Publisher： Bentham Science Publishers
E-ISSN： 1873-4286|12|23|2863-2865
ISSN： 1381-6128
Source： Current Pharmaceutical Design, Vol.12, Iss.23, 2006-08, pp. : 2863-2865
Disclaimer: Any content in publications that violate the sovereignty, the constitution or regulations of the PRC is not accepted or approved by CNPIEC.
Abstract
We are delighted to introduce this Special Issue of Current Pharmaceutical Design. This collection of review articles from leading international experts in the field explores the main aspects of pharmacological modulation of liver ischemia-reperfusion injury (IRI) and confirms this Journal's commitment to publication of high-quality reviews at the interface between life sciences and clinical application.IRI is a phenomenon whereby the perfusion of a previously ischemic tissue or organ, paradoxically leads to further injury [1]. The local tissue injury is associated with a systemic response resulting in remote organ dysfunction. It is a major factor influencing the outcome of a wide variety of human disease processes including cerebro-vascular events (stroke), myocardial infarction, coronary artery bypass surgery, organ transplantation, liver resection, hemorrhagic shock with fluid resuscitation, limb revascularization and laparoscopic surgery. In the field of liver transplantation ischemia-reperfusion (IR) can lead to graft dysfunction or primary non function. These are associated with a high morbidity and mortality. IR also predisposes to graft rejection. The effect of IRI is particularly evident where liver resection or transplantation is being carried out using steatotic livers. Hepatic steatosis is associated with an impaired microcirculation, poor graft function and increased postoperative morbidity and mortality [2, 3].The pathophysiology is complex involving many biochemical pathways, some of which have yet to be fully elucidated [4, 5]. Two distinct phases of liver reperfusion injury [5,6,7] have been recognized. During the two hour period of the early phase liver Kupffer cells become activated leading to formation of extracellular reactive oxygen species (ROS) and production of cytokines. ROS and cytokines have a direct cytotoxic effect on endothelial cells and hepatocytes, but they also induce the expression of adhesion molecules and recruitment of neutrophils. These activated neutrophils release ROS and proteases which are responsible for the induced oxidative stress during the late phase (3-48 hours post-reperfusion). Also inducible nitric oxide synthase (iNOS) is expressed resulting in formation of high concentrations of nitric oxide (NO). NO can react with superoxide (O2.-) to yield toxic reactive nitrogen species (RNS) such as peroxynitrite (ONOO-). The injury during the late phase is much more severe compared with that during the early phase.Understanding the mechanisms of liver IR allows therapeutic strategies to be developed. The current strategies are either mechanical (e.g. ischemic preconditioning or remote preconditioning) or pharmacological. Ischemic preconditioning is the application of short periods of ischemia and reperfusion to an organ prior to prolonged ischemia whereas in remote preconditioning cycles of brief ischemia are applied to a remote organ (e.g. lower limb) prior to prolonged ischemia of the target organ (e.g. liver, heart). Preliminary studies with both techniques have shown a reduction in liver IRI although further studies and refinement of technique are required [8-10]. Mechanical methods of reducing IRI are worthwhile but are limited in their application whereas pharmacological modulation may have universal application. The challenge to scientists and clinicians is to gain a better understanding of the basic mechanisms of IR, to develop new targets and drugs therapies and then to translate this to improved outcomes in clinical practice. This special issue brings together international experts in the field of IR pathophysiology to review the main mechanisms and the pharmacological approaches which can be used to ameliorate liver IRI. Hepatic IR results in an inflammatory cascade involving pro inflammatory cytokines which initiate leukocyte recruitment. However there are also endogenous mechanisms for limiting the inflammatory response which include anti-inflammatory cytokines. Husted e
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