LY255283, a novel leukotriene B4 receptor antagonist, limits activation of neutrophils and prevents acute lung injury induced by endotoxin in pigs.

Abstract

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.

• Authors: P S Wollert, M J Menconi, B P O'Sullivan, H Wang, V Larkin, M P Fink
• Journal: Surgery (Surgery) Vol. 114 Issue 2 Pg. 191-8 (Aug 1993) ISSN: 0039-6060 [Print] United States
• PMID: 8393594 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Lipopolysaccharides
• Receptors, Immunologic
• Receptors, Leukotriene B4
• Tetrazoles
• LY 255283

Topics

• Acute Disease
• Animals
• Dose-Response Relationship, Drug
• Lipopolysaccharides (toxicity)
• Male
• Neutrophils (drug effects, physiology)
• Receptors, Immunologic (antagonists & inhibitors)
• Receptors, Leukotriene B4
• Respiratory Distress Syndrome (chemically induced, prevention & control)
• Swine
• Tetrazoles (pharmacology)