title: Ursodeoxycholyl lysophosphatidylethanolamide protects against hepatic ischemia and reperfusion injury in mice.
abstract: The ischemia and reperfusion (I/R) injury that occurs during liver transplantation causes severe complications leading to transplantation failure. We have designed a cytoprotective agent, ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE), which promotes the survival of cultured hepatocellular cell lines and inhibits apoptosis and inflammation in the in vivo models of liver injury. Here, we show that UDCA-LPE increased the viability of mouse hepatocytes by activating the Akt/glycogen synthase kinase 3β survival signaling pathways. We further tested whether UDCA-LPE could protect hepatic I/R injury in mice by clamping liver lobes of C57/BL6 mice for 90 min of ischemia followed by unclamping and reperfusion for 2 h. Two regimens for UDCA-LPE treatment were carried out; with a single dose of 100 mg/kg UDCA-LPE intraperitoneally injected 30 min prior to ischemia and a double dose of 50 mg/kg UDCA-LPE given 30 min prior to ischemia and just prior to reperfusion. Using histology and liver enzyme determination, we observed that hepatic I/R caused significant hepatic necrosis, which was decreased in UDCA-LPE-treated mice undergoing I/R. Ursodeoxycholyl LPE concomitantly protected against I/R-induced apoptosis (cleaved caspase 3, cleaved poly[ADP-ribose] polymerase 1), inflammation (IL-1β, CD11b, chemokine ligands 2 and 3, chemokine receptor 2), and portal fibrogenesis (α-smooth muscle actin, plasminogen activator inhibitor 1), as determined by Western blot, quantitative real-time polymerase chain reaction, and immunohistochemical analyses. The protection by UDCA-LPE was found to be better in the double-dose than in the single-dose regimen. Thus, UDCA-LPE promoted the survival of mouse hepatocytes and protected against hepatic I/R injury and thus may be of therapeutic use in liver transplantation settings.
authors.affiliation: *Internal Medicine IV, Gastroenterology and Hepatology, University Heidelberg Hospital, Heidelberg, Germany; †Department of General Surgery and Laparoscopic Surgery, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; ‡Mass Spectrometry Laboratory, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Jiliang
authors.initials: J
authors.lastname: Wang
authors.forename: Xiuling
authors.initials: X
authors.lastname: Deng
authors.forename: Shengen
authors.initials: S
authors.lastname: Yi
authors.forename: Anita
authors.initials: A
authors.lastname: Pathil
authors.forename: Wujuan
authors.initials: W
authors.lastname: Zhang
authors.forename: Kenneth
authors.initials: K
authors.lastname: Setchell
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stremmel
authors.forename: Walee
authors.initials: W
authors.lastname: Chamulitrat
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D004492:Edetic Acid / Q000737:chemistry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D007249:Inflammation / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism / Q000517:prevention & control*; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D008246:Lysophospholipids; C000598975:ursodeoxycholyl lysophosphatidylethanolamide; D014580:Ursodeoxycholic Acid; D004492:Edetic Acid; C505409:Casp3 protein, mouse; D053148:Caspase 3