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Airway smooth muscle (ASM) remodeling is a hallmark in chronic obstructive pulmonary disease (COPD). NADPH oxidase 4\u2010 (NOX4\u2010) 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. <jats:italic>Methods<\/jats:italic>. The expression of NOX4 and TGF\u2010<jats:italic>\u03b2<\/jats:italic><jats:sub>1<\/jats:sub> in the airway of the lung was measured in COPD patients and the control group. Cigarette smoke\u2010 (CS\u2010) induced emphysema mice were generated, and the alteration of <jats:italic>\u03b1<\/jats:italic>\u2010SMA, NOX4, TGF\u2010<jats:italic>\u03b2<\/jats:italic><jats:sub>1<\/jats:sub>, and collagen I was accessed. The changes of the expression of ECM markers, NOX4, components of TGF\u2010<jats:italic>\u03b2<\/jats:italic>\/Smad, and MAPK\/Akt signaling in human bronchial smooth muscle cells (HBSMCs) were ascertained for delineating mechanisms of NOX4\u2010mediated ROS production on cell differentiation and remodeling in human ASM cells. <jats:italic>Results<\/jats:italic>. An increased abundance of NOX4 and TGF\u2010<jats:italic>\u03b2<\/jats:italic><jats:sub>1<\/jats:sub> 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 <jats:italic>\u03b1<\/jats:italic>\u2010SMA was observed in the lungs of the CS\u2010induced emphysema mouse model. TGF\u2010<jats:italic>\u03b2<\/jats:italic><jats:sub>1<\/jats:sub> displayed abilities to increase the oxidative burden and collagen I production, along with enhanced phosphorylation of ERK, p38MAPK, and p\u2010Akt473 in HBSMCs. These effects of TGF\u2010<jats:italic>\u03b2<\/jats:italic><jats:sub>1<\/jats:sub> could be inhibited by the ROS scavenger N\u2010acetylcysteine (NAC), siRNA\u2010mediated knockdown of Smad3 and NOX4, and pharmacological inhibitors SB203580 (p38MAPK inhibitor) and LY294002 (Akt inhibitor). <jats:italic>Conclusions<\/jats:italic>. NOX4\u2010mediated ROS production alters TGF\u2010<jats:italic>\u03b2<\/jats:italic><jats:sub>1<\/jats:sub>\u2010induced cell differentiation and collagen I protein synthesis in HBSMCs in part through the p38MAPK\/Akt signaling pathway in a Smad\u2010dependent manner.<\/jats:p>","DOI":"10.1155\/2021\/6668971","type":"journal-article","created":{"date-parts":[[2021,3,22]],"date-time":"2021-03-22T20:35:09Z","timestamp":1616445309000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["NOX4\u2010Derived ROS Promotes Collagen I Deposition in Bronchial Smooth Muscle Cells by Activating Noncanonical p38MAPK\/Akt\u2010Mediated TGF\u2010<i>\u03b2<\/i> 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