2005 Fiscal Year Final Research Report Summary
Multiple organ failure and macrophage function in severe liver injury: Toll-like receptor and endotoxin clearance
| Project/Area Number |
15590678
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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, Faculty of Medicine, Professor, 医学部, 教授 (80145838)
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| Co-Investigator(Kenkyū-buntansha) |
FUJIMOTO Masao Nara Medical University, Faculty of Medicine, Lecturer, 医学部, 講師 (60295805)
MITORO Akira Nara Medical University, Faculty of Medicine, Assistant professor, 医学部, 助教 (10382285)
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| Project Period (FY) |
2003 – 2005
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| Keywords | Toll-like receptor / endotoxin / acute hepatic failure / Tumor necrosis factor-α / Kupffer cell / macrophage / nonalcoholic steatohepatitis / innate immunity |
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| Research Abstract |
Role of innate immunity in the progression of liver injury was investigated in various experimental models of rats.
Firstly, Acute hepatic failure (AHF) was induced in rats by injection of D-galactosamine (GalN, 1g/kg b.w.). In this model, the expression of Toll-like receptor (TLR) 4 mRNA of Kupffer cells was increased compared with controls but those of splenic macrophages and alveolar macrophages did not change. The expressions of liver TNF-α mRNA and TLR4 mRNA were increased in parallel with the progression of liver injury.
Secondly, AHF with multiple organ failure was induced in rats by the concomitant administration of GalN (500mg/kg b.w.) and endotoxin (LPS; E.coli 055:B55,50μg/kg b.w.). In this model, more than 90% animals died of AHF within 24 hrs after the injection of GalN and LPS. The expression of liver TNF-α mRNA and CD14 mRNA were increased in parallel with the progression of liver injury. However, TLR4 mRNA was down-regulated at first (at 1lhr and 3hr) and recovered later (at 24hr) in survivors. TLR4 antagonist E5564 revealed rescue effect on this lethal AHF model.
Thirdly, the expressions of liver TNF-α mRNA, CD14 mRNA and TLR4 mRNA were gradually increased with the progression of inflammation and fibrosis in non-alcoholic steatohepatitis (NASH) of rat induced by choline-deficient 1-amino acid-defined (CDAA) diet. This suggests that gut-derived endotoxin may activate TLR4-TNF-α axis and induce liver injury in this NASH model.
In conclusion, activated innate immunity through TLR4 may be important in the development and progression of AHF and NASH.
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Research Products
(11 results)
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[Journal Article] A potent angiogenic factor, vascular endothelial growth factor, improves the survival of the on-going acute hepatic failure in rats.2006
Author(s)
Namisaki T, Yoshiji H, Kuriyama S, Kojima H, Yoshii J, Ikenaka Y, Noguti R, Sakurai S, Yanase K, Kitade M, Yamazaki M, Asada K, Tsujimoto T, Akahane T, Uemura M, Fukul H
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Journal Title
Hepatology Research 35
Pages: 199-203
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Salvage effect of the vascular endothelial growth factor on chemically induced acute severe liver injury in rats.2006
Author(s)
Namisaki T, Yoshiji H, Kojima H, Yoshii J, Ikenaka Y, Noguchi R, Sakurai S, Yanase K, Kitade M, Yamazaki M, AsadaK, Uemura M, Nakamura M, Fukul H
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Journal Title
J Hepatol 44
Pages: 568-575
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Leptin-mediated neovascularization is a prerequisite for progression of nonalcoholic steatohepatitis in rats.2006
Author(s)
Kitade M, Yoshiji H, Kojima H, Ikenaka Y, Noguchi R, Kaji K, Yoshii J, Yanase K, Namisaki T, Asada K, Yamazaki M, Tsujimoto T, Akahane T, Uemura M, Fukui H
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Journal Title
Hepatology 44(4)
Pages: 983-991
Description
「研究成果報告書概要(欧文)」より
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