The protective effect of soluble tumor necrosis factor receptor Ⅰ against liver failure caused by drugs in immunity-induced cirrhotic rats / 中华传染病杂志

ABSTRACT

Objective To investigate whether a novel long-acting tumor necrotic factor (TNF) antagonist (soluble TNF receptorIgG Fc [sTNFRIgG-Fc]) can protect hepatocyte damage against liver failure caused by drugs in immunity-induced cirrhotic rats.Methods Wistar rats were repeatedly sensitized by human serum albumin (HSA) emulsified in complete freud adjuvant.The blood was collected at day 10 after the final sensitization.If anti-albumin antibody was positive,the rats were intravenously injected with HSA twice a week.After six weeks,liver cirrhosis was induced by immunity.All the model rats were divided into three groups with 15 each.Liver failure was induced with D-galactosamine/ lipopolysaccharide (LPS) intraperitoneal injection in the rats with liver cirrhosis in model group.The rats in pretreatment group were intraperitoneally injected with long-acting soluble TNF receptor p55 18 h before D-galactosamine/LPS injection.The control group were injected with 0.9％ sodium chloride.General condition,survival rate,liver function and pathological changes were all examined.Serum levels of interleukin (IL)-6,IL-22 and intrahepatic level of IL-6 were detected by enzyme linked immunosorbent assay (ELISA).The activity of Caspase 3 in hepatocyte lysis solution was measured by spectrophotography.Real-time polymerase chain reaction (PCR) was used to detect mRNA expressions of proliferating cell nuclear antigen (PCNA),bcl-2,bax and IL-22 receptor.Data were analyzed by variance analysis among groups.Results Rats in model group were dispirited with poor response after 12 hours and only 3 survived,compared with soluble TNF receptor p55 pre-treated group rats,in which all survived (P=0.029 8) with flexible response.Serum alanine aminotransferase levels in these two groups were (6 533± 360) and (105 ± 7) U/L,respectively.Hepatic regenerative nodule developed massive or submassive necrosis with septal fibrosis in model group,whereas soluble TNF receptor p55 alleviated the inflammatory and necrosis reaction of hepatic tissue.Serum IL-6 levels in model group and pretreatment group were (842.0±12.9) and (91.9±1.6) pg/mL,respectively (F=380.30,P＜0.01).Intrahepatic levels of IL-6 in these two groups were (26.2±1.2) and (11.1±0.8) pg/mL,respectively (F=176.90,P＜0.01),and serum IL-22 levels were (167.0±27.8) and (988.0±109.6) pg/mL,respectively (F=37.91,P＜0.01).Hepatic Caspase-3 activity was reduced by almost 60％ by soluble TNF receptor p55 pretreatment (F=303.70,P＜0.01) and bax expression reduced by 22％ (F=108.80,P＜0.01),while bcl-2 and PCNA expressions were up-regulated by 3.6-folds and 23.0-folds,respectively (F=115.60,P＜0.01; F=594.20,P＜0.01).Conclusions Long acting soluble TNF receptor p55 could improve survival rate,liver function and reduce inflammatory reaction of rats with liver failure induced by drugs on the basis of liver cirrhosis caused by immunity,which indicates that this drug may process a potential therapeutic value.