(Circulation. 2000;101:1436.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Monoclonal Anti-CD18 Antibody Prevents Transcellular Biosynthesis of Cysteinyl Leukotrienes In Vitro and In Vivo and Protects Against Leukotriene-Dependent Increase in Coronary Vascular Resistance and Myocardial Stiffness
From the Center for Cardiopulmonary Pharmacology, University of Milan (Italy) (A.S., G.R., C.B., A.B., G.F.); the Department of Pharmacology, Chemotherapy, and Toxicology, University of Milan (Italy) (F.B.); and U-348, INSERM, Hopital Lariboisière, Paris, France (J.M.).
Correspondence to G. Folco, Center for Cardiopulmonary Pharmacology, University of Milan, Via Balzaretti 9, 0133 Milan, Italy. E-mail giancarlo.folco{at}unimi.it
Background—Cysteinyl leukotrienes (cys-LT) can constrict small and large vessels and increase vascular permeability. Formation of cys-LT arising from polymorphonuclear leukocytes (PMNL) and endothelial cell cooperation (transcellular synthesis) led to the hypothesis that PMNL–endothelial cell adhesion may represent a key step toward the formation of vasoactive cys-LT.
Methods and Results—We studied the effect of pretreatment with a monoclonal antibody directed against the CD18 subunit of PMNL ß2-integrin on the synthesis of cys-LT in a PMNL-perfused isolated rabbit heart in vitro and in a model of permanent ligature of the left descending coronary artery in the rabbit in vivo. Challenge of PMNL-perfused rabbit hearts with formyl-met-leu-phe (0.3 µmol/L) caused synthesis of cys-LT and increase in coronary perfusion pressure that were prevented by the anti-CD18 antibody. Similar results were obtained with the use of A-23187 (0.5 µmol/L) as a challenge. Persistence of PMNL-associated myeloperoxidase activity in the perfusion buffer was observed in the presence of the anti-CD18 antibody, indicating decreased PMNL infiltration. Coronary artery ligature in vivo increased urinary excretion of leukotriene E4, supporting the activation of the 5-lipoxygenase pathway during experimental acute myocardial infarction. Pretreatment with the anti-CD18 antibody (1 mg/kg) prevented the increase in leukotriene E4 excretion.
Conclusions—These data support the importance of adhesion in promoting cys-LT formation, originating from PMNL–endothelial cell cooperation, and contributing to myocardial stiffness and increased coronary resistance.
Key Words: leukocytes • endothelium • cell adhesion molecules • prevention
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