PMID- 29266279 OWN - NLM STAT- MEDLINE DCOM- 20181001 LR - 20181001 IS - 1525-1594 (Electronic) IS - 0160-564X (Linking) VI - 42 IP - 3 DP - 2018 Mar TI - Donor Treatment With a Hypoxia-Inducible Factor-1 Agonist Prevents Donation After Cardiac Death Liver Graft Injury in a Rat Isolated Perfusion Model. PG - 280-289 LID - 10.1111/aor.13005 [doi] AB - The protective role of hypoxia-inducible factor-1 (HIF-1) against liver ischemia-reperfusion injury has been well proved. However its role in liver donation and preservation from donation after cardiac death (DCD) is still unknown. The objective of this study was to test the hypothesis that pharmaceutical stabilization of HIF-1 in DCD donors would result in a better graft liver condition. Male SD rats (6 animals per group) were randomly given the synthetic prolyl hydroxylase domain inhibitor FG-4592 (Selleck, 6 mg/kg of body weight) or its vehicle (dimethylsulfoxide). Six hours later, cardiac arrest was induced by bilateral pneumothorax. Rat livers were retrieved 30 min after cardiac arrest, and subsequently cold stored in University of Wisconsin solution for 24 h. They were reperfused for 60 min with Krebs-Henseleit bicarbonate buffer in an isolated perfused liver model, after which the perfusate and liver tissues were investigated. Pretreatment with FG-4592 in DCD donors significantly improved graft function with increased bile production and synthesis of adenosine triphosphate, decreased perfusate liver enzyme release, histology injury scores and oxidative stress-induced cell injury and apoptosis after reperfusion with the isolated perfused liver model. The beneficial effects of FG-4592 is attributed in part to the accumulation of HIF-1 and ultimately increased PDK1 production. Pretreatment with FG-4592 in DCD donors resulted in activation of the HIF-1 pathway and subsequently protected liver grafts from warm ischemia and cold-stored injury. These data suggest that the pharmacological HIF-1 induction may provide a clinically applicable therapeutic intervention to prevent injury to DCD allografts. CI - (c) 2017 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc. FAU - Zhang, Xingjian AU - Zhang X AUID- ORCID: 0000-0001-9496-7973 AD - Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China, Hubei. FAU - Liu, Zhongzhong AU - Liu Z AD - Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China, Hubei. FAU - Xiao, Qi AU - Xiao Q AD - Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology, The 3rd Xiangya Hospital of Central South University, Changsha, Hunan, China. FAU - Zeng, Cheng AU - Zeng C AD - Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China, Hubei. FAU - Lai, Chin-Hui AU - Lai CH AD - Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China, Hubei. FAU - Fan, Xiaoli AU - Fan X AD - Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China, Hubei. FAU - Ye, Qifa AU - Ye Q AD - Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China, Hubei. AD - Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology, The 3rd Xiangya Hospital of Central South University, Changsha, Hunan, China. FAU - Wang, Yanfeng AU - Wang Y AD - Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China, Hubei. FAU - Xiong, Yan AU - Xiong Y AD - Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China, Hubei. LA - eng PT - Journal Article DEP - 20171220 PL - United States TA - Artif Organs JT - Artificial organs JID - 7802778 RN - 0 (Hypoxia-Inducible Factor 1) RN - 0 (Insulin) RN - 0 (Organ Preservation Solutions) RN - 0 (University of Wisconsin-lactobionate solution) RN - 63CZ7GJN5I (Allopurinol) RN - GAN16C9B8O (Glutathione) RN - K72T3FS567 (Adenosine) RN - N5O3QU595M (Raffinose) SB - IM MH - Adenosine/metabolism MH - Allopurinol/metabolism MH - Animals MH - Death MH - Glutathione/metabolism MH - Graft Survival/drug effects MH - Hypoxia-Inducible Factor 1/*agonists/metabolism MH - Insulin/metabolism MH - Liver/*drug effects/*physiology MH - Liver Transplantation/*methods MH - Male MH - Organ Preservation/*methods MH - Organ Preservation Solutions/metabolism MH - Perfusion/*methods MH - Raffinose/metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Rats, Wistar OTO - NOTNLM OT - -Hypoxia-inducible factor-1alpha OT - -Liver injury OT - Donation after cardiac death EDAT- 2017/12/22 06:00 MHDA- 2018/10/03 06:00 CRDT- 2017/12/22 06:00 PHST- 2017/04/17 00:00 [received] PHST- 2017/06/05 00:00 [revised] PHST- 2017/07/12 00:00 [accepted] PHST- 2017/12/22 06:00 [pubmed] PHST- 2018/10/03 06:00 [medline] PHST- 2017/12/22 06:00 [entrez] AID - 10.1111/aor.13005 [doi] PST - ppublish SO - Artif Organs. 2018 Mar;42(3):280-289. doi: 10.1111/aor.13005. Epub 2017 Dec 20.