Gasotransmitters: Potential Therapeutic Molecules of Fibrotic Diseases

Figure 1

Molecular and cellular mechanisms of fibrosis. TGF-β recognizes and combines with TGF-βR II and TGF-βR I successively, and then, the glycine-serine- (GS-) rich region of TGF-βR I phosphorylates Smad2/3 to facilitate the formation of oligomeric complex with Smad4 and which translocates into the nucleus and participates in the transcription of fibrotic genes, such as galectin 3, collagen I, collagen III, α-SMA, and TGF-β. Besides that, the TGF-β signaling pathway can be activated by oxidative stress and cellular senescence, which further affects the activation of the downstream factors ASK-1. ASK-1 can promote MKK3/6 phosphorylation and which subsequently activates p38 MAPK and phosphorylates ATF2, thereby promoting the transcription of fibrosis-associated genes. NOX2/4 can stimulate ROS production and provoke the NF-κB signaling pathway to upregulate inflammatory-associated genes, such as NLRP3, IL-6, IL-1β, TNF-α, and MMPs, to promote the development of fibrosis. IL-4 and IL-13 secreted by Th2 cells can activate STAT6 and which can promote the expression of fibrotic genes and inflammatory cytokines to accelerate the process of fibrosis. Autophagy exerts a protective role in fibrotic diseases by downregulating the TGF-β/Smad4 pathway and NLRP3 inflammasome.