2000 Fiscal Year Final Research Report Summary
Mechanism of vulnerability to endotoxin of regenerating liver and its treatment
| Project/Area Number |
10671170
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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 |
Digestive surgery
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| Research Institution | Hamamatsu University School of Medicine |
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Principal Investigator |
NAKAMURA Satoshi Hamamatsu University School of Medicine, Second Department of Surgery, Professor, 医学部, 教授 (00090027)
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| Co-Investigator(Kenkyū-buntansha) |
ODA Toshiaki Hamamatsu University School of Medicine, First Department of Biochemistry, Associate Professor, 医学部, 助教授 (90126805)
SUZUKI Shohachi Hamamatsu University School of Medicine, Second Department of Surgery, Assistant Professor, 医学部・附属病院, 講師 (20196827)
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| Project Period (FY) |
1998 – 2000
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| Keywords | Hepatic resection / Endotoxin / Platelet-activating factor / PAF-receptor / TNF-a / NF-kB / hepatic regeneration |
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| Research Abstract |
Background. Platelet-activating factor (PAF) has been shown to be an important mediator in the pathogenesis of lipopolysaccharide (LPS)-induced liver ijury in regenerating rat livers. Both LPS and PPAF activate nuclear factor-kappa B (NF-kB), a key transcription factor for tumor necrosis factor-a (TNF-a) and cytokine-induced neutrophil attractant (CINC). The aim of this study is to investigate how PAF participates in the LPS-induced and NF-kB-mediated regulation of TNF-a and CINCin regenerating rat livers.
Methods. LPS (1.5 mg/kg) was intravenously administered into 70 % hepatectomized rats and sham-operated rats 46 hours postoperatively.
Results. LPS administration caused a high mortality rate, scattered necrosis in the liver with infiltration of CINC-positive neutrophils, and a continuous CINC messenger RNA up-regulation and activation of NF-kB in the liver only in hepatectomized rats. These phenomena were all effectively prevented by pretreatment and posttreatment with a PAF receptor antagonist, TCV-309. Heptectomized rats showed NF-kB staining in hepatocytes, Kupffer cells, and neutrophils around necrosis 4 hours after the LPS injection, representing the activation of this factor in these cells.
Conclusions. Based on these results, we propose that PAD contributes to continuous CINC up-regulation and NF-kB activation via accumulation and activation of neutrophils, and thereby is involved in LPS-induced liver injury in regenerating rat liver.
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