白细胞来源趋化因子2在脓毒症相关肝损伤中的作用及机制研究OA

Background Leukocyte cell-derived chemotaxin 2(LECT2),secreted by hepatocytes,participates in the regulation of inflammatory responses and may play a pivotal role in sepsis-associated liver injury.Objective To investigate the function and molecular mechanisms of LECT2 in sepsis-associated liver injury and to evaluate the protective effects of LECT2 gene knockout.Methods An in vitro model of septic hepatocellular injury was established by stimulating THLE-2 cells with lipopolysaccharide(LPS).Cells were randomly assigned to four groups:untreated control(Control),exogenous LECT2 supplementation(LECT2),LPS stimulation(LPS),and LPS with exogenous LECT2(LPS+LECT2).The effects of LECT2 on cell viability,apoptosis,cell death,and levels of alanine aminotransferase(ALT)and aspartate aminotransferase(AST)in supernatants were assessed.In vivo,a murine sepsis model was generated using cecal ligation and puncture(CLP).Mice were randomly divided into six groups(n=6 per group):wild-type(WT)mice,LECT2 knockout(LECT2 KO)mice,WT mice receiving tail vein injection of AAV8 control vector(WT+AAV8-vehicle),WT mice injected with AAV8 carrying full-length LECT2 plasmid(WT+AAV8-LECT2 overexpression),WT mice injected with 100 μL PBS as vehicle control(WT+PBS),and WT mice injected with 100 μL recombinant LECT2 protein(WT+rLECT2).CLP-induced sepsis models and corresponding sham operations were performed in all groups.Liver histopathological changes were evaluated by H&E staining,expression levels of inflammatory cytokines including interleukin-1β(IL-1β),IL-6,and tumor necrosis factor-α(TNF-α)were measured,and serum concentrations of ALT and AST were determined.Results In vitro,compared with the LPS group,the LPS+LECT2 group showed further reduced THLE-2 cell viability(P＜0.01),aggravated cellular injury,and a further increase in ALT concentration in the culture supernatant(P＜0.05).In vivo,hepatic and serum LECT2 expression in sepsis model groups was markedly downregulated compared to sham groups(both P＜0.01).The liver histopathological injury score in the LECT2 KO group was lower than in the WT group(P＜0.01).Hepatic expression of IL-1β and TNF-α in the LECT2 KO group was lower than in the WT group(P＜0.05 and P＜0.001,respectively).Serum levels of ALT and AST in the LECT2 KO group were also significantly lower than in the WT group(both P＜0.01).Conclusion LECT2 gene knockout attenuates sepsis-associated liver injury,suppresses inflammatory cytokine release,and improves liver histopathological structure and function.