title: c7E3Fab reduces postischemic leukocyte-thrombocyte interaction mediated by fibrinogen. Implications for myocardial reperfusion injury.
abstract: Reperfusion injury after coronary occlusion is in part mediated by leukocyte activation and adhesion. Platelets may interact with polymorphonuclear granulocytes (PMNs), causing aggravated reperfusion injury. We studied whether c7E3Fab, a chimeric Fab fragment blocking platelet glycoprotein (GP) IIb/IIIa, decreases PMN-platelet-dependent myocardial dysfunction after ischemia. Isolated guinea pig hearts (n=5 per group) perfused at a constant flow of 5 mL/min were subjected to ischemia (15 minutes, 37 degrees C) and reperfusion. Human PMNs (10x10(6) cells, 3 mL), platelets (400x10(6), 3 mL), and fibrinogen (1 mg/mL) were infused for 3 minutes after 2 minutes of reperfusion, with or without c7E3Fab. Flow cytometry detected GPIIb/IIIa (platelets) and MAC-1 (aMbeta2, PMNs) as well as coaggregates of both in the effluent, whereas double-fluorescence microscopy visualized intracoronary PMN-platelet coaggregates. Postischemic recovery of pressure-volume work (12-cm H(2)O preload and 60-mm Hg afterload) was defined as the ratio of postischemic to preischemic external heart work (mean+/-SEM). c7E3Fab reduced platelet GPIIb/IIIa detection to 10% of controls, blocked a transcoronary MAC-1 increase (+25% without versus -23% with c7E3Fab), and inhibited PMN-platelet coaggregation in the effluent (49+/-12% without versus 17+/-2% with c7E3Fab) as well as in the hearts themselves (5.0+/-0.7/cm(2) without versus 1.2+/-0.3/cm(2) surface area with c7E3Fab). Postischemic recovery of external heart work (83+/-5% in cell-free hearts) declined to 46+/-4% after postischemic PMN-platelet infusion, but not in the presence of c7E3Fab (74+/-11%) or LPM19c (71+/-6%). We conclude that c7E3Fab inhibits formation of PMN-platelet aggregates during myocardial reperfusion, an effect that protects against PMN-platelet-dependent stunning.
authors.affiliation: Internal Medicine I, Klinikum Grosshadern, the Institute for Surgical Research, Ludwig-Maximilians-University of Munich, Munich, Germany. c.kupatt@lrz.uni-muenchen.de
authors.forename: C
authors.initials: C
authors.lastname: Kupatt
authors.forename: H
authors.initials: H
authors.lastname: Habazettl
authors.forename: P
authors.initials: P
authors.lastname: Hanusch
authors.forename: R
authors.initials: R
authors.lastname: Wichels
authors.forename: D
authors.initials: D
authors.lastname: Hahnel
authors.forename: B F
authors.initials: BF
authors.lastname: Becker
authors.forename: P
authors.initials: P
authors.lastname: Boekstegers
mesh_terms: D000077284:Abciximab; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001667:Binding, Competitive; D001792:Blood Platelets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication; D004734:Energy Metabolism; D005340:Fibrinogen / Q000494:pharmacology*; D005434:Flow Cytometry; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology*; D066298:In Vitro Techniques; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008856:Microscopy, Fluorescence; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D005340:Fibrinogen; D000077284:Abciximab