| Project/Area Number |
04454244
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Gastroenterology
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| Research Institution | Osaka University |
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Principal Investigator |
KAWANO Sunao Osaka University First Dept.of Medicine Assistant Prof., 医学部, 助手 (60133138)
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| Co-Investigator(Kenkyū-buntansha) |
HAYASHI Nobuhiko Osaka University Hospital Senior Staff, 医学部・附属病院, 医員
TAKEI Yoshiyuki Osaka University Hospital Senior Staff, 医学部・附属病院, 医員
TSUJI Shingo Osaka University Hospital Senior Staff, 医学部・附属病院, 医員
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| Project Period (FY) |
1992 – 1993
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| Project Status |
Completed (Fiscal Year 1993)
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| Budget Amount *help |
¥6,800,000 (Direct Cost: ¥6,800,000)
Fiscal Year 1993: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1992: ¥5,700,000 (Direct Cost: ¥5,700,000)
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| Keywords | Liver Transplantation / Kupffer Cells / Endothelial Cells / Ito Cells / TNF / Apoptosis / Endothelin-1 / Nitric Oxide / 肝類洞細胞 / 再潅流障害 / エンドセリン / 微小循環障害 |
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| Research Abstract |
1) We have established the methods and technology to separate Kupffer cells, endothelial cells and Ito cells from rat liver. The purity of the isolated cells are more than 90%. This contributed much to the follwing research projects.
2) We revealed that Kupffer cells become activated during cold storage of liver grafts and reperfusion. Activated Kupffer cells produce variety of mediators including TNF, which causes damage to the grafts. Anti-TNF therapy was shown to be effective to prevent the liver damge after prolonged cold graft storage. We conducted further study to elucidate the precise mechanism of the TNF-dependent graft damage, showing that activated Kupffer cells induce apoptosis in endothelial cells and Kupffer cells themselves by juxtacrine and/or autocine mechanisms. Membrane-bound TNF expressed on the membrane of activated Kupffer cells is likely involved in this event. We enginnered antisense DNA oligomers which were designed to target various sites of mRNA encoding rat TNF-alpha. The antisense oligomers specifically suppressed TNF expression by Kupffer cells. Thus, the antisense technology appears to be promising to modulate Kupffer cell function.
3) Microcirculatory disturbance occurs after orthotopic liver transplantation. Using an in vivo microscopy system, we were able to demonstrate that a vasoactive substance, endothelin-1, causes vasoconstriction in hepatic microvasculature. Endothelin-1 was shown to elevate after ischemia/reflow and liver transplantation. Anti-endothelin-1 therapy reduced the graft damage after orthotopic liver transplantation. We further elucidated that sinusoidal tone is regulated by the balance between two vasoactive substances, endothelin-1 and nitric oxide. Our study also suggests that endogenous NO acts as a vasodilator which attenuates endothelin-induced vasoconstriction, thereby improving microcirculation. The results indicate a novel concept that hepatic blood flow is regulated at the sinusoidal level.
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