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 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.


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-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 micromol/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 micromol/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.
Sala
A
A
Center for Cardiopulmonary Pharmacology, University of Milan, Italy.
Rossoni
G
G
Berti
F
F
Buccellati
C
C
Bonazzi
A
A
Maclouf
J
J
Folco
G
G
D000818:Animals; D000911:Antibodies, Monoclonal; D018821:CD18 Antigens / Q000276:immunology*; D000001:Calcimycin / Q000494:pharmacology; D003545:Cysteine / Q000096:biosynthesis* / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000494:pharmacology; D015289:Leukotrienes / Q000096:biosynthesis* / Q000502:physiology* / Q000652:urine; D009203:Myocardial Infarction / Q000652:urine; D009504:Neutrophils / Q000737:chemistry; D011817:Rabbits; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology*
D000911:Antibodies, Monoclonal; D018821:CD18 Antigens; D018836:Inflammation Mediators; D015289:Leukotrienes; C112381:cysteinyl-leukotriene; D000001:Calcimycin; D003545:Cysteine