| Project/Area Number |
13671282
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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 | CHIBA UNIVERSITY |
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Principal Investigator |
YOSHIDOME Hiroyuki Chiba University, University Hospital, Assistant, 医学部附属病院, 助手 (10312935)
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| Co-Investigator(Kenkyū-buntansha) |
SHIMIZU Hiroaki Chiba University, University Hospital, Lecturer, 医学部附属病院, 講師 (80272318)
MIYAZAKI Masaru Chiba University, Graduate School of Medicine, Professor, 大学院・医学研究院, 教授 (70166156)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2001: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | ischemia / reperfusion / chemokine / transcriptional factor / neutrophil / preconditioning / 肝阻血再灌流障害 / NFκB / NF_(k)B |
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| Research Abstract |
BACKGROUND. Interruption of hepatic inflow during hepatectomy (Pringle's maneuver) and vascular reconstruction of hepatic transplantation causes hepatic ischemia. An acute inflammation associated with this unfavorable event induces significant organ damage/dysfunction. Regulation of hepatic ischemia/reperfusion injury (I/R) is an important clinical consideration.
METHODS. Using a murine model of partial hepatic ischemia and reperfusion, we investigated endogenous regulation of IL-18 in this inflammatory injury.
RESULTS. Hepatic ischemia for 90 minutes and reperfusion for up to 8 hours upregulated IL-18 expression. Hepatic I/R activates transcriptional factor, NF-κB and AP-1. In addition, hepatic I/R caused significant increases in liver neutrophil recruitment, hepatocellular injury, and liver edema, as defined by liver myeloperoxidase content, serum ALT, and liver wet to dry weight ratios, respectively. In mice treated with neutralizing antibody to IL-18, I/R -induced increases in CXC chemokine expression and activation of transcriptional factor were greatly diminished. Furthermore, under blockade of IL-18, anti-inflammatory cytokines such as IL-4 and IL-10 were greatly upregulated. These conditions also caused significant reductions in liver neutrophil sequestration and liver injury.
CONCLUSIONS. The data suggest that IL-18 is required for facilitating neutrophil-dependent hepatic ischemia and reperfusion injury through suppressing anti-inflammatory cytokine expression.
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