Current progress in the understanding of and therapeutic strategies for ischemia and reperfusion injury of the liver.
Current progress in the understanding of and therapeutic strategies for ischemia and reperfusion injury of the liver.
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DOI：
10.1007/s00534-002-0720-z
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发表时间：
2003-01-01
期刊：
影响因子：
--
通讯作者：
Kawamura, Toru
中科院分区：
文献类型：
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作者：
Arii, Shigeki;Teramoto, Kennichi;Kawamura, Toru
肝脏的缺血再灌注损伤包括两个不同的阶段。第一阶段由再灌注后3至6 h的急性细胞损伤引起，这可能主要是由氧自由基产生增加引起的。继发性亚急性期由18至24小时的炎症反应引起，导致肝损伤的进展。炎症反应是由促炎性细胞因子和分泌氧化剂、蛋白酶等的中性粒细胞聚集引起的，促炎性细胞因子包括趋化因子和粘附分子的产生受转录因子核因子κ B（NF κ B B）和AP-1的调节。损伤的进展是由募集白细胞释放氧化剂和蛋白酶产生的。中性粒细胞向肝脏的募集和粘附通过多个步骤完成，其中许多化学引诱物和粘附分子参与。近年来的研究表明，在众多的蛋白酶中，钙依赖性蛋白酶在IR损伤的加重中也起重要作用。基于上述机制，已经提出了许多预防和治疗策略。这些治疗策略中的大多数来自于抑制氧自由基、炎性细胞因子和粘附分子的产生;抑制白细胞浸润和弹性蛋白酶的产生;以及抑制微循环损伤、炎症相关分子和膜磷脂的分解;此外，最近的研究阐明，短期缺血和随后的再灌注，称为缺血预处理，对包括肝脏在内的各种器官的IR损伤发挥预防作用。基于澄清的候选人负责这一现象，药理学缺血预处理已被提出。在这篇评论文章中，作者概述了目前对肝脏IR损伤的认识和治疗策略的进展。
Ischemia and reperfusion (IR) injury of the liver consists of two distinct phases. The first phase is caused by acute cellular injury at 3 to 6 h postreperfusion, which may be mainly induced by the increased production of oxygen radical species. The secondary, subacute, phase results from inflammatory responses at 18 to 24 h, leading to the progression of liver damage. The inflammatory response observed here is caused by proinflammatory cytokines and accumulating neutrophils which secrete oxidants, proteases, and so on. The production of proinflammatory cytokines, including chemokines and adhesion molecules, is regulated by transcriptional factors nuclear factor kappa B (NFKappaB), and AP-1. The progression of the injury is generated by the recruiting leucocytes which release oxidants and proteases. Recruitment and adhesion of neutrophils to the liver are accomplished by multiple steps in which many chemoattractants and adhesion molecules participate. Recent investigations suggest that calcium-dependent proteases, among various kinds of proteases, also play important roles in the aggravation of IR injury. Based on the mechanisms stated above, numerous strategies have been proposed as for prophylaxis and treatment. Most of these therapeutic strategies are derived from the inhibition of the production of oxygen radicals, inflammatory cytokines, and adhesion molecules; inhibition of leucocyte infiltration and elastase production; and inhibition of microcirculatory impairment, apoptosis-related molecules, and the breakdown of membrane phospholipids; and so on. Moreover, recent studies clarified that short periods of ischemia and subsequent reperfusion, termed ischemic preconditioning, exert a preventive effect against IR injuries in various organs, including the liver. Based on clarification of the candidates responsible for this phenomenon, pharmacological ischemic preconditioning has been proposed. In this review article, the authors outline the current progress in the understanding of and therapeutic strategies for hepatic IR injury.