NOX4-Derived ROS Promotes Collagen I Deposition in Bronchial Smooth Muscle Cells by Activating Noncanonical p38MAPK/Akt-Mediated TGF-β Signaling

Figure 7

Schematic representation of Smad3-NOX4-derived ROS-mediated p38MAPK/Akt signaling in TGF-β₁-induced ECM production of HBSMCs. We previously demonstrated an increased expression of NOX4 and TGF-β₁ with the severity of remodeling in ASM of the small airway of the COPD lung, which was inversely associated with the pulmonary function. The findings in the present study demonstrated that NOX4 mediated TGF-β₁-induced ECM protein synthesis and differentiation in HBSMCs; NOX4-derived ROS in response to TGF-β₁ may activate the p38MAPK or Akt pathway, resulting in the differentiation and ECM protein synthesis based on the Smad3 canonical pathway. And NAC, a scavenger of ROS, attenuates HBSMC remodeling by scavenging intracellular ROS to inhibit NOX4 expression and block the Smad3 and MAPK pathways. Current findings indicated that NOX4 is critical for modulation in TGF-β₁-induced ECM synthesis in HBSMCs, which contributes to airway remodeling in the pathogenesis of COPD, and the antioxidant (NAC) might serve as a valuable therapeutic strategy.