| Co-Investigator(Kenkyū-buntansha) |
MIYAZAKI Masaru Chiba University, Department of Surgery, Professor, 大学院・医学研究院, 教授 (70166156)
KIMURA Fumio Chiba University, Department of Surgery, Associate Professor, 大学院・医学研究院, 講師 (70334208)
KATO Atsushi Chiba University, Department of Surgery, Assistant Professor, 医学部附属病院, 助手 (70344984)
|
|---|
| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
|
|---|
| Research Abstract |
Hepatic ischemia/reperfusion injury is a clinically important problem. While the mechanisms of the initial event and subsequent neutrophil-dependent injury are somewhat understood, little is known with respect to regulation of endogenous hepatoprotective effect on this injury. IL-12 plays a role in the induction of this injury, but involvement of IL-18 has not been clarified. Using a murine model of partial hepatic ischemia (subjected to 90 minutes) and subsequent reperfusion, the aim of the current study was to determine whether IL-18 is upregulated during hepatic ischemia/reperfusion and to determine the role of endogenous IL-18 in the development and regulation of inflammatory hepatic ischemia/reperfusion injury. Hepatic IL-18 expression was upregulated from 1 to 8 hours after reperfusion. Hepatic ischemia/reperfusion induced NF-κB and AP-1 activation as defined by electrophoretic mobility shift assay, and caused significant increases in liver neutrophil recruitment, apoptosis, hepatocellular injury, and liver edema as defined by liver myeloperoxidase content, TUNEL staining, serum aminotransferase levels, and liver wet to dry weight ratios, respectively. In mice treated with neutralizing antibody to IL-18,ischemia/reperfusion-induced increases in CXC chemokine expression, activation of NF-κB and AP-1,and apoptosis were greatly reduced. Furthermore, under blockade of IL-18, anti-inflammatory cytokmes such as IL-4 and IL-10 were greatly upregulated. Transcriptional factor, STAT6,was significantly activated under blockade of IL-18. These conditions also caused significant reduction in liver neutrophil sequestration and liver injury. In conclusion, the data suggest that IL-18 is required for facilitating neutrophil-dependent hepatic ischemia/reperfusion injury through suppressing anti-inflammatory cytokine expression.
|
