Complement C5a, TGF-beta-1, and MCP-1, in sequence, induce migration of monocytes into ischemic myocardium within the first 1 to 5 hrs following reperfusion

To study mechanisms that regulate accumulation of monocytes in injured tissues, we examined the tissues and the lymphatic fluids draining canine myocardium after a one hour ischemic interval. We found that radiolabeled monocytes accumulated selectively in the ischemic myocardium within the first hour following reperfusion. At that time we could identify CD68+ monocytes in perivascular foci in small venules of myocardium bordering the central zone of dense ischemia. By the third hour some had transformed into actively phagocytic macrophages. Lymph draining the cardiac tissue contained increasing numbers of neutrophils and monocytes between one and four hours after reperfusion. In the first hour after reperfusion, monocyte chemotactic activity in cardiac lymph was wholly attributable to C5a. TGF-beta-1 con-tributed to the chemotactic activity beginning 60 min after reperfusion. After 180 min, monocyte chemotactic activity was largely due to MCP-1 acting in concert with TGF-beta-1. Flow cytometric analysis of permeabilized cells revealed that post-reperfusion cardiac lymph contained increased numbers of monocytes producing IL-1 and TNF-alpha. These results suggest that an organized hierarchy of chemotactic signals directs the migration of monocytes selectively into sites of ischemic injury where these are activated and may differentiate into tissue macrophages.