title: Tauroursodeoxycholic acid and 4-phenyl butyric acid alleviate endoplasmic reticulum stress and improve prognosis of donation after cardiac death liver transplantation in rats.
abstract: BACKGROUND
  Inevitable warm ischemia time before organ procurement aggravates posttransplantation ischemia-reperfusion injury. Endoplasmic reticulum (ER) stress is involved in ischemia-reperfusion injury, but its role in donation after cardiac death (DCD) liver transplantation is not clear and the effect of ER stress inhibitors, tauroursodeoxycholic acid (TUDCA) and 4-phenyl butyric acid (PBA), on the prognosis of recipient of DCD liver transplantation remains unclear.
  
  
  METHODS
  Male Sprague-Dawley rats (8-10 weeks) were randomly divided into the control group: liver grafts without warm ischemia were implanted; DCD group: warm ischemia time of the liver grafts was 60 minutes; TUDCA and PBA groups: based on the DCD group, donors were intraperitoneally injected with TUDCA or PBA 30 minutes before the organ procurements. Serum aminotransferase levels, oxidative stress activation and expression of ER stress signal molecules were evaluated. Pathological examinations were performed. The survivals of the recipients in each group were compared for 14 days.
  
  
  RESULTS
  Compared with the control group, DCD rats had significantly higher levels of serum aminotransferase at 6 hours, 1 day and 3 days after operation (P<0.01, 0.01 and 0.05, respectively) and oxidative indices (P<0.01 for both malondialdehyde and 8-hydroxy deoxyguanosine), more severe liver damage (P<0.01) and up-regulated ER stress signal expressions (P<0.01 for GRP78, phos-eIF2alpha1, CHOP, ATF-4, ATF-6, PERK, XBP-1 and pro-caspase-12). All recipients died within 3 days after liver transplantation. Administration of TUDCA or PBA significantly decreased aminotransferase levels (P<0.05), increased superoxide dismutase activities (P<0.01), alleviated liver damage (P<0.01), down-regulated ER stress signal expressions (P<0.01) and improved postoperative survivals (P<0.01).
  
  
  CONCLUSIONS
  ER stress was involved with DCD liver transplantation in rats. Preoperative intraperitoneally injection of TUDCA or PBA protected ER stress and improved prognosis.
authors.affiliation: Translation Medicine Research Center, Affiliated Jiangning Hospital; Department of Liver Surgery, First Affiliated Hospital, Nanjing Medical University; Key Laboratory of Living Donor Liver Transplantation, National Health and Family Planning Commission of China, Nanjing 210029, China. zhangfeng1958@hotmail.com.
authors.forename: Hao
authors.initials: H
authors.lastname: Lu
authors.forename: Ling
authors.initials: L
authors.lastname: Lu
authors.forename: Zhen-Chao
authors.initials: ZC
authors.lastname: Xu
authors.forename: Yun-Jie
authors.initials: YJ
authors.lastname: Lu
authors.forename: Bo
authors.initials: B
authors.lastname: Zhao
authors.forename: Lin
authors.initials: L
authors.lastname: Zhuang
authors.forename: Bao-Bing
authors.initials: BB
authors.lastname: Hao
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002756:Cholagogues and Choleretics / Q000494:pharmacology* / Q000627:therapeutic use; D003643:Death; D051799:Delayed Graft Function / Q000188:drug therapy; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D016031:Liver Transplantation / Q000379:methods*; D008297:Male; D023421:Models, Animal; D018384:Oxidative Stress / Q000187:drug effects; D010654:Phenylbutyrates / Q000494:pharmacology* / Q000627:therapeutic use; D011379:Prognosis; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control; D015996:Survival Rate; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D002756:Cholagogues and Choleretics; D010654:Phenylbutyrates; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; C075773:4-phenylbutyric acid; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase