Effect of a leukotriene B4 receptor antagonist, LY293111, on allergen induced responses in asthma.
BACKGROUND
Leukotriene (LT) B4 is a potent neutrophil chemoattractant and also stimulates eosinophils in vitro, but its role in asthmatic inflammation is unknown.


METHODS
The effect of the novel LTB4 receptor antagonist, LY293111, was examined using allergen challenge as a model for asthmatic inflammation in 12 atopic asthmatic subjects in a double blind placebo controlled crossover trial. Subjects with an established early (EAR) and late asthmatic response (LAR) to allergen at screening received oral LY293111 in a dose of 112 mg three times daily for seven days or placebo before further allergen challenge. Each treatment was separated by a washout period of 28 days. Individuals underwent histamine challenge one hour before and three hours after allergen challenge. Bronchoalveolar lavage (BAL) fluid was obtained at bronchoscopy 24 hours after allergen challenge.


RESULTS
There was no difference in baseline lung function, EAR, LAR, or in airway responsiveness to histamine before and after allergen between placebo and LY293111. By contrast, treatment with LY293111 significantly reduced the number of neutrophils in BAL fluid expressed as both absolute cell numbers and percentage cell differential counts: absolute cell counts, median (range) 0.04 (0.02-0.15) x 10(6) after LY293111, 0.09 (0.02-0.43) x 10(6) after placebo; percentage differential cell counts 0.35 (0.1-2.0) after LY293111, 0.80 (0.1-3.6) after placebo (p < 0.05). Eosinophils, macrophages, and lymphocytes in BAL fluid did not differ between treatments. There was a significant reduction in the concentration of myeloperoxidase (MPO) with both placebo (16 (6.6) ng/ml) and LY293111 (3.5 (1.8) ng/ml) and of LTB4 (placebo 4.6 (1.2) pg/ml, LY293111 2.2 (0.2) pg/ml). Concentrations of LTC4 and interleukin 8 were reduced, although not significantly, whereas concentrations of interleukin 6, GM-CSF, and TNF-alpha were unchanged by LY293111.


CONCLUSIONS
These results demonstrate an influence of LTB4 on neutrophil influx and activation in the airway following allergen challenge. Despite this anti-inflammatory effect, there was no measured physiological benefit and this questions the functional role of the neutrophil in the pathophysiology of allergen induced asthma.
Evans
D J
DJ
Clinical Studies Unit, Royal Brompton Hospital, London, UK.
Barnes
P J
PJ
Spaethe
S M
SM
van Alstyne
E L
EL
Mitchell
M I
MI
O'Connor
B J
BJ
D000328:Adult; D000485:Allergens / Q000009:adverse effects*; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology / Q000276:immunology; D018592:Cross-Over Studies; D016207:Cytokines / Q000032:analysis; D004311:Double-Blind Method; D005541:Forced Expiratory Volume / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D007975:Leukotriene B4 / Q000032:analysis; D008297:Male; D009195:Peroxidase / Q000032:analysis; D011453:Prostaglandins / Q000032:analysis; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors*; D013931:Thromboxanes / Q000032:analysis
D000485:Allergens; D016207:Cytokines; D011453:Prostaglandins; D018102:Receptors, Leukotriene B4; D013931:Thromboxanes; D007975:Leukotriene B4; D006632:Histamine; D009195:Peroxidase