Objective To investigate the effect abnormal gut metabolites on the occurrence of neutrophil extracellular traps to exacerbate acute liver failure through hepatic intestinal axis.Methods The acetaminophen-induced acute liver failure(ALF)mouse model was applied to investigate the intrinsic connection between disease state and hepatic neutrophil infiltration and the formation of neutrophil extracellular traps(NETs).Untargeted metabolomic analysis systematically examined the similarities and differences in metabolic products within the intestinal mucosa to identify key metabolites that trigger hepatic NETs.Antibody arrays were employed to explore the potential links between cytokines and NETs during ALF progression,and the regulatory effects of NETs on macrophage polarization and inflammation-mediated disease progression were investigated with flow cytometry and immunofluorescence methods.Results In the acetaminophen-induced ALF mouse model,the significant infiltration of neutrophils and the formation of NETs were observed in the liver.Analysis of intestinal mucosal metabolites revealed a notable increase in the levels of leukotriene D4(LTD4),which compromised the barrier function of the intestinal mucosa.This condition facilitated the transfer of endotoxins and LTD4 to the liver,promoting the formation of NETs.Analysis of liver cytokines indicated that NETs could mediate the further release of pro-inflammatory factors by regulating the polarization of macrophages towards an Ml phenotype.Conclusion During ALF,a substantial infiltration of neutrophils into the liver is stimulated by ectopic metabolic products translocated from the gut to the liver,leading to the formation of NETs.The NETs formed can modulate the differentiation of macrophages,further exacerbating the inflammatory response in ALF.
国家科技期刊平台
NSTL
万方数据
