Cyclooxygenase-2 deficiency exacerbates bleomycin-induced lung dysfunction but not fibrosis.
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.
Card
Jeffrey W
JW
Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, NC 27709, USA.
Voltz
James W
JW
Carey
Michelle A
MA
Bradbury
J Alyce
JA
Degraff
Laura M
LM
Lih
Fred B
FB
Bonner
James C
JC
Morgan
Daniel L
DL
Flake
Gordon P
GP
Zeldin
Darryl C
DC
D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000172:deficiency* / Q000235:genetics; D015777:Eicosanoids / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015656:Respiratory Mechanics
D015777:Eicosanoids; D011994:Recombinant Proteins; D001761:Bleomycin; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2