C5a-induced myocardial ischemia: role for CD18-dependent PMN localization and PMN-platelet interactions.

Intracoronary C5a in swine decreases coronary blood flow and regional myocardial segment shortening, responses mediated by thromboxane (Tx) A2-induced coronary vasoconstriction and intramyocardial trapping of granulocytes (PMNs). We sought to determine the origin of TxA2 and to investigate the role of CD18-dependent PMN function by utilizing an anti-CD18 monoclonal antibody, IB4. Isolated C5a-stimulated PMNs or platelets did not produce TxB2. However, together, C5a-stimulated PMNs and platelets produced TxB2. IB4 bound porcine PMN surface CD18 and blocked C5a-induced PMN functions. In vivo, IB4 loading (2 mg/kg) transiently decreased arterial blood pressure and circulating platelet counts in six of nine animals (390 +/- 31 vs. 176 +/- 41 X 10(6)/ml, control vs. IB4; P < 0.002) and significantly ameliorated C5a-induced decreases in coronary venous PMN count (-4.1 +/- 0.6 vs. -1.4 +/- 0.8 X 10(6) cells/ml), coronary artery blood flow (-10 +/- 1 vs. -4 +/- 1 ml/min), and segment shortening (-15 +/- 2 vs. -8 +/- 2%, C5a vs. C5a + IB4). We conclude that 1) production of TxB2 in response to C5a is mediated by a PMN-platelet interaction, 2) IB4 functionally blocks CD18 on porcine PMNs, and 3) C5a-induced myocardial PMN extraction is mediated, in part, by a CD18-dependent mechanism. These results suggest that PMN-platelet interactions and CD18-dependent PMN extraction are important in C5a-induced myocardial ischemia.