NOX4‐Derived ROS Promotes Collagen I Deposition in Bronchial Smooth Muscle Cells by Activating Noncanonical p38MAPK/Akt‐Mediated TGF‐<i>β</i> Signaling
Binwei Hao, Ruiting Sun, Xiaotong Guo, Lili Zhang, Jieda Cui, Yumin Zhou, Wei Hong, Yanan Zhang, Jinxi He, Xiaoming Liu, Bing Li, Pixin Ran, Juan Chen
Abstract
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‐ β 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 α ‐SMA, NOX4, TGF‐ β 1 , 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‐ β 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 α ‐SMA was observed in the lungs of the CS‐induced emphysema mouse model. TGF‐ β 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‐ β 1 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‐ β 1 ‐induced cell differentiation and collagen I protein synthesis in HBSMCs in part through the p38MAPK/Akt signaling pathway in a Smad‐dependent manner.