| Project/Area Number |
01304038
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| Research Category |
Grant-in-Aid for Co-operative Research (A)
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| Allocation Type | Single-year Grants |
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| Research Field |
Gastroenterology
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| Research Institution | Gifu University |
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Principal Investigator |
MUTO Yasutoshi Gifu Univ. Dept. of Med., Prof., 医学部, 教授 (20010069)
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| Co-Investigator(Kenkyū-buntansha) |
OBATA Hiroshi Tokyo Women's Medical College, Prof., 教授 (20075237)
KAKUMU Shin-ichi Nagoya Univ., Dept. of Med., Assistant Prof., 医学部, 講師 (10115545)
MIZOGUCHI Yasuhiro Osaka City Univ., Dept. of Med., Associate Prof., 医学部, 助教授 (00094491)
TSUJI Takao Okayama Univ., Dept. of Med., Prof., 医学部, 教授 (80033306)
KAMATA Takenobu Osaka Univ., Dept. of Med., Prof., 医学部, 教授 (80028399)
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| Project Period (FY) |
1989 – 1991
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| Project Status |
Completed (Fiscal Year 1991)
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| Budget Amount *help |
¥15,200,000 (Direct Cost: ¥15,200,000)
Fiscal Year 1991: ¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 1990: ¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 1989: ¥6,400,000 (Direct Cost: ¥6,400,000)
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| Keywords | Fulminant hepatitis / Liver necrosis / Tumor necrosis (TNF) / Arachidonic acid metabolite / Complements / Limphocytes subpopulation / Microcirculation / Extracellular matrix / interleukinー6(ILー6) / 肝微小循環 / 肝細胞膜モノクロ-ナル抗体 / interleukin-l(IL-l) |
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| Research Abstract |
We investigated possible mechanisms of the development of fatal hepatitis / extensive hepatic cell necrosis by conducting seven projects as follows : 1. animal models, 2. arachidonic acid metabolites, 3. cytokines, 4. complements, 5. lymphocytes, 6. microcirculation, 7. extracellular matrix.
1. Animal models : (1) Impaired copper metabolism was found to be responsible to the liver necrosis in LEC(Long-Evans Cinnamon) rats, (2) Induction of liver damage by anti-rat liver cell membrane momoclonal antibody was demonstrated. (3) Administration of TNF (tumor nccrosis factor) following treatment with Propionibacterium acnes(P. acnes) or D-galactosamine (GaiN) induced extensive liver nccrosis. Administration of non-lethal doses of TNF and IL-1 (interlcukin-U) after P. acnes also induced severe hepatic cell necrosis.
2. Arachidonic acid metabolites : (1) Impaired regulation of arachidonic avid cascade in perisibysoidal liver cells participated in the development of extensive liver nccrosis. (2)
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Majority of leukotrienes were found to be synthesized in infiltrating ncutrophils.
3. Cytokines : (1) Administration of anti-TNF antibody inhibited the development of total hepatitis in micetreated with P. acnes and lipopolysaccharide (LPS)/endotoxin. (2) Hepatocytes in primary culture were damaged strongly by TNF and IFN(interferron)-r, showing apoptosis. (3) Chemoatractant activity was induced in endothelial cclls vy TNF. (4) TGF (transforming growth factr) beta reduced the cytotoxicity of T-lymphocytes against HepG2 cells and inhibited DNA synthesis in the cells. (5) Calciumion was found to participate in the intracelluar signal transduction system elicited by hHGF (human hepatocyte growth factor).
4. Complements : (1)Liver nccrosis induced by Galn + LPS or monoclonal antibody was inhibited by administration of anti-complementary agent. (2) Kupffer cells enhanced the liver damage infused by complement-binding reaction.
5. Lymphocytes : (1) In clinical cases with fulminant hepatitis, increment of CD8(+) 11b(-) cells and decrecase of CD8(+) 11b(+)cells were noted. (2) NK (natural killer) cells activated by IFN-r was found to damage specifically the regencera the regencrating liver cells, leading to impaired liver regeneration.
6. Micreciculathion : (1) Impaired oxygen demand in liver lobules appeared in advance to the development of hepar hepatocyte nverosis. (2) Endothelin-1 induced the contraction of sinusoid.
7. Extracellular matracellular matricegulated the liver regeneration. Less
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