Regulation of hepatic schemia/reperfusion injury by gene transfer and its usefulness of prevention for organ failure

基因转移对肝缺血/再灌注损伤的调节及其预防器官衰竭的作用

基本信息

批准号：
15591382
负责人：
YOSHIDOME Hiroyuki
金额：
$ 2.24万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591382/
关键词：
ischemia reperfusion transcriptional factor infection organ failure cytokine chemokine

项目摘要

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.

肝缺血/再灌注损伤是临床上的一个重要问题，虽然对初始事件和随后的中性粒细胞依赖性损伤的机制有所了解，但对于内源性肝保护作用在这种损伤中的作用知之甚少。这种损伤的诱导，但尚未阐明 IL-18 的参与，使用部分肝缺血（经历 90 分钟）和随后的再灌注的小鼠模型。本研究的目的是确定IL-18在肝缺血/再灌注过程中是否上调，并确定内源性IL-18在炎症性肝缺血/再灌注损伤的发生和调节中的作用。肝脏IL-18表达从1上调。根据电泳迁移率变化测定，肝脏缺血/再灌注诱导 NF-κB 和 AP-1 激活，并导致肝脏显着增加。在用 IL-18 中和抗体治疗的小鼠中，中性粒细胞募集、细胞凋亡、肝细胞损伤和肝水肿分别通过肝髓过氧化物酶含量、TUNEL 染色、血清转氨酶水平和肝脏湿重与干重比来定义。诱导的 CXC 趋化因子表达增加、NF-κB 和 AP-1 激活以及细胞凋亡大大减少。此外，在 IL-18 阻断下， IL-4 和 IL-10 等抗炎细胞因子在 IL-18 的阻断下显着上调。数据表明，IL-18 是通过抑制抗炎细胞因子表达促进中性粒细胞依赖性肝缺血/再灌注损伤所必需的。