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: Jeffrey W Card, Michelle A Carey, J Alyce Bradbury, Joan P Graves, Fred B Lih, Michael P Moorman, Daniel L Morgan, Laura M DeGraff, Yun Zhao, Julie F Foley, Darryl C Zeldin
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 177 Issue 7 Pg. 4785-93 (Oct 01 2006) ISSN: 0022-1767 [Print] United States
• PMID: 16982919 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Methacholine Chloride
• Ovalbumin
• Cyclooxygenase 1
• Cyclooxygenase 2
• Dinoprostone

Topics

• Animals
• Bronchial Hyperreactivity (enzymology, immunology, pathology)
• Bronchial Provocation Tests
• Bronchoalveolar Lavage Fluid (chemistry)
• Cyclooxygenase 1 (genetics, immunology, metabolism)
• Cyclooxygenase 2 (deficiency)
• Dinoprostone (metabolism)
• Humans
• Hypersensitivity (enzymology, immunology, pathology)
• Inflammation (enzymology, immunology, pathology)
• Lung (immunology, metabolism, pathology)
• Methacholine Chloride (pharmacology)
• Mice
• Mice, Transgenic
• Ovalbumin (immunology)
• Plethysmography, Whole Body
• Respiratory Function Tests
• Reverse Transcriptase Polymerase Chain Reaction
• Transgenes