Tauroursodeoxycholic acid and 4-phenyl butyric acid alleviate endoplasmic reticulum stress and improve prognosis of donation after cardiac death liver transplantation in rats

摘要

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 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 signiifcantly 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-eIF2α1, 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 signiifcantly 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 trans-plantation in rats. Preoperative intraperitoneally injection of TUDCA or PBA protected ER stress and improved prognosis.