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

Background-Cysteinyl leukotrienes (cys-LT) can constrict small and large ve ssels and increase vascular permeability. Formation of cys-LT arising from polymorphonuclear leukocytes (PMNL) and endothelial cell cooperation (trans cellular synthesis) led to the hypothesis that PMNL-endothelial cell adhesi on 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 beta(2)-integrin on the synthesis of cys-LT in a PMNL-pel-fused 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-m et-leu-phe (0.3 mu mol/L) caused synthesis of cys-LT and increase in corona ry pel fusion pressure that were prevented by the anti-CD18 antibody. Simil ar results were obtained with the use of A-23187 (0.5 mu mol/L) as a challe nge. Persistence of PMNL-associated myeloperoxidase activity in the pel fus ion buffer was observed in the presence of the anti-CD18 antibody, indicati ng decreased PMNL infiltration. Coronary artery ligature in vivo increased urinary excretion of leukotriene E-4, supporting the activation of the 5-li poxygenase pathway during experimental acute myocardial infarction, Pretrea tment with the anti-CD18 antibody (1 mg/kg) prevented the increase in leuko triene E-4 excretion. Conclusions-These data support the importance of adhesion in promoting cys- LT formation, originating from PMNL-endothelial cell cooperation, and contr ibuting to myocardial stiffness and increased coronary resistance.