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Cyclooxygenase-1 Overexpression Decreases Basal Airway Responsiveness but Not Allergic Inflammation¹

Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709

Pharmacological inhibition or genetic disruption of cyclooxygenase (COX)-1 or COX-2 exacerbates the inflammatory and functional responses of the lung to environmentally relevant stimuli. To further examine the contribution of COX-derived eicosanoids to basal lung function and to allergic lung inflammation, transgenic (Tr) mice were generated in which overexpression of human COX-1 was targeted to airway epithelium. Although no differences in basal respiratory or lung mechanical parameters were observed, COX-1 Tr mice had increased bronchoalveolar lavage fluid PGE₂ content compared with wild-type littermates (23.0 ± 3.6 vs 8.4 ± 1.4 pg/ml; p < 0.05) and exhibited decreased airway responsiveness to inhaled methacholine. In an OVA-induced allergic airway inflammation model, comparable up-regulation of COX-2 protein was observed in the lungs of allergic wild-type and COX-1 Tr mice. Furthermore, no genotype differences were observed in allergic mice in total cell number, eosinophil content (70 vs 76% of total cells, respectively), and inflammatory cytokine content of bronchoalveolar lavage fluid, or in airway responsiveness to inhaled methacholine (p > 0.05). To eliminate the presumed confounding effects of COX-2 up-regulation, COX-1 Tr mice were bred into a COX-2 null background. In these mice, the presence of the COX-1 transgene did not alter allergen-induced inflammation but significantly attenuated allergen-induced airway hyperresponsiveness, coincident with reduced airway leukotriene levels. Collectively, these data indicate that COX-1 overexpression attenuates airway responsiveness under basal conditions but does not influence allergic airway inflammation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. J.W.C. is a recipient of a Research Fellowship Award from the Davies Charitable Foundation, and of a Senior Research Training Fellowship from the American Lung Association of North Carolina.

² Address correspondence and reprint requests to Dr. Darryl C. Zeldin, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T. W. Alexander Drive, Building 101, Room D236, Research Triangle Park, NC 27709. E-mail address: zeldin{at}niehs.nih.gov

³ Abbreviations used in this paper: COX, cyclooxygenase; WT, wild type; BAL, bronchoalveolar lavage; Tr, transgenic; bGH, bovine growth hormone; R_t, retention time; cysLT, cysteinyl leukotriene; LTB₄, leukotriene B₄; PC, provocative concentration; CC10, Clara cell 10-kDa protein; Penh, enhanced pause.

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