Cyclooxygenase-1 overexpression decreases Basal airway responsiveness but not allergic inflammation.
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.
Card
Jeffrey W
JW
Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709.
Carey
Michelle A
MA
Bradbury
J Alyce
JA
Graves
Joan P
JP
Lih
Fred B
FB
Moorman
Michael P
MP
Morgan
Daniel L
DL
DeGraff
Laura M
LM
Zhao
Yun
Y
Foley
Julie F
JF
Zeldin
Darryl C
DC
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
D016210:Methacholine Chloride; D010047:Ovalbumin; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone