AMPLIFICATION OF THE INFLAMMATORY RESPONSE - ADHESION MOLECULES ASSOCIATED WITH PLATELET WHITE CELL RESPONSES

Cardiopulmonary bypass (CPB) causes leukocyte and platelet activation, resulting in upregulation of the adhesion receptor CD11b/CD18 on leuk ocytes and upregulation of P-selectin, the adhesion receptor that bind s the activated platelet to polymorphonuclear neutrophils (PMNs) and m onocytes. Our laboratory has studied the expression of activation-depe ndent adhesion receptors during in vivo CPB. Both PMN and monocyte CD1 1b were upregulated during CPB but with differing time courses, Peak P MN CD11b levels occurred at the end of the hypothermic phase of bypass , whereas monocyte CD11b levels increased steadily throughout the cour se of CPB, peaked at 2-4 h after CPB, and remained significantly eleva ted as late as 18-24 h post CPB. The percentage of P-selectin-positive platelets increased significantly during bypass, peaking around the e nd of bypass and remaining elevated in the early post-bypass period. T he level then returned to normal by 18 h post-bypass. Monocyte-platele t binding paralleled the increase in P-selectin-positive platelets dur ing bypass and similarly remained elevated in the post-bypass period. PMN-platelet binding also increased but peaked early during CPB. Upreg ulation of these adhesive receptors and formation of platelet-leukocyt e conjugates may influence the prothrombotic activity of monocytes and the proinflammatory activity of PMNs in the post-CPB period. Our labo ratory has developed an in vitro model of extracorporeal circulation, and recirculation of blood on this circuit results in significant acti vation of PMNs and monocyte CD11b expression, increasing progressively over time. Likewise, the percentage of P-selectin-positive platelets increased and was paralleled by the formation of leukocyte-platelet co njugates comparable to the pattern found in vivo. Generation of the co mplement fragments C5a and the C5b-9 membrane-attack complex may contr ibute to platelet P-selectin expression and formation of leukocyte-pla telet conjugates during CPB. The in vitro model has been used to test the cellular effects of complement inhibition employing a monoclonal a ntibody that blocks cleavage of C5 into C5a and C5b to determine the r ole of early vs. late complement components in the cellular activation induced by CPB. Preliminary results demonstrate that blockade of the formation of C5a and the C5b-9 membrane-attack complex during simulate d extracorporeal circulation effectively inhibits platelet and PMN act ivation and the formation of leukocyte-platelet conjugates.