Complement C5a, TGF-β1, and MCP-1, in Sequence, Induce Migration of Monocytes Into Ischemic Canine Myocardium Within the First One to Five Hours After Reperfusion

Abstract

Background Recent studies suggest that reperfusion promotes healing of formerly ischemic heart tissue even when myocardial salvage is no longer possible. Since monocyte-macrophage infiltration is the hallmark of the healing infarct, we have attempted to identify mechanisms that attract monocytes into the heart after reperfusion of ischemic canine myocardium. Methods and Results Isolated autologous 99m Tc-labeled mononuclear leukocytes injected into the left atrium localized preferentially in previously ischemic myocardium within the first hour after reperfusion. Histological studies revealed CD64+ monocytes in small venules and the perivascular connective tissue within the first hour after reperfusion. Flow cytometric analysis of cells in cardiac lymph showed systematically increasing numbers of neutrophils and monocytes between 1 and 4 hours 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)-β1 contributed significantly to this chemotactic activity after 60 to 180 minutes, and after 180 minutes, monocyte chemotactic activity in lymph was largely dependent on monocyte chemoattractant protein (MCP)-1 acting in concert with TGF-β1. Conclusions Beginning in the first 60 minutes after reperfusion, C5a, TGF-β1, and MCP-1, acting sequentially, promote infiltration of monocytes into formerly ischemic myocardium. These events may promote the healing of myocardial injury facilitated by reperfusion.