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

Author:

Sala Angelo1,Rossoni Giuseppe1,Berti Ferruccio1,Buccellati Carola1,Bonazzi Albino1,Maclouf Jacques1,Folco Giancarlo1

Affiliation:

1. 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.).

Abstract

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 β 2 -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 E 4 , 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 E 4 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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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