Melatonin Attenuates Sepsis-Induced Acute Lung Injury via Inhibiting Excessive Mitophagy.

Abstract

Epidemiological studies have indicated that lung injury is a frequent complication of sepsis. Mitophagy is vital to multiple pathological processes and diseases; however, its influence on sepsis-induced acute lung injury remains elusive. Melatonin has multiple antioxidant action and anti-inflammatory effects, including regulating mitophagy and inflammatorycytokine expression. Whereas, little is known about the affection of melatonin and mitophagy on CLP-induced ALI. The in vivo effect of melatonin on OPTN-mediated mitophagy was studied by CLP-induced ALI in a mouse model using C57BL/6 followed by treatment with vehicle and melatonin (30 mg/kg/d, intraperitoneal injection). ALI was assayed by lung wet /dry ratio, hematoxylin and eosin staining, and immunohistochemical staining. Signaling pathway changes were subsequently determined by Western blotting and immunofluorescence staining. The effects of melatonin on STAT3 activation and TNF-α production were detected by Western blotting, PCR, and immunohistochemical staining. Our results indicated that OPTN, mitophagy adaptors were significantly repressed in CLP-induced ALI, accompanied by overactivation ofmitophagy and inflammation. At the same time, we found that melatonin treatment alleviated ALI caused by CLP, and the effect was highly correlated with OPTN-related mitophagy. Furthermore, we demonstrated that OPTN-related mitophagy, which was normalized by melatonin, blocked STAT3 involved epithelial barrier and inflammation in vivo. Overall, our results confirm that mitophagy is adjusted by melatonin in the CLP-induced ALI. Moreover, manipulation of mitophagy through melatonin could be a possible treatment to reduce sepsis-associated lung injury.