title: Ischemic preconditioning improves liver tolerance to congestion-reperfusion injury in mice.
abstract: BACKGROUND
  Congestion-reperfusion injury (CRI) is a common complication after living donor liver transplantation, which has not been fully understood. It causes more severe inflammatory response as compared with ischemia-reperfusion injury (IRI). Ischemic preconditioning (IPC) has been endowed with powerful protective properties toward IRI. This study aimed to investigate whether IPC also has a protective effect against CRI and potential underlying mechanisms.
  
  
  METHODS
  Mice were randomly divided into sham operation, CRI, IPC-CRI, and congestion precondition (CPC-CRI) group. The hepatic vein of the left anterior hepatic lobe was occluded for 75 min followed by reperfusion in the CRI group. The blood inflow was previously clamped for 10 min followed by 10 min of reperfusion just before occluding the hepatic vein in the IPC-CRI group. To imitating IPC in the CPC-CRI group, 10 min of congestion followed by 10 min of reperfusion just before CRI was performed. The animals were sacrificed at 2, 6, 24, 48 h, and 7 d after reperfusion. The blood and liver samples were collected for hepatic function assay, histology, terminal deoxynucleotidyl transferase dUTP nick end labeling, myeloperoxidase, and real-time polymerase chain reaction analysis.
  
  
  RESULTS
  Mice in the CRI, IPC-CRI, and CPC-CRI group demonstrated elevated liver enzymes, histologic damage, cellular apoptosis, and inflammatory response compared with those in the sham operation group. Compared with the CRI group, mice in the IPC-CRI group expressed lower alanine transaminase activities (2 h: 839.2 ± 132.5 versus 384.2 ± 94.8, P < 0.01; and 6 h: 680 ± 142.4 versus 342.3 ± 99.7, P < 0.01) and lower myeloperoxidase levels (2 h: 7.1 ± 4.0 U/g versus 3.8 ± 1.6 U/g, P < 0.05; and 6 h: 8.1 ± 1.3 U/g versus 5.2 ± 3.0 U/g, P < 0.05). However, the alanine transaminase level in the CPC-CRI group was notably higher at 2 h (839.2 ± 132.5 versus 1087.5 ± 192.5, P < 0.05). Livers from mice in the IPC-CRI group showed better tissue integrity, diminished hepatocellular injury, and apoptosis at 2 and 6 h. The messenger RNA transcriptions of interleukin 1 and interleukin 6 were significantly lower after 2-24 h of reperfusion, whereas tumor necrosis factor α and monocyte chemoattractant protein 1 were significantly lower after 24 h of reperfusion in the IPC-CRI group.
  
  
  CONCLUSIONS
  IPC can significantly improve liver tolerance to CRI by attenuating neutrophil infiltration, proinflammatory cytokine formation, and hepatocytes apoptosis. This pretreatment strategy holds greater prospect of being translated into clinical use in living donor liver transplantation.
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, China; Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
authors.forename: Qiyi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, China; Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Yan
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, China; Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, China; Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, China; Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Yao
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, China; Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, China; Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, China; Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
authors.forename: Kwabena
authors.initials: K
authors.lastname: Owusu-Ansah
authors.affiliation: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, China; Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China. Electronic address: shusenzheng@zju.edu.cn.
authors.forename: Shusen
authors.initials: S
authors.lastname: Zheng
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D018925:Chemokines / Q000096:biosynthesis; D020287:In Situ Nick-End Labeling; D018836:Inflammation Mediators / Q000502:physiology; D019194:Ischemic Preconditioning / Q000379:methods; D008107:Liver Diseases / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D011897:Random Allocation; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*
chemical_list: D018925:Chemokines; D018836:Inflammation Mediators; D009195:Peroxidase; D000410:Alanine Transaminase
keywords: Congestion; Ischemia reperfusion injury; Ischemic precondition; Living donor liver transplantation