| Project/Area Number |
08670612
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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 |
Gastroenterology
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| Research Institution | Nara Medical University |
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Principal Investigator |
FUKUI Hiroshi Nara Medical University, 3rd Dept of Int Med, Professor, 医学部, 教授 (80145838)
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| Co-Investigator(Kenkyū-buntansha) |
KURIYAMA Shigeki Nara Medical University, 3rd Dept of Int Med, Lecturer, 医学部, 講師 (50244710)
UEMURA M Nara Medical University, 3rd Dept of Int Med, Lecturer, 医学部, 講師 (90151836)
KIKUCHI E Nara Medical University, 3rd Dept of Int Med, Lecturer, 医学部, 講師 (50214747)
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| Project Period (FY) |
1996 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1997: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1996: ¥1,000,000 (Direct Cost: ¥1,000,000)
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| Keywords | endotoxin / alcohol / acute hepatic failure / liver cirrhosis / macrophage / tumor necrosis factor |
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| Research Abstract |
Macrophage function related to endotoxin and cytokines was evaluated in severe alcoholic liver disturbance. Clinical studies : Prognostic factors were studied in patients with alcoholic liver disturbances. Nonsurvivors with severe alcoholic liver diseases (severe alcoholic hepatitis or alcoholic hepatitis with cirrhosis) showed severe hyperbilirubinemia, reduced hepatic biosynthetic capacity, and marked acute inflammatory reactions, and developed multiple organ failure (MOF), such as disseminated intravascular coagulation (DIC) or renal failure.
Multivariate analysis using Cox proportional hazards model showed serum CRP and DIC as significant independent prognostic factors. Plasma endotoxin was elevated in all patients and marked elevations of IL-6, IL-8 and IL-l0 were noted in nonsurvivors. The percentage of positive CDl4 cells in peripheral blood monocytes was increaed in these patients. Experimental studies : 1) An addition of ethanol inhibited the uptake of FITC-labelled endotoxin b
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y Kupffer cells but did not affect that by hepatocytes. 2) In cirrhotic rats given thio-acetamide, the clearance of Salmonela endotoxin by the liver was delayed. The amount of endotoxin in the spleen, kidney and blood was larger and that excreted in the stool was smaller. Serum total bilirubin, AST, ALT, LDH, BUN, creatinine and TNF- alphawere higher and prothrombin time was lower after the injection of Salmonela endotoxin in cirrhotic rats than those in control. The uptake of Salmonela endotoxin and the secretion of TNF- alphaby the Kupffer cells were decreased and those by the splenic macrophages and the peripheral blood monocytes were increaed in cirrhotic rats.
TNF- alphasecretion from unstimulated Kupffer cells and E coli endotoxin-stimulated Kupffer cells were decreased. TNF- alphasecretion from E coli endotoxin-stimulated alveolar macrophages were markedly increaed in these rats.
These results suggest that macrophages are generally overstimulated for endotoxin clearance in patients with severe liver diseases, which may lead to the oversecretion of cytokines and finally to the development of MOF. Less
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