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Abstract
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.
Copyright 2000 John Wiley & Sons, Ltd.