Abstract
Higher concentrations of reactive oxygen species (ROS) have been associated with epithelial cell damage, cell shedding, and airway hyperresponsiveness. Previous studies have indicated that transforming growth factor-beta (TGF-β) mediates ROS production and NADPH oxidase (NOX) activity. In our previous study, we also observed that TGF-β3 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-β3 induction. Using an allergic inflammation mouse model induced by house dust mite (HDM), we observed elevated lung amounts of TGF-β3 accompanied by increased ROS levels. And we found that ROS levels were elevated and NOX4 expression was increased in TGF-β3-induced epithelial cells, while the lack of NOX4 in the epithelial cells could reduce ROS generation and autophagy-dependent MUC5AC expression treated with TGF-β3. Furthermore, our studies demonstrated that the Smad2/3 pathway was involved in TGF-β3-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 in vivo as well as in vitro. Finally, TGF-β3-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-β3 activation increased ROS levels in a NOX4-dependent pathway and subsequently induced autophagy as well as MUC5AC expression in the epithelial cells.
Highlights
Reactive oxygen species (ROS), identified as signaling molecules that regulate both cell survival and cell death, have an important role in the pathogenesis of airway inflammation and tissue injury associated with asthma [1,2,3]
We found that NOX4 was required for reactive oxygen species (ROS) generation induced by TGF-β3
These results suggested that Smad2/3 signaling serves a key function in the regulation of NOX4 expression and ROS generation induced by TGF-β3
Summary
Reactive oxygen species (ROS), identified as signaling molecules that regulate both cell survival and cell death, have an important role in the pathogenesis of airway inflammation and tissue injury associated with asthma [1,2,3]. Autophagy is a dynamic process responsible for the turnover of organelles and long-lived proteins, which plays a crucial role in maintaining cellular integrity and adaptation to adverse environments [4]. HDM can directly lead to the production of reactive oxygen [14]. Studies have suggested that the relationship between ROS and autophagy is cell context-dependent and that ROS production regulates MUC5AC expression [15]; MUC5AC is considered a marker of mucus cell hyperplasia or metaplasia because of its high expression in mucus-
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