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Cyclooxygenase-2 Deficiency Exacerbates Bleomycin-Induced Lung Dysfunction but Not Fibrosis

Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health; and CIIT Centers for Health Research, Research Triangle Park, North Carolina

Correspondence and requests for reprints should be addressed to Darryl C. Zeldin, M.D., NIH/NIEHS, 111 T.W. Alexander Drive, Building 101, Room D236, Research Triangle Park, NC 27709. E-mail: zeldin{at}niehs.nih.gov

Cyclooxygenase (COX)-derived eicosanoids have been implicated in the pathogenesis of pulmonary fibrosis. Uncertainty regarding the influence of COX-2 on experimental pulmonary fibrosis prompted us to clarify the fibrotic and functional effects of intratracheal bleomycin administration in mice genetically deficient in COX-2. Further, the effects of airway-specific COX-1 overexpression on fibrotic and functional outcomes in wild-type and COX-2 knockout mice were assessed. Equivalent increases in airway cell influx, lung collagen content, and histopathologic evidence of fibrosis were observed in wild-type and COX-2 knockout mice 21 d after bleomycin treatment, suggesting that COX-2 deficiency did not alter the extent or severity of fibrosis in this model. However, bleomycin-induced alterations in respiratory mechanics were more severe in COX-2 knockout mice than in wild-type mice, as illustrated by a greater decrease in static compliance compared with genotype-matched, saline-treated control mice (26 ± 3% versus 11 ± 4% decreases for COX-2 knockout and wild-type mice, respectively; P < 0.05). The influence of COX-1 overexpression in airway Clara cells was also examined. Whereas the fibrotic effects of bleomycin were not altered in wild-type or COX-2 knockout mice overexpressing COX-1, the exaggerated lung function decrement in bleomycin-treated COX-2 knockout mice was prevented by COX-1 overexpression and coincided with decreased airway cysteinyl leukotriene levels. Collectively, these data suggest an important regulatory role for COX-2 in the maintenance of lung function in the setting of lung fibrosis, but not in the progression of the fibrotic process per se.

Key Words: cyclooxygenase • fibrosis • respiratory mechanics • prostaglandin • transgenic

CLINICAL RELEVANCE Cyclooxygenases (COXs) may be involved in the pathogenesis of lung fibrosis. Disruption of COX-2 activity worsens fibrosis-associated lung function decline but not fibrosis itself, indicative of important regulatory effects of this enzyme in lung fibrosis.

 

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