FGF10 mitigated sepsis-induced pulmonary coagulopathy via Nrf2/PINK1/Parkin-modulated mitophagy

Severe coagulation and endothelial dysfunction are characteristics of sepsis-induced acute pulmonary coagulopathy with high morbidity and mortality. The primary objective of this research is to investigate the role rFGF10 in ameliorating sepsis-induced coagulation and endothelial dysfunction. FGF10 expression levels in sepsis-induced mice lung tissues and lipopolysaccharide (LPS) stimulated Human umbilical vein endothelial cells (HUVECs) were detected and the results showed that they were both elevated. Supplementation with rFGF10 protected HUVECs against LPS stimulation and ameliorated sepsis-induced pulmonary coagulation evidenced by the suppressed coagulation factors and alleviated lung injury. Mechanistically, rFGF10 activated Nrf2-modulated mitophagy by PINK1/Parkin pathway in septic mice, which maintained mitochondrial quality, promoted activities of anti-oxidation and suppressed mitochondrial reactive oxygen species (mtROS), therefore, suppressed phosphorylation of NF-𝑘B, Erk1/2 and P38, which thus, is crucial for rFGF10 protection against sepsis induced pulmonary coagulation. Suppression of Nrf2 with its inhibitor ML385 abolished all beneficial effects of rFGF10 on sepsis-induced mice. These findings revealed the therapeutic effects of rFGF10 on sepsis-induced pulmonary coagulation and endothelial dysfunction, which could be a potential pharmacological strategy for clinic.