Gasotransmitters: Potential Therapeutic Molecules of Fibrotic Diseases

Table 1

Related mechanisms of gasotransmitters in fibrotic diseases.

Gasotransmitters		Diseases	Mechanisms	References
NO	SNAP	Liver fibrosis	SNAP can eliminate the generation of ROS, inhibit the activation and proliferation of HSC, and inhibit the generation of fibrosis.	[66]
		Renal fibrosis	SNAP can amplify the expression of TIMP-1 in a TGF-β-dependent manner and reduce fibrosis.	[71]
		Peyronie’s disease	SNAP can inhibit fibrosis by inhibiting the production of ROS, decreasing the expression of collagen 1, and reducing the abundance of myofibroblasts.	[91]
	eNOS	Liver fibrosis	eNOS can reduce fibrosis by promoting HSC apoptosis and ROS-mediated mitochondrial membrane depolarization to inhibit HSC activation.	[77–79]
	L-arginine	Renal fibrosis	L-arginine can be mediated through a variety of pathways, including inhibiting the expression of TGF-β to reduce fibrosis.	[73]
	CINOD	Idiopathic pulmonary fibrosis	CINOD can inhibit the expression of COX1 and COX2, showing anti-inflammatory and antioxidant effects to resist fibrosis.	[75]
CO	CORM3	Activation of mouse embryonic fibroblasts	1 mM CORM3 can reduce the production of collagen I and III and interact with plasma fibronectin to prevent fibrosis.	[96]
	CO-HbV	Idiopathic pulmonary fibrosis	CO-HbV reduces the production of ROS by inhibiting the NOX4 signaling and attenuating the TGF-β signaling pathway.	[98]
	CO gas	Idiopathic pulmonary fibrosis	Exogenous 250 ppm CO gas inhibits the synthesis of deposition of ECM and interferes with the proliferation of fibroblasts through the regulation of Id1 expression.	[97]
		Renal fibrosis	250 ppm CO can ameliorate UUO-induced renal fibrosis and protect against kidney injury.	[100]
		Myocardial fibrosis	250 ppm CO can play an antifibrosis effect by inhibiting the TGF-β signaling and stimulating autophagy.	[103, 104]
H2S	NaHS	Idiopathic pulmonary fibrosis	NaHS can reduce the deposition of collagen and reduce pulmonary fibrosis.	[113]
		Renal fibrosis	NaHS can significantly reduce fibrosis through phosphorylation of the NF-κB and IL-4/STAT6 signaling pathway and inactivation of NLRP3 and its downstream signaling pathways, inhibiting the infiltration of M1 and M2 macrophages and downregulating fibrogenic genes.	[118]
		Renal fibrosis	NaHS can accelerate the proliferation of renal tubular cells and delay renal fibrosis by reducing oxidative stress and inflammation.	[119]
		Renal fibrosis	NaHS can prevent the formation of fibrosis by reducing the expression of TGF-β.	[120]
		Renal fibrosis	NaHS can inhibit the ERK- and β-catenin-dependent signaling pathways to improve renal fibrosis.	[121]
		Myocardial fibrosis	The chronic aerobic exercise or NaHS administration can downregulate myocardial hydroxyproline level and fibrotic area.	[125]
		Myocardial fibrosis	NaHS can reduce the content of Nox2/4, the phosphorylation of ERK1/2, and ROS, thereby reducing the myocardial fibrosis mediated by oxidative stress.	[115, 122]
		Myocardial fibrosis	NaHS inhibits the accumulation of extracellular matrix and increases blood vessel density to reduce myocardial fibrosis.	[124]
		Liver fibrosis	NaHS can elevate serum H2S level, decrease hyaluronic acid, and reduce the number of activated HSCs.	[131–133]
		Diabetic diaphragm fibrosis	NaHS can inhibit the inflammatory response mediated by NLRP3 inflammasome and reduce collagen deposition.	[137]
	GYY4137	Myocardial fibrosis	GYY4137 exerts antifibrosis and cardioprotective effects by enhancing the activation of endogenous natriuretic peptides after early ischemia.	[123, 126]
	SAC	Liver fibrosis	SAC can reduce liver fibrosis through its antioxidant and anti-inflammatory properties, as well as inhibiting the STAT3/SMAD3 signaling pathway.	[127]
	H2S	Idiopathic pulmonary fibrosis	H2S can inhibit the expression of NF-κB p65 and downregulate Th2 cells to reduce fibrosis.	[135]