpha; SIRT: sirtuine 1; SOD: supeoxide dismutase Created with Biorender.com.
FIGURE 5
FIGURE 5
Simplified diagram of the principal molecular mechanisms of the antioxidant enhancers Pirfenidone (PFD), Thalidomide (THAL) and Isorhamnetin (ISO). αSMA: alpha smooth muscle actin; ARE: antioxidant responsive element; CAT: catalase; CYS: cysteine; GLUT: glutamate; GPX: glutathione peroxidase; HO-1: heme oxygenase 1; IL-1β: interleuquina 1beta; IL-6: interleuquina 6; iNOS: inducible nitrogen oxide synthase; LPO: lipoperoxidation; NFκβ: nuclear factor kappa beta; NOX1,2,4: NADPH oxidases; NQO1: NAD(P)H:quinone oxidoreductase 1; NRF2: nuclear factor erythroid 2-related factor 2; ROS/RNS: reactive oxygen species/reactive nitrogen species; TGF-β1: transforming growth factor beta 1; THRX: thioredoxin; TNFα: tumoral necrosis factor alpha; SIRT: sirtuine 1; SOD: supeoxide dismutase Created with Biorender.com.
FIGURE 6
FIGURE 6
Simplified diagram of the principal molecular mechanisms of the SOD mimetics AEL10150 and MnTBAP. αSMA: alpha smooth muscle actin; CAT: catalase; IL-1β: interleuquina 1beta; IL-6: interleuquina 6; NFκβ: nuclear factor kappa beta; ROS/RNS: reactive oxygen species/reactive nitrogen species; TGF-β1: transforming growth factor beta 1; TNFα: tumoral necrosis factor alpha; SOD: supeoxide dismutase Created with Biorender.com.
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