Protective role of Ursodeoxycholyl Lysophosphatidylethanolamide during hepatic ischemia and reperfusion injury in mice

Introduction: Ischemia and reperfusion (I/R) injury of the liver which may occur during liver transplantation can cause severe complications leading to transplantation failure. We have designed cytoprotective agent ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE), which has been shown to be protective in ameliorating apoptosis and inflammation in acute and chronic liver injury models, such as, endotoxic shock and feeding with high-fat diet. This study is aimed to explore whether UDCA-LPE can also serve as a protective agent against hepatic I/R injury in mice. Methods: Ischemia in C57/BL6 mice was introduced by blocking blood supply to middle and left liver lobes for 90 min, and reperfusion was allowed for 2h causing I/R injury in 75% of the liver. Four groups were studied, i.e., sham, I/R for 2h (IR), UDCA-LPE1 and UDCA-LPE2. UDCA-LPE1 represented intraperitoneal (i.p.) injection with 100 mg/kg UDCA-LPE 30 min prior to ischemia induction. UDCA-LPE2 represented two i.p. injections of 50 mg/kg UDCA-LPE at 30 min prior to ischemia and just prior to reperfusion. Liver injury was assessed by liver enzyme activities, hepatic mRNA expression of inflammatory genes, apoptosis protein expression by Western Blot, and histological evaluation. Results: I/R under our experimental protocol caused significant liver injury compared with sham. I/R increased serum transaminase activities (ALT, AST, LDH) which were decreased by UDCA-LPE treatment (ALT: 215.2 ± 40.5 U/L for IR; 130.3 ± 22.4 U/L for UDCA-LPE1; 91.3 ± 37.1 U/L for UDCA-LPE2, n = 9). I/R caused increased hepatic expression of inflammatory TNF-α, IL-6, IL-1β, MCP-1 mRNA as well as apoptosis cleaved caspase-3 and PARP-1 proteins. This elevation was inhibited by UDCA-LPE treatment with UDCA-LPE2 being better than UDCA-LPE1. Histology revealed that I/R caused significant hepatic necrosis, and increased immunohistochemical staining of MCP-1 receptor (CCR2) and cleaved caspase-3. UDCA-LPE treatment, particularly UDCA-LPE2, significantly improved these histological abnormalities to the sham levels. Conclusions: UDCA-LPE was a hepatoprotectant in attenuating liver injury induced by I/R in mice. Multiple dosages of UDCA-LPE given during I/R were more effective than a single pre-I/R dose. Thus, UDCA-LPE may be of therapeutic use in a liver transplantation setting.