Current progress in the understanding of and therapeutic strategies for ischemia and reperfusion injury of the liver.

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.