The role of 5-lipoxygenase products in preclinical models of asthma
| Autor: | Jager Paul D, L. Gordon Letts, Mark J. Kontny, C. C. Clarke, William M. Abraham, Peter R. Farina, Craig D. Wegner, Lazer Edward S, Carol A. Torcellini, Walter W. Wolyniec, R. H. Gundel, Edward S. Schulman, Carol Ann Homon, A. G. Graham |
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| Rok vydání: | 1993 |
| Předmět: |
Male
Bronchoconstriction Immunology Guinea Pigs Prostaglandin Pharmacology Bronchospasm chemistry.chemical_compound Phenols medicine Immunology and Allergy Animals Humans Lipoxygenase Inhibitors Leukotriene Arachidonate 5-Lipoxygenase Sheep biology medicine.diagnostic_test Dose-Response Relationship Drug business.industry Prostaglandin D2 Asthma Ovalbumin Macaca fascicularis Bronchoalveolar lavage chemistry Arachidonate 5-lipoxygenase biology.protein Methacholine SRS-A medicine.symptom business medicine.drug |
| Zdroj: | The Journal of allergy and clinical immunology. 91(4) |
| ISSN: | 0091-6749 |
| Popis: | Background: The action of 5-lipoxygenase on arachidonic acid generates potent inflammatory mediators that may contribute to the pathophysiology of asthma. Methods: Using the potent and selective 5-lipoxygenase inhibitor BI-L-239, we have examined the role of 5-lipoxygenase products in three animal models of asthma. Results: In vitro BI-L-239 inhibited 5-lipoxygenase product generation from human lung mast cells, alveolar macrophages, and peripheral blood leukocytes with a concentration that would provide 50% inhibition values of 28 to 340 nmollL. A 36-fold selectivity for immunoreactive leukotriene C 4 versus immunoreactive prostaglandin D 2 inhibition was demonstrated in mast cells. In anesthetized cynomolgus monkeys, inhaled BI-L-239 provided dose-dependent inhibition of the inhaled Ascaris -induced immunoreactive leukotriene C 4 release (maximum, 73%; bronchoalveolar lavage [BAL], 20 minutes), late-phase bronchoconstriction (maximum, 41%; +6 to 8 hours), and neutrophil infiltration (maximum, 63%; BAL, +8 hours). In conscious sheep, inhaled BI-L-239 provided dose-dependent inhibition of the inhaled Ascaris-induced late-phase bronchoconstriction (maximum, 66%; +6 to 8 hours) and increase in airway responsiveness (maximum, 82%; carbachol, +24 hours). The acute bronchoconstriction was shortened, and neutrophil infiltration diminished (maximum, 61%; BAL, +8 hours) in this model. Finally in conscious actively sensitized guinea pigs pretreated with pyrilamine and indomethacin, inhaled BI-L-239 attenuated acute bronchoconstriction (maximum, 80%; +5 to 15 minutes), leukocyte infiltration (58%; BAL, +3 days) and increase in airway responsiveness (100%; methacholine, +3 days) induced by three alternate-day ovalbumin inhalations. Conclusions: In conclusion, results in these three animal models indicate that 5-lipoxygenase products may be major contributors to the bronchoconstriction (especially late phase), leukocyte infiltration, and airway hyperresponsiveness that characterize asthma. |
| Databáze: | OpenAIRE |
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