1999 Fiscal Year Final Research Report Summary
TNF-α a antisense transfer improves ischemia / reperfusion injury of the hepatic graft
| Project/Area Number |
08407031
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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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 | KYUSHU UNIVERSITY |
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Principal Investigator |
SUGIMACHI Keizo Kyushu University, Graduate School of Medical Scienccs, Department of Surgery and Science, Professor, 医学系研究科, 教授 (00038762)
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| Co-Investigator(Kenkyū-buntansha) |
NISHIZAKI Takashi Kyusyu University, Graduate School of Medical Sciences, Department of Surgery and Science, Research Associate, 医学部・附属病院, 助手 (70253416)
YANAGA Katsuhiko Kyusyu University, Graduate School of Medical Sciences, Department of Surgery and Science, instructor, 医学部・附属病院, 講師 (70220176)
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| Project Period (FY) |
1996 – 1999
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| Keywords | cold ischemia / reperfusion injury / liver transplantation / HVJ-CL / TNF-α antisense / Kupffer cells / oligodeoxynucleotides |
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| Research Abstract |
Cold ischemia/reperfusion injury of the hepatic graft, an unsolved problem in liver transplantation that has been attributed to the release of inflammatory cytokines from activated Kupffer cells. We recently designed a novel vehicle composed of cationic liposomes fused with hemagglutinating virus of Japan (HVJ), namely HVJ-cationic liposomes (HVJ-CL), and using this vector system, we assessed the cytotoxicity, efficiency of Fluorescein isothiocyanate (FITC)-labeled oligodeoxynucleotides (FITC-ODNs) delivery to Kupffer cells and effects of TNF-α antisense delivery against ischemia/reperfusion injury in a rodent hepatic graft. FITC signals were recognized in over 95% of ED2-positive Kupffer cells of transplanted liver 4hrs after FITC-ODNs transfer. The transfer efficiency (18.5 ± 3.1%) using HVJ-CL applied at one-eighth the amount of HVJ and lipids of conventional HVJ-liposomes (HVJ-L) was much higher than that achieved by HVJ-L (10.4 ± 1.2%, p<0.01), while there was no signincant difference in the vector-induced release of cytosolic enzymes from hepatocytes into the blood circulation between HVJ-CL and HVJ-L groups. Treatment with TNF-α antisense transfer significantly suppressed the release of cytosolic enzymes from hepatocytes, the serum levels of TNF-α and immunohistochemical expression of TNF-α by Kupffer cells 4hrs after liver transplantation. This HVJ-CL method provides a safe and effective ODNs delivery to Kupffer cells of hepatic grafts in rats
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