COMPLEMENT C5A, TGF-BETA-1, AND MCP-1, IN SEQUENCE, INDUCE MIGRATION OF MONOCYTES INTO ISCHEMIC CANINE MYOCARDIUM WITHIN THE FIRST ONE TO 5HOURS AFTER REPERFUSION

Recent studies suggest that reperfusion promotes healing of formerly i schemic heart tissue even when myocardial salvage is no longer possibl e. Since monocyte-macrophage infiltration is the hallmark of the heali ng infarct, we have attempted to identify mechanisms that attract mono cytes into the heart after reperfusion of ischemic canine myocardium. Methods and Results Isolated autologous Tc-99m-labeled mononuclear leu kocytes injected into the left atrium localized preferentially in prev iously ischemic myocardium within the first hour after reperfusion. Hi stological studies revealed CD64+ monocytes in small venules and the p erivascular connective tissue within the first hour after reperfusion. Flow cytometric analysis of cells in cardiac lymph showed systematica lly increasing numbers of neutrophils and monocytes between 1 and 4 ho urs after reperfusion; monocyte enrichment was eventually greater than neutrophil enrichment. Monocyte chemotactic activity in cardiac lymph collected in the first hour after reperfusion was wholly attributable to C5a. Transforming growth factor (TGF)-beta 1 contributed significa ntly to this chemotactic activity after 60 to 180 minutes, and after 1 80 minutes, monocyte chemotactic activity in lymph was largely depende nt on monocyte chemoattractant protein (MCP)-1 acting in concert with TGF-beta 1. Conclusions Beginning in the first 60 minutes after reperf usion, C5a, TGF-beta 1, and MCP-1, acting sequentially, promote infilt ration of monocytes into formerly ischemic myocardium. These events ma y promote the healing of myocardial injury facilitated by reperfusion.