2001 Fiscal Year Final Research Report Summary
Interleukin-1 Receptor Antagonist Gene Transfer into Rat Liver after Ischemia-Reperfusion
| Project/Area Number |
11671183
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General surgery
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| Research Institution | Keio University |
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Principal Investigator |
WAKABAYASHI Go Keio University, School of Medicine, Assistant Professor, 医学部, 講師 (50175064)
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| Co-Investigator(Kenkyū-buntansha) |
KAMEI Syusaku Keio University, School of Medicine, Assistant, 医学部, 助手 (10286495)
SHIMAZU Motohide Keio University, School of Medicine, Assistant Professor, 医学部, 講師 (70124948)
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| Project Period (FY) |
1999 – 2000
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| Keywords | liver transplantation / gene therapy / IL-1Ra / reperfusion injury / adenovirus / living donor liver transplantation |
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| Research Abstract |
Background. The anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1Ra) is known to reduce hepatic ischemia-reperfusion injury. Therefore, we wished to examine the effect of IL-1Ra gene delivery into the rat liver on hepatic ischemia-reperfusion injury.
Methods. IL-1Ra cDNA was delivered into the rat liver by a single injection of the transgene vector into the portal vein using either the plasmid-cationic liposome or the recombinant adenoviral vector. At 24 hours after the gene delivery, rats were subjected to partial liver ischemia for 90 minutes followed by reperfusion. Liver tissue and serum samples were taken at 180 minutes of reperfusion, and the degree of the liver injury as well as the expression level of pro-inflammatory cytokines in the serum and tissue were investigated. In addition, we assessed the effect of IL-1Ra gene delivery on the 7-day survival rate when the nonischemic liver lobe was partially excised immediately following reperfusion.
Results. In both cases of delivery methods, gene transfer of IL-1Ra resulted in significant elevation of serum IL-1Ra concentration, which reached maximal levels at 24 hours following the delivery. However, the highest serum concentration with the adenoviral vector was 1, 000-fold of that in the liposome-treated animals. In the IL-1Ra delivered rats, liver damage, as well as production of pro-inflammatory cytokines, at 180 minutes of reperfusion was significantly reduced in a concentration-dependent manner of the circulating IL-1Ra protein. Rats subjected to the adenoviral vector gene delivery had higher 7-day survival rates compared with control animals.
Conclusions. IL-1Ra gene delivery into the liver may be of therapeutic use for abrogating hepatic ischemia-reperfusion injury after transplantation.
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Research Products
(12 results)
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[Publications] Kumamoto Y, Suematsu M, Shimazu M, Kato Y, Sano T, Makino N, Hirano K, Naito M, Wakabjayashi G, Ishimura Y, Kitajima M: "Kupffer Cell-Independent Acute Hepatocellular Oxidative Stress and Decreased Bile Formation in Post-Cold-Ischemic Rat Liver"Hepatology. 30(6). 1454-1463 (1999)
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[Publications] Kato Y, Shimazu M, Walabayashi G, Tanabe M, Morikawa Y, Hoshino K, Harada H, Kadomura T, Obara H, Urakami H, Shinoda M, Kitajima M.: "Significance of Portal Venous Flow in Graft Regeneration After Living Liver Transplantation"Transplantation Proceedings. 33. 1484-1485 (2001)
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