Oral administration of polyamines ameliorates liver ischemia/reperfusion injury and promotes liver regeneration in rats.
Polyamines are essential for cell growth and differentiation. They play important roles in protection from liver damage and promotion of liver regeneration. However, little is known about the effect of oral exogenous polyamine administration on liver damage and regeneration. This study investigated the impact of polyamines (spermidine and spermine) on ischemia/reperfusion injury (IRI) and liver regeneration. We used a rat model in which a 70% hepatectomy after 40 minutes of ischemia was performed to mimic the clinical condition of living donor partial liver transplantation (LT). Male Lewis rats were separated into 2 groups: a polyamine group given polyamines before and after operation as treatment and a vehicle group given distilled water as placebo. The levels of serum aspartate aminotransferase and alanine aminotransferase at 6, 24, and 48 hours after reperfusion were significantly lower in the polyamine group compared with those in the vehicle group. Polyamine treatment reduced the expression of several proinflammatory cytokines and chemokines at 6 hours after reperfusion. Histological analysis showed significantly less necrosis and apoptosis in the polyamine group at 6 hours after reperfusion. Sinusoidal endothelial cells were also well preserved in the polyamine group. In addition, the regeneration of the remnant liver at 24, 48, and 168 hours after reperfusion was significantly accelerated, and the Ki-67 labeling index and the expressions of proliferating cell nuclear antigen and phosphorylated retinoblastoma protein at 24 hours after reperfusion were significantly higher in the polyamine group compared with those in the vehicle group. In conclusion, perioperative oral polyamine administration attenuates liver IRI and promotes liver regeneration. It might be a new therapeutic option to improve the outcomes of partial LT. Liver Transplantation 22 1231-1244 2016 AASLD.
Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan.
Shinya
S
Okumura
Center for Development of Advanced Medical Technology, Jichi Medical University, Tochigi, Japan.
Takumi
T
Teratani
Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan.|Department of Surgery, Shizuoka Municipal Hospital, Shizuoka, Japan.
Yasuhiro
Y
Fujimoto
Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
Xiangdong
X
Zhao
Department of Pathology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Tatsuaki
T
Tsuruyama
Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan.
Yuki
Y
Masano
Center for Development of Advanced Medical Technology, Jichi Medical University, Tochigi, Japan.
Naoya
N
Kasahara
Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan.
Taku
T
Iida
Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan.
Shintaro
S
Yagi
Transplant Institute, Allegheny General Hospital, Pittsburgh, PA.
Tadahiro
T
Uemura
Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan.
Toshimi
T
Kaido
Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University, Kyoto, Japan.
Shinji
S
Uemoto
D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019394:Ki-67 Antigen / Q000032:analysis; D008099:Liver / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects*; D016031:Liver Transplantation / Q000009:adverse effects* / Q000379:methods; D008297:Male; D009336:Necrosis / Q000517:prevention & control; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000097:blood / Q000517:prevention & control*; D016160:Retinoblastoma Protein / Q000032:analysis; D013095:Spermidine / Q000008:administration & dosage / Q000627:therapeutic use*; D013096:Spermine / Q000008:administration & dosage / Q000627:therapeutic use*
D019394:Ki-67 Antigen; D018809:Proliferating Cell Nuclear Antigen; D016160:Retinoblastoma Protein; D013096:Spermine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D013095:Spermidine