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Previous studies have indicated that transforming growth factor-beta (TGF-<jats:italic>\u03b2<\/jats:italic>) mediates ROS production and NADPH oxidase (NOX) activity. In our previous study, we also observed that TGF-<jats:italic>\u03b2<\/jats:italic>3 increases mucus secretion in airway epithelial cells in an autophagy-dependent fashion. Although it is well known that the relationship between ROS and autophagy is cell context-dependent, the exact mechanism of action remains unclear. The following study examined whether ROS act as upstream of autophagy activation in response to TGF-<jats:italic>\u03b2<\/jats:italic>3 induction. Using an allergic inflammation mouse model induced by house dust mite (HDM), we observed elevated lung amounts of TGF-<jats:italic>\u03b2<\/jats:italic>3 accompanied by increased ROS levels. And we found that ROS levels were elevated and NOX4 expression was increased in TGF-<jats:italic>\u03b2<\/jats:italic>3-induced epithelial cells, while the lack of NOX4 in the epithelial cells could reduce ROS generation and autophagy-dependent MUC5AC expression treated with TGF-<jats:italic>\u03b2<\/jats:italic>3. Furthermore, our studies demonstrated that the Smad2\/3 pathway was involved in TGF-<jats:italic>\u03b2<\/jats:italic>3-induced ROS generation by promoting NOX4 expression. The inhibition of ROS generation by N-Acetyl-L-cysteine (NAC) resulted in a decrease in mucus expression and autophagy activity <jats:italic>in vivo<\/jats:italic> as well as <jats:italic>in vitro<\/jats:italic>. Finally, TGF-<jats:italic>\u03b2<\/jats:italic>3-neutralizing antibody significantly reduced the ROS generation, mucus expression, and autophagy activity and also decreased the phosphorylation of Smad2 and Smad3. Taken together, the obtained results revealed that persistent TGF-<jats:italic>\u03b2<\/jats:italic>3 activation increased ROS levels in a NOX4-dependent pathway and subsequently induced autophagy as well as MUC5AC expression in the epithelial cells.<\/jats:p>","DOI":"10.1155\/2019\/3153240","type":"journal-article","created":{"date-parts":[[2019,12,31]],"date-time":"2019-12-31T18:32:16Z","timestamp":1577817136000},"page":"1-17","source":"Crossref","is-referenced-by-count":19,"title":["TGF-<i>\u03b2<\/i>3 Induces Autophagic Activity by Increasing ROS Generation in a NOX4-Dependent Pathway"],"prefix":"10.1155","volume":"2019","author":[{"given":"Yun","family":"Zhang","sequence":"first","affiliation":[{"name":"Inflammation & Allergic Diseases Research Unit, Affiliated Hospital of Southwest Medical University, Luzhou, 646000 Sichuan, China"},{"name":"First Department of Respiratory Disease, Affiliated Hospital of Southwest Medical University, Luzhou, 646000 Sichuan, 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