期刊
OXIDATIVE MEDICINE AND CELLULAR LONGEVITY
卷 2021, 期 -, 页码 -出版社
HINDAWI LTD
DOI: 10.1155/2021/6668971
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资金
- National Natural Science Foundation of China [81360004, 81760004]
- Key research and development program of Ningxia Hui Autonomous [2018BEG03035]
- Open Project of State Key Laboratory of Respiratory Disease [SKLRD-OP-201903]
- Science and Technology Program of Guangzhou [201504010018]
- National Key Research and Development Program [2016YFC1304101]
- Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program [2017BT01S155]
- National Science Foundation of China [81970045, 81670040]
NOX4-mediated ROS production alters TGF-beta(1) induced cell differentiation and collagen I protein synthesis in HBSMCs through the p38MAPK/Akt signaling pathway in a Smad-dependent manner.
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-beta(1) 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 alpha-SMA, NOX4, TGF-beta(1), and collagen I was accessed. The changes of the expression of ECM markers, NOX4, components of TGF-P/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-beta(1), 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 alpha-SMA was observed in the lungs of the CS-induced emphysema mouse model. TGF-beta(1), 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-beta(1) could be inhibited by the ROS scavenger N-acetylcysteine (NAC), siRNA-mediated knockdown of Smad3 and NOX4, and pharmacological inhibitors 5B203580 (p38MAPK inhibitor) and LY294002 (Akt inhibitor). Conclusions. NOX4-mediated ROS production alters TGF-beta(1) 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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