Diapedesis of leukocytes: Antisense oligonucleotides for rescue

Ischemia-reperfusion injury is an acute inflammatory process during which l eukocytes are intimately involved. In this review, we summarize the current data on the leukocyte cell adhesion cascade in ischemia-reperfusion injury , focus upon studies which have demonstrated specific cell adhesion molecul e interactions which mediate the leukocyte involvement in ischemia-reperfus ion injury, and suggest future avenues of therapeutic interventions. The in creased adhesion between activated vascular endothelium and peripheral bloo d leukocytes is central to the structural and the functional impairment in ischemia-reperfusion injury. Several families of adhesion molecules, namely the selectins, the intercellular adhesion molecules (ICAMs), and the integ rins expressed either on the endothelium or on the leukocytes, are involved the cascade of events. Sequential and overlapping cellular interactions be tween the members of the three gene families of adhesion receptors result i n adhesion of the leukocytes to the endothelium and extravasation at the si te of ischemia. The functional importance of ICAM-1 and its beta(2) integri n ligands in ischemia-reperfusion of the kidney has been demonstrated by mo noclonal antibody blockade studies, in knockout mice and by treatment with antisense oligodeoxynulceotides (ODN). We have shown that antisense ODN for ICAM-1 protected the kidney against ischemic renal failure. In addition, i n transplanted kidneys, ICAM-1 inhibition by antisense ODN ameliorates isch emia-reperfusion injury and prevents delayed graft function. Recent develop ments in antisense ODN technology make this a promising therapeutic approac h, and antisense ODN treatment of donors or donor organs for ICAM-1 may be useful for the prevention of reperfusion injury in human renal transplantat ion and could influence acute and chronic graft function.