title: Cyclooxygenase-1 overexpression decreases Basal airway responsiveness but not allergic inflammation.
abstract: 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 PGE(2) 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.
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Card
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Carey
authors.forename: J Alyce
authors.initials: JA
authors.lastname: Bradbury
authors.forename: Joan P
authors.initials: JP
authors.lastname: Graves
authors.forename: Fred B
authors.initials: FB
authors.lastname: Lih
authors.forename: Michael P
authors.initials: MP
authors.lastname: Moorman
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Morgan
authors.forename: Laura M
authors.initials: LM
authors.lastname: DeGraff
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Julie F
authors.initials: JF
authors.lastname: Foley
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000172:deficiency; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D006967:Hypersensitivity / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D007249:Inflammation / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D010993:Plethysmography, Whole Body; D012129:Respiratory Function Tests; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes
chemical_list: D016210:Methacholine Chloride; D010047:Ovalbumin; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone