Role Of Modified Organ Preservation In Rat Liver Transplantation Using Grafts Donated After Cardiac Death

Liver transplantation(LTx)using grafts donated after cardiac death(DCD)resulted in more postoperative complications and lower survival rate due to prolonged warm ischemia time(WIT)and consequential severe ischemia-reperfusion injury(IRI).Reportedly,endoplasmic reticulum stress(ERS)plays an essential role in IRI;while in DCD LTx,the underlying mechanism remains unclear.In the present study,rat DCD LTx model was employed to elucidate the involvement of ERS in DCD LTx and protective effects of ERS-targeted modified organ preservation on prognosis after DCD LTx.Part ? Aim:To evaluate the role of ERS in DCD LTx and inhibitory effects of TUDCA and PBA on ERS.Methods:All rats were randomized into following groups:group 1.1(control group):liver grafts with a WIT less than 1 min were used for LTx;group 1.2(DCD group):WIT of the liver grafts was 60 min;group 1.3 and 1.4(TUDCA group and PBA group):same as group 1.2 but donors were intraperitoneally injected with TUDCA and PBA(100 mg/kg BW),respectively.Serum transaminases levels,oxidative stress activation and expression of ERS signal molecules were investigated,and pathological changes and survival rates were observed.Results:Compared with group 1.1,group 1.2 indicated higher levels of serum transaminases and oxidative products,severe pathological changes,up-regulated ERS signal expressions and all recipients died within 3 days after LTx.Administration of TUDCA and PBA(group 1.3 and 1.4)led to decreased transaminases levels,strengthened superoxide dismutase(SOD)activities,milder pathological changes,down-regulated ERS signal expressions and improved postoperative survivals.Conclusion:ERS was involved in rat DCD LTx;preoperative intraperitoneal injection of TUDCA or PBA provided protection against liver damages and improved prognosis.Part II Aim:To evaluated protective effects of combined application of modified UW solution supplemented with TUDCA or PBA and continuous hypothermic oxygenation perfusion system(CHOPS)on DCD liver grafts.Methods:All liver grafts were divided into following groups:group 2.1(control group):liver grafts with a WIT less than 1 min were cold stable stored(CSS)for 6 h;group 2.2(DCD group):WIT was 60 min and liver grafts were CSS for 6 h;group 2.3(CHOPS group):DCD liver grafts were preserved with CHOPS using UW solution;group 2.4-2.6(CHOPS+TUDCA groups)and 2.7-2.9(CHOPS+PBA groups):same as group 2.3,but the UW solution was supplemented with TUDCA or PBA(25,50 and 100 mg/L for both drugs),respectively.Transaminases levels in organ preservation solutions and pathological changes of livers were evaluated.Results:Transaminases levels in group 2.5 and 2.8 were significantly decreased,and pathological changes were also alleviated contrasting to group 2.2 and 2.3.Conclusion:Combined application of CHOPS and modified UW solution supplemented with TUDCA or PBA(50 mg/L)provided a significant and better protection than CHOPS alone against liver grafts cold ischemia injury.Part III Aim:To evaluate effect of CHOPS combining modified UW solution on prognosis of rat DCD LTx.Methods:All operations were grouped as followed:group 3.1(control group),group 3.2(DCD group),group 3.3(CHOPS group),group 3.4(CHOPS+TUDCA(50 mg/L)group)and group 3.5(CHOPS+PBA(50 mg/L)group).Postoperative serum transaminases and oxidative stress markers were measured;pathological examinations and survival curves were performed.Results:Contrasting to group 3.2,CHOPS provided better preservation of DCD liver grafts(group 3.3)evidenced by decreased serum transaminases and oxidative products levels,improved pathological performances,and elevated survival rate;while this protection was enhanced after concomitant use of UW solution containing TUDCA or PBA.Conclusion:Combination of CHOPS and modified UW solution supplemented with TUDCA or PBA relieved liver damages after DCD LTx and provided a comparable survival rate to normal LTx.