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Allergen-Induced Airway Hyperresponsiveness Mediated by Cyclooxygenase Inhibition Is Not Dependent on 5-Lipoxygenase or IL-5, but Is IL-13 Dependent¹

R. Stokes Peebles, Jr^2,*, Koichi Hashimoto^3,*, James R. Sheller^*, Martin L. Moore^*, Jason D. Morrow^*, Shaoquan Ji, Jack A. Elias, Kasia Goleniewska^*, Jamye O’Neal^*, Daphne B. Mitchell^*, Barney S. Graham and Weisong Zhou^*

^* Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; LINCO Research, St. Charles, MO 63304; Department of Medicine, Yale University, New Haven, CT 06520; and Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892

Cyclooxygenase (COX) inhibition during allergic sensitization and allergen airway challenge results in augmented allergic inflammation. We hypothesized that this increase in allergic inflammation was dependent on increased generation of leukotrienes that results from COX inhibition, as leukotrienes are important proinflammatory mediators of allergic disease. To test this hypothesis, we allergically sensitized and challenged mice deficient in 5-lipoxygenase (5-LO). We found that 5-LO knockout mice that were treated with a COX inhibitor during allergic sensitization and challenge had significantly increased airway hyperresponsiveness (AHR) (p < 0.01) and airway eosinophilia (p < 0.01) compared with 5-LO knockout mice that were treated with vehicle. The proinflammatory cytokines have also been hypothesized to be critical regulators of airway inflammation and AHR. We found that the increase in airway eosinophilia seen with COX inhibition is dependent on IL-5, whereas the increase in AHR is not dependent on this cytokine. In contrast, the COX inhibition-mediated increase in AHR is dependent on IL-13, but airway eosinophilia is not. These results elucidate the pathways by which COX inhibition exerts a critical effect of the pulmonary allergen-induced inflammatory response and confirm that COX products are important regulators of allergic inflammation.

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				W. Zhou, D. C. Newcomb, M. L. Moore, K. Goleniewska, J. F. O'Neal, and R. S. Peebles Jr. Cyclooxygenase Inhibition during Allergic Sensitization Increases STAT6-Independent Primary and Memory Th2 Responses J. Immunol., October 15, 2008; 181(8): 5360 - 5367. [Abstract] [Full Text] [PDF]