Acute
inflammation has been suggested as a potential mechanism for some of the injury associated with reperfusion of the ischemic myocardium. This hypothesis implies that viable myocardial cells adjacent to the lethally injured cells are vulnerable to injury induced by the neutrophil influx observed to attend reperfusion. In our previous work, we demonstrated that the presence of
ICAM-1 on the surface of cardiac myocytes is required for neutrophils to directly damage them; blocking
monoclonal antibodies to either
ICAM-1 on cardiac myocytes or Mac-1 on activated neutrophils completely precluded neutrophil-induced myocyte injury. We also demonstrated that postischemic cardiac lymph (cardiac extracellular fluid) contained leukotactic factors (primarily C5a) and
cytokines present in concentrations sufficient to maximally induce Mac-1 on the surface of neutrophils and
ICAM-1 on the surface of isolated dog cardiac myocytes. The present study sought to further these observations by examining the site of potential
ICAM-1 induction as a function of time of reperfusion, degree of
ischemia, and viability of myocardial cells. Our evidence suggests that
ICAM-1 mRNA is induced very early after reperfusion only in the previously ischemic myocardium and is not seen in the nonischemic myocardium during the early hours of reperfusion. Moreover,
ICAM-1 mRNA induction is seen most intensely in the ischemic area directly bordering the necrotic area (which, after 1-hr reperfusion, does not contain any ICAM-1
mRNA) and immediately abutting the site of maximal influx of neutrophils. Thus, the induction of
ICAM-1 and the influx of neutrophils (presumably activated by the
chemotactic factors that guided their migration) exists on the border between viable and necrotic cells. This provides the first direct molecular evidence for a jeopardized border zone on the edge of
myocardial infarction during reperfusion. As previously demonstrated, this reaction is wholly dependent upon tissue injury of the ischemic myocardium and therefore represents an example of a mechanism of injury extension induced as a reaction to a primary injury. The degree of specificity of this reaction demonstrated by the subendocardial sparing directly adjacent to ischemic cells suggests finely modulated mechanisms by which this process is controlled.