ROLE OF EARLY REPERFUSION IN THE INDUCTION OF ADHESION MOLECULES AND CYTOKINES IN PREVIOUSLY ISCHEMIC MYOCARDIUM

Our studies in vitro demonstrate that neutrophil mediated injury of is olated cardiac myocytes requires the presence of ICAM-1 on the surface of the myocyte and CD11b/CD18 activation on the neutrophil. In post-i schemic cardiac lymph, there is rapid appearance of C5a activity durin g the first hours of reperfusion. Interleukin-6 activity is present th roughout the first 72 h of reperfusion and is sufficient to induce ICA M-1 on the surface of the cardiac myocyte. In situ hybridization studi es suggest that ICAM-1 mRNA is found in viable myocardial cells on the edge of the myocardial infarction within 1 h of reperfusion. ICAM-1 p rotein expression on cardiac myocytes is seen after 6 h of reperfusion , and increases thereafter. Non-ischemic tissue demonstrates no early induction of ICAM-1 mRNA or ICAM-1 protein on myocardial cells. In our most recent experiments, we have determined that reperfusion is an ab solute requirement for the early induction of myocardial ICAM-1 mRNA i n previously ischemic myocardial cells. To further assess this, we hav e cloned and sequenced a canine interleukin-6 (IL-6) cDNA. The data su ggest that early induction of IL-6 mRNA is also reperfusion dependent as it could be demonstrated in the same ischemic and reperfused segmen ts in which ICAM-1 mRNA was found. Peak expression of IL-6 mRNA occurr ed much earlier than that for ICAM-1 mRNA. Similar experiments were th en performed with a molecular probe for interleukin-8 (IL-8). This che mokine is a potent neutrophil stimulant and has a higher degree of spe cificity for neutrophils than classic chemoattractants such as C5a. Th e results suggest a similar pattern of induction that occurs within th e first hour and is markedly increased by reperfusion. The relationshi p of reperfusion to ICAM-1 and cytokine induction is discussed.