title: C5a-induced myocardial ischemia: role for CD18-dependent PMN localization and PMN-platelet interactions.
abstract: 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.
authors.affiliation: Department of Internal Medicine, University of California, Davis 95616.
authors.forename: M P
authors.initials: MP
authors.lastname: Fletcher
authors.forename: G L
authors.initials: GL
authors.lastname: Stahl
authors.forename: J C
authors.initials: JC
authors.lastname: Longhurst
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000502:physiology*; D001792:Blood Platelets / Q000502:physiology*; D001794:Blood Pressure; D018821:CD18 Antigens; D002448:Cell Adhesion; D002449:Cell Aggregation / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D015936:Complement C5a / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects; D005260:Female; D006339:Heart Rate; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D017202:Myocardial Ischemia / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010976:Platelet Count; D016028:Receptors, Leukocyte-Adhesion / Q000502:physiology; D013552:Swine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013929:Thromboxane B2 / Q000097:blood; D013997:Time Factors; D014661:Vasoconstriction; D016277:Ventricular Function, Left
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018821:CD18 Antigens; D016028:Receptors, Leukocyte-Adhesion; D013929:Thromboxane B2; D015936:Complement C5a; D013755:Tetradecanoylphorbol Acetate