| Background:donor of brain death liver transplantation has a poorer grafting effect and shorter graft survival after transplantation compared to living donor liver transplantation.Brain death is considered to be an important factor affecting the effect of brain death after liver transplantation.Apart from hemodynamics,the mechanism underlying the deteriorating effect of brain death on the organs and the outcomes after transplantation is mainly associated with a systemic inflammatory response.The pro-inflammatory cytokines released during and after brain death lead to histological damage and dysfunction of potential donor organs by eliciting systemic inflammatory responses.Ischemia/reperfusion injury is another factor causing initial insufficiency of grafts and non-functional primary grafts after liver transplantation and inflammatory responses is also involved in Ischemia/reperfusion injury.Therefore,inhibition of inflammatory responses not only attenuates brain death-induced donor liver injury,but also ameliorates ischemia-reperfusion injury after transplantation.Etanercept is a recombinant protein composed of human TNF-R2 extracellular domain dimer fused to the Fc portion of human IgG1.As one of the TNF-α-specific antagonists,It exerts anti-inflammatory effects by neutralizing TNF-α and is currently used to improve rheumatoid arthritis and ankylosing spondylitis.Recent studies have shown that treatment with etanercept can also attenuate brain injury and acute liver injury.Purpose:1.To study the protective effect of etanercept brain injury-associated liver injury in rats2.To study the protective effect of etanercept on ischemia-reperfusion injury donor of brain death liver transplantation in a rat modelMethods:1.Using a rat model,BD-induced liver injury and the potential protective effects of etanercept were evaluated.Rats were randomly assigned to four groups(n=8 per group):including sham+saline,sham+etanercept,BD+saline,and BD＋etanercept groups.Six hours after the establishment of the model,the rats were sacrificed and blood and liver specimens were obtained.Liver injury was evaluated by liver function measurements and histological examinations.Serum and hepatic TNF-αlevels were measured by ELISA and in-situ immunofluorescence(IF-IC),respectively.The expression levels of genes related to inflammation were monitored by quantitative real-time polymerase chain reaction.Additionally,hepatocellular apoptosis was examined by IF-IC analyses of caspase-3 and terminal deoxynucleotidyl transferase-mediated nick end labeling(TUNEL).2.SD rats were randomly divided into 5 groups(n=6 per group):sham operation group,non-BD,non-BD+etanercept recipient treatment,BD and BD +etanercept recipient treatment group.Except the sham group,donors from different donors were transplanted into recipients of the same type of SD rats,and serum and liver specimens were taken 12 h after liver transplantation.Recipient rats received intravenous injection of etanercept or saline.Liver injury was assessed by liver function measurements and histological examination.Serum and hepatic TNF-a levels were measured by ELISA and immunohistochemistry,respectively.The level of expression of genes involved in inflammation was detected by semi-quantitative real-time polymerase chain reaction.The expression of caspase-3 was analyzed by IF-IC.Hepatic oxidative stress was assessed by detecting malondialdehyde and superoxide dismutase.Results:1.Etanercept administration neutralized the increased TNF-a in the liver and plasma induced by BD and resulted in noticeable down-regulation of IL-1β,VCAM-1,and ICAM-1 mRNA expression(P<0.01 versus BD group).Etanercept administration also resulted in a significant improvement in apoptosis,as evidenced by a dramatic decline in the levels of cleaved caspase-3 and apoptosis compared to those in the BD+saline rats.These changes were accompanied by improved liver function(P<0.05 versus BD group)and histopathological changes.2.In the rat model,donor brain death exacerbated ischemia/reperfusion injury,as demonstrated by increased liver injury,serum transaminase,cellular infiltration,inflammatory cytokine levels,apoptosis and oxidative stress markers.Etanercept treatment of recipients significantly reduced all measured outcomes in grafts from both BD and non-BD donors compared with controls.Conclusions:1.Our results indicated that etanercept has protective effects against BD-induced liver injury in rats.Accordingly,the inhibition of TNF-a is a promising therapeutic strategy to improve the outcomes of transplantation for livers from brain-dead donors.2.BD exacerbates posttransplantation liver ischemia/reperfusion injury in rats and etanercept treatment in recipient rats ameliorates BD-exacerbated ischemia/reperfusion injury. |
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