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Effect of a leukotriene B4 receptor antagonist, LY293111, on allergen induced responses in asthma.
Thorax. 1996 Dec; 51(12):1178-84.T

Abstract

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.

Authors+Show Affiliations

Clinical Studies Unit, Royal Brompton Hospital, London, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

8994512

Citation

Evans, D J., et al. "Effect of a Leukotriene B4 Receptor Antagonist, LY293111, On Allergen Induced Responses in Asthma." Thorax, vol. 51, no. 12, 1996, pp. 1178-84.
Evans DJ, Barnes PJ, Spaethe SM, et al. Effect of a leukotriene B4 receptor antagonist, LY293111, on allergen induced responses in asthma. Thorax. 1996;51(12):1178-84.
Evans, D. J., Barnes, P. J., Spaethe, S. M., van Alstyne, E. L., Mitchell, M. I., & O'Connor, B. J. (1996). Effect of a leukotriene B4 receptor antagonist, LY293111, on allergen induced responses in asthma. Thorax, 51(12), 1178-84.
Evans DJ, et al. Effect of a Leukotriene B4 Receptor Antagonist, LY293111, On Allergen Induced Responses in Asthma. Thorax. 1996;51(12):1178-84. PubMed PMID: 8994512.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of a leukotriene B4 receptor antagonist, LY293111, on allergen induced responses in asthma. AU - Evans,D J, AU - Barnes,P J, AU - Spaethe,S M, AU - van Alstyne,E L, AU - Mitchell,M I, AU - O'Connor,B J, PY - 1996/12/1/pubmed PY - 1996/12/1/medline PY - 1996/12/1/entrez SP - 1178 EP - 84 JF - Thorax JO - Thorax VL - 51 IS - 12 N2 - 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. SN - 0040-6376 UR - https://www.unboundmedicine.com/medline/citation/8994512/Effect_of_a_leukotriene_B4_receptor_antagonist_LY293111_on_allergen_induced_responses_in_asthma_ L2 - https://thorax.bmj.com/lookup/pmidlookup?view=long&amp;pmid=8994512 DB - PRIME DP - Unbound Medicine ER -