| Project/Area Number |
63570313
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Gastroenterology
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| Research Institution | Tokyo University |
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Principal Investigator |
SHIRATORI Yasushi Tokyo University, Dept. of Medicine,, 医学部(病), 助手 (70196624)
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| Co-Investigator(Kenkyū-buntansha) |
SHIINA Shuichiro Tokyo University, Dept. of Medicine Summary of research results, 医学部(病), 医員
KAWASE Tateo Dokkyo University School of Medicine, 講師 (40169727)
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| Project Period (FY) |
1988 – 1989
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| Project Status |
Completed (Fiscal Year 1989)
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| Budget Amount *help |
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1989: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1988: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Keywords | macrophages / Kupffer cells / endotoxin / lps gene / hepatic injury / superoxide / leukotriene / collagen / 活性酵素 / 走化物質 / Kupffer cells / マクロファージ / クッパー細胞 / 遺伝子 |
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| Research Abstract |
In an attempt to clarify a role of hepatic macrophages in hepatotoxicity and their relation with lipopolysaccharide (LPS), we investigated C3H/HeN (LPS sensitive strain) and C3H/HeJ (LPS resistant strain) mice. By an administration of galactosamine (GalN), hepatotoxicity was demonstrated in the C3H/HeN mice, while GalN-induced hepatotoxicity was scarcely demonstrated in the C3H/HeJ strain mice. Transfer of LPS responsive macrophages into the LPS resistant mouse strain induced marked hepatotoxicity after GalN administration. Although hydrolytic enzymes bertha-glucuronidase activities were nearly identical both in LPS responsive and LPS resistant macrophages after LPS administration, superoxide anion production by macrophages was markedly enhanced in LPS responsive strain. This enhancement was not demonstrated in the LPS resistant mice. The enhanced production of superoxide by macrophages was reduced in the presence of lipoxygenase inhibitors or calcium channel blocker, suggesting that s
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uperoxide anion by macrophages could be modulated by calcium-dependent enzymes.
In addition, in an attempt to elucidate a mechanism of accumulation and activation of macrophages and polymorphonuclear cells during hepatic injury, we found novel chemotactic factor released from hepatocytes when exposed to ethanol or GalN. Chemotactic activity of this protein was still active after freeze-thawing and was reduced by the treatment of heat or trypsin. Molecular analysis revealed that this protein eluted at a fraction of 20-25 Kd and 40-50 Kd. This protein not only attract Kupffer cells, monocutes or polymorpho- nuclear cells but also activate these accumulated cells to release toxic mediators such as superoxide.
During an inflammatory process, fibrogenesis was demonstrated, but its mechanism was still obscure. In the present study, collagen production by fat storing cells (main cells contributing to liver fibrosis) increased by the stimulation of superoxide. In addition, activating Kupffer cells enhanced an amount of total collagen produced by fat storing cells even though collagenase activities released from Kupffer cells increased simultaneously.
These results indicate that cellular interaction among sinusoidal cells and hepatocytes could play an important role in pathogenesis of liver diseases. Less
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