Journal article
The role of 5-lipoxygenase products in preclinical models of asthma
Journal of allergy and clinical immunology, v 91(4), pp 917-929
1993
PMID: 8473681
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
Metrics
Details
- Title
- The role of 5-lipoxygenase products in preclinical models of asthma
- Creators
- Craig D. Wegner - Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Conn., USA.Robert H. Gundel - Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Conn., USA.William M. Abraham - Mount Sinai Medical CenterEdward S. Schulman - Hahnemann University HospitalMark J. Kontny - Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Conn., USA.Edward S. Lazer - Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Conn., USACarol A. Homon - Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Conn., USA.Anne G. Graham - Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Conn., USA.Carol A. Torcellini - Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Conn., USA.Cosmos C. Clarke - Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Conn., USA.Paul Jager - Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Conn., USAWalter W. Wolyniec - Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Conn., USA.L.Gordon Letts - Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Conn., USA.Peter R. Farina - Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Conn., USA.
- Publication Details
- Journal of allergy and clinical immunology, v 91(4), pp 917-929
- Publisher
- Mosby, Inc
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pulmonary, Critical Care, and Sleep (Medicine)
- Web of Science ID
- WOS:A1993KY25100013
- Scopus ID
- 2-s2.0-0027477589
- Other Identifier
- 991019184079004721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- Web of Science research areas
- Allergy
- Immunology