Hydrogen sulfide attenuates cigarette smoke-induced airway remodeling by upregulating SIRT1 signaling pathway

Guan, Ruijuan; Wang, Jian; Cai, Zhou; Li, Ziying; Wang, Lan; Li, Yuanyuan; Xu, Jingyi; Li, Defu; Yao, Hongwei; Liu, Wei; Deng, Bingxian; Lu, Wenju

doi:10.1016/j.redox.2019.101356

Cited by 91 publications

(56 citation statements)

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“…We did find airway remodelling in COPD patients and CS‐exposed mice, manifesting as collagen deposition and epithelial‐mesenchymal transition (EMT). These findings are in accordance with previous observations 32,33 . During this process, myofibroblasts, which originate directly from lung bronchial fibroblasts, are involved in the formation of airway fibrosis 34 .…”

Section: Discussionsupporting

confidence: 93%

Let‐7 mediated airway remodelling in chronic obstructive pulmonary disease via the regulation of IL‐6

Yang

et al. 2020

Eur J Clin Investigation

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Background Myofibroblast differentiation and extracellular matrix (ECM) deposition are observed in chronic obstructive pulmonary disease (COPD). However, the mechanisms of regulation of myofibroblast differentiation remain unclear. Materials and methods We detected let‐7 levels in peripheral lung tissues, serum and primary bronchial epithelial cells of COPD patients and cigarette smoke (CS)‐exposed mice. IL‐6 mRNA was explored in lung tissues of COPD patients and CS‐exposed mice. IL‐6 protein was detected in cell supernatant from primary epithelial cells by ELISA. We confirmed the regulatory effect of let‐7 on IL‐6 by luciferase reporter assay. Western blotting assay was used to determine the expression of α‐SMA, E‐cadherin and collagen I. In vitro, cell study was performed to demonstrate the role of let‐7 in myofibroblast differentiation and ECM deposition. Results Low expression of let‐7 was observed in COPD patients, CS‐exposed mice and CS extract (CSE)‐treated human bronchial epithelial (HBE) cells. Increased IL‐6 was found in COPD patients, CS‐exposed mice and CSE‐treated HBE cells. Let‐7 targets and silences IL‐6 protein coding genes through binding to 3’ untranslated region (UTR) of IL‐6. Normal or CSE‐treated HBE cells were co‐cultured with human embryonic lung fibroblasts (MRC‐5 cells). Reduction of let‐7 in HBE cells caused myofibroblast differentiation and ECM deposition, while increase of let‐7 mimics decreased myofibroblast differentiation phenotype and ECM deposition. Conclusion We demonstrate that CS reduced let‐7 expression in COPD and, further, identify let‐7 as a regulator of myofibroblast differentiation through the regulation of IL‐6, which has potential value for diagnosis and treatment of COPD.

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Section: Discussionsupporting

confidence: 93%

Let‐7 mediated airway remodelling in chronic obstructive pulmonary disease via the regulation of IL‐6

Yang

et al. 2020

Eur J Clin Investigation

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“…It was also revealed that H 2 S inhibited airway remodeling caused by CS by attenuating oxidative injury and epithelial-mesenchymal transition. 53 Perry et al . 54 reported that H 2 S inhibited the proliferation of smooth muscle and cytokine release in airway.…”

Section: Discussionmentioning

confidence: 99%

Hydrogen sulfide alleviates cigarette smoke-induced COPD through inhibition of the TGF-β1/smad pathway

Wang

Meng

Wang

et al. 2020

Exp Biol Med (Maywood)

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Smoking has become a major cause of chronic obstructive pulmonary disease through weakening of the respiratory mucus-ciliary transport system, impairing cough reflex sensitivity, and inducing inflammation. Recent researches have indicated that hydrogen sulfide is essential in the development of various lung diseases. However, the effect and mechanism of hydrogen sulfide on cigarette smoke-induced chronic obstructive pulmonary disease have not been reported. In this study, rats were treated with cigarette smoke to create a chronic obstructive pulmonary disease model followed by treatment with a low concentration of hydrogen sulfide. Pulmonary function, histopathological appearance, lung edema, permeability, airway remodeling indicators, oxidative products/antioxidases levels, inflammatory factors in lung, cell classification in bronchoalveolar lavage fluid were measured to examine the effect of hydrogen sulfide on chronic obstructive pulmonary disease model. The results showed that hydrogen sulfide effectively improved pulmonary function and reduced histopathological changes, lung edema, and permeability. Airway remodeling, oxidative stress, and inflammation were also reduced by hydrogen sulfide treatment. To understand the mechanisms, we measured the expression of TGF-β1, TGF-βIand TGF-βII receptors and Smad7 and phosphorylation of Smad2/Smad3. The results indicated that the TGF-β1 and Smad were activated in cigarette smoke-induced chronic obstructive pulmonary disease model, but inhibited by hydrogen sulfide. In conclusion, this study showed that hydrogen sulfide treatment alleviated cigarette smoke-induced chronic obstructive pulmonary disease through inhibition of the TGF-β1/Smad pathway. Impact statement COPD has become a severe public health issue in the world and smoking has become a major cause of COPD. As a result, it is a demandingly needed to explore new potential therapy for cigarette smoke-associated COPD. The present study suggested that H2S treatment improved pulmonary function and reduced histopathological changes, lung edema, permeability, inflammation, airway remodeling and oxidative injury in a COPD model induced by cigarette smoke. Although additional studies are required to elucidate the pharmacodynamics, pharmacokinetics, and pharmacology of H2S in the cigarette smoke-associated COPD, our findings provide an experimental basis for the potential clinical application of H2S in COPD treatment.

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“…All experimental protocols were approved by the Ethics Committee of Animal Experiments of Guangzhou Medical University. Mice were exposed to cigarette smoke (CS) as described previously [ 27 ]. The control mice were exposed to clean air.…”

Section: Methodsmentioning

confidence: 99%

NOX4‐Derived ROS Promotes Collagen I Deposition in Bronchial Smooth Muscle Cells by Activating Noncanonical p38MAPK/Akt‐Mediated TGF‐β Signaling

Hao

Sun

Guo

et al. 2021

Oxidative Medicine and Cellular Longevity

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Background. Airway smooth muscle (ASM) remodeling is a hallmark in chronic obstructive pulmonary disease (COPD). NADPH oxidase 4- (NOX4-) mediated reactive oxygen species (ROS) production plays a crucial role in cell differentiation and extracellular matrix (ECM) synthesis in ASM remodeling. However, the precise mechanisms underpinning its pathogenic roles remain elusive. Methods. The expression of NOX4 and TGF-β1 in the airway of the lung was measured in COPD patients and the control group. Cigarette smoke- (CS-) induced emphysema mice were generated, and the alteration of α-SMA, NOX4, TGF-β1, and collagen I was accessed. The changes of the expression of ECM markers, NOX4, components of TGF-β/Smad, and MAPK/Akt signaling in human bronchial smooth muscle cells (HBSMCs) were ascertained for delineating mechanisms of NOX4-mediated ROS production on cell differentiation and remodeling in human ASM cells. Results. An increased abundance of NOX4 and TGF-β1 proteins in the epithelial cells and ASM of lung was observed in COPD patients compared with the control group. Additionally, an increased abundance expression of NOX4 and α-SMA was observed in the lungs of the CS-induced emphysema mouse model. TGF-β1 displayed abilities to increase the oxidative burden and collagen I production, along with enhanced phosphorylation of ERK, p38MAPK, and p-Akt473 in HBSMCs. These effects of TGF-β1 could be inhibited by the ROS scavenger N-acetylcysteine (NAC), siRNA-mediated knockdown of Smad3 and NOX4, and pharmacological inhibitors SB203580 (p38MAPK inhibitor) and LY294002 (Akt inhibitor). Conclusions. NOX4-mediated ROS production alters TGF-β1-induced cell differentiation and collagen I protein synthesis in HBSMCs in part through the p38MAPK/Akt signaling pathway in a Smad-dependent manner.

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Hydrogen sulfide attenuates cigarette smoke-induced airway remodeling by upregulating SIRT1 signaling pathway

Cited by 91 publications

References 50 publications

Let‐7 mediated airway remodelling in chronic obstructive pulmonary disease via the regulation of IL‐6

Let‐7 mediated airway remodelling in chronic obstructive pulmonary disease via the regulation of IL‐6

Hydrogen sulfide alleviates cigarette smoke-induced COPD through inhibition of the TGF-β1/smad pathway

NOX4‐Derived ROS Promotes Collagen I Deposition in Bronchial Smooth Muscle Cells by Activating Noncanonical p38MAPK/Akt‐Mediated TGF‐β Signaling

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