Blocking oxygen radical production or leukocyte adhesion in ischemic and reperfused tissues prevents the occurrence of endothelial damage. However, in the clinical setting, patients may present with established inflammation and so measures need to be taken to reverse pre-existing microvascular injury. Exciting data which may prove to be clinically important have been obtained from studies of lung ischemia-reperfusion in which the role of the intracellular second messenger cAMP has been evaluated. It has been shown that cAMP-elevating compounds can actually reverse endothelial barrier damage associated with the inflammatory response. It was established several years ago that increased microvascular permeability due to histamine exposure in skeletal muscle could be reversed with the cAMP-elevating compounds epinephrine (adrenaline) and isoproterenol (isoprenaline). Recent studies of endothelial damage induced by ischemia-reperfusion in isolated rat lungs have also shown that elevating cAMP by activation of b-adrenergic and adenosine A 2 receptors, direct stimulation of adenylyl cyclase, inhibition of cAMP phosphodiesterase, or addition of cAMP analogs can reverse increased microvascular permeability. Thus changes in cAMP levels during the inflammatory process appear to regulate endothelial permeability ( MQ9I.§.M...§L 1996a).
It is not yet clear how cAMP prevents and reverses the increases in microvascular permeability that occur during inflammation. However, the reversal effect of cAMP was dependent on protein kinase A in an isolated rat lung model of ischemia-reperfusion. An antagonistic effect of increased intracellular Ca 2+ levels on cAMP
production has also been demonstrated. Ca2+ entering isolated pulmonary endothelial cells grown in culture inactivated a specific isoform of adenylyl cyclase, causing decreased cAMP production and increased monolayer permeability. Thus the inflammatory process induced by ischemia-reperfusion may produce microvascular injury by increasing endothelial cell Ca2+ levels which in turn causes decreased cAMP production.
In addition to a direct effect of Ca2+ on adenylyl cyclase, increased intracellular Ca 2+ levels can stimulate endothelial contraction by a mechanism dependent on calmodulin and myosin light-chain kinase. Activation of myosin light-chain kinase is necessary for endothelial damage to occur in isolated rat lungs subjected to ischemia-reperfusion. Therefore the reversal effects of cAMP in lungs damaged by ischemia-reperfusion occur because the activity of myosin light-chain kinase is inhibited, thus promoting endothelial cell relaxation and decreased barrier permeability ( Khimenkoef a/ 1996).
Regardless of the detailed mechanism by which cAMP acts, its usefulness as a therapeutic agent for preventing inflammatory-induced microvascular injury is well known. Analogs of cAMP are now included in some preservation solutions for storing lungs for transplantation. This appears to suppress the initial lung injury that occurs following reperfusion of lungs in the transplant recipient.
Figure.2 summarizes some of the known factors which both produce and reverse microvascular damage associated with lung ischemia-reperfusion. Xanthine-oxidase-derived oxygen radicals promote leukocyte (neutrophil) sequestration in pulmonary microvessels that is dependent on P-selectin, CD18, and ICAM-1. Subsequent activation of endothelial cell myosin light-chain kinase by increased intracellular Ca 2+ causes endothelial cell contraction and the microvascular barrier becomes highly permeable to fluid and solute. This process is prevented by blocking leukocyte rolling and adherence factors and inhibiting xanthine oxidase. It can also be reversed by elevating intracellular cAMP levels ( M°oie.,..§t§/ 19.96a).
Fig. 2 Representation of factors that produce endothelial damage in lungs subjected to ischemia-reperfusion. Causative factors include integrins (CD18), P-selectin ligand (P-s-L), P-selectin (P-s), intercellular adhesion molecule 1 (ICAM-1), endothelin, activated calmodulin (CaM), and activated myosin light-chain kinase. On the right are shown factors that can reverse the damage: opening of ATP-sensitive K + channels, activating adenosine A2 receptors (AA2R), activating b-adrenergic receptors (b2), and activation of protein kinase A.
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