Fig. 2.

ROS contribute to the induction and persistence of TGF-β-mediated fibrosis. The presence of ROS induces the conversion of latent TGF-β complex to its active form, which binds to its receptor and triggers signaling pathways such as SMAD2/3, PI3K, and JNK. This in turn increases the transcriptional activity of various pro-fibrotic genes, such as NOX4, αSMA, and COL I. Increase in NOX4 expression also results in ROS generation, which leads activation of other ROS-dependent signaling transduction pathways such as, NFκB and JNK. Elevated ROS also causes irreversible DNA damage, through oxidization of its bases. Together, enhanced ROS and activated TGF-β signaling contributes to proliferation and transdifferentiation of fibroblast cells into myofibroblasts, and excessive ECM deposition leading to fibrosis.