Pathophysiology of ischaemia-reperfusion injury.
Reperfusion of ischaemic tissues is often associated with microvascular dysfunction that is manifested as impaired endothelium-dependent dilation in arterioles, enhanced fluid filtration and leukocyte plugging in capillaries, and the trafficking of leukocytes and plasma protein extravasation in postcapillary venules. Activated endothelial cells in all segments of the microcirculation produce more oxygen radicals, but less nitric oxide, in the initial period following reperfusion. The resulting imbalance between superoxide and nitric oxide in endothelial cells leads to the production and release of inflammatory mediators (e.g. platelet-activating factor, tumour necrosis factor) and enhances the biosynthesis of adhesion molecules that mediate leukocyte-endothelial cell adhesion. Some of the known risk factors for cardiovascular disease (hypercholesterolaemia, hypertension, and diabetes) appear to exaggerate many of the microvascular alterations elicited by ischaemia and reperfusion (I/R). The inflammatory mediators released as a consequence of reperfusion also appear to activate endothelial cells in remote organs that are not exposed to the initial ischaemic insult. This distant response to I/R can result in leukocyte-dependent microvascular injury that is characteristic of the multiple organ dysfunction syndrome. Adaptational responses to I/R injury have been demonstrated that allow for protection of briefly ischaemic tissues against the harmful effects of subsequent, prolonged ischaemia, a phenomenon called ischaemic preconditioning. There are two temporally and mechanistically distinct types of protection afforded by this adaptational response, i.e. acute and delayed preconditioning. The factors (e.g. protein kinase C activation) that initiate the acute and delayed preconditioning responses appear to be similar; however the protective effects of acute preconditioning are protein synthesis-independent, while the effects of delayed preconditioning require protein synthesis. The published literature in this field of investigation suggests that there are several potential targets for therapeutic intervention against I/R-induced microvascular injury.
Carden
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DL
Departments of Medicine, and Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA.
Granger
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DN
D002318:Cardiovascular Diseases / Q000209:etiology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D019194:Ischemic Preconditioning; D008833:Microcirculation / Q000503:physiopathology; D009102:Multiple Organ Failure / Q000209:etiology / Q000503:physiopathology; D018384:Oxidative Stress / Q000502:physiology; D015427:Reperfusion Injury / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D012307:Risk Factors
D015815:Cell Adhesion Molecules