LY255283, a novel leukotriene B4 receptor antagonist, limits activation of neutrophils and prevents acute lung injury induced by endotoxin in pigs.
BACKGROUND
Polymorphonuclear neutrophils (PMNs) have been implicated in the pathogenesis of the adult respiratory distress syndrome (ARDS). Because leukotriene B4 (LTB4) is a potent activator of PMNs, we sought to determine whether LY255283, an LTB4 receptor antagonist, could block PMN activation and lung injury in a porcine model of lipopolysaccharide-induced ARDS.


METHODS
Eighteen hours before being studied, pigs were injected with lipopolysaccharide (20 micrograms/kg). From 0 to 60 minutes, pigs received either Ringer's lactate solution (n = 5) or lipopolysaccharide (250 micrograms/kg). Among the pigs that were infused with lipopolysaccharide, nine received no other treatment, six received a low dose of LY255283 (30 mg/kg loading dose; 3 mg/kg-hr infusion), and six received a high dose of LY255283 (30 mg/kg loading dose; 30 mg/kg-hr). In vivo PMN activation was assessed with an automated chemiluminescence assay wherein results are expressed as CORE/MORE (i.e., the ratio of complement-opsonized zymosan receptor expression on circulating cells [CORE] divided by the maximal complement-opsonized zymosan receptor expression induced by incubating the cells in vitro with LTB4 or platelet-activating factor [MORE]).


RESULTS
In control pigs, lipopolysaccharide induced hypoxemia, pulmonary hypertension, and neutrophil activation (increased CORE/MORE ratio). These changes were attenuated by LY255283, particularly when pigs were infused with the higher dose of the compound. The drug also blunted lipopolysaccharide-induced recruitment of PMNs in pulmonary air spaces, as assessed by bronchoalveolar lavage performed at 240 minutes, although the degree of pulmonary leukosequestration caused by lipopolysaccharide was not affected.


CONCLUSIONS
In a dose-dependent fashion, LY255283 ameliorated lipopolysaccharide-induced ARDS in pigs, possibly by blocking the recruitment of activated PMNs into alveoli.
Department of Surgery, Massachusetts General Hospital, Boston.
P S
PS
Wollert
M J
MJ
Menconi
B P
BP
O'Sullivan
H
H
Wang
V
V
Larkin
M P
MP
Fink
D000208:Acute Disease; D000818:Animals; D004305:Dose-Response Relationship, Drug; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D018102:Receptors, Leukotriene B4; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000517:prevention & control*; D013552:Swine; D013777:Tetrazoles / Q000494:pharmacology*
D008070:Lipopolysaccharides; D011971:Receptors, Immunologic; D018102:Receptors, Leukotriene B4; D013777:Tetrazoles; C063823:LY 255283