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(American Journal of Pathology. 2002;161:459-470.)
© 2002 American Society for Investigative Pathology

Regular Articles

Susceptibility of Cyclooxygenase-2-Deficient Mice to Pulmonary Fibrogenesis

James C. Bonner*, Annette B. Rice*, Jennifer L. Ingram*, Cindy R. Moomaw{dagger}, Abraham Nyska{dagger}, Alyce Bradbury*, Alisha R. Sessoms{ddagger}, Patricia C. Chulada*, Daniel L. Morgan§, Darryl C. Zeldin* and Robert Langenbach{ddagger}

From the Laboratories of Pulmonary Pathobiology,*Experimental Pathology,{dagger}Molecular Toxicology,§and Experimental Carcinogenesis and Mutagenesis,{ddagger}National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina

The cyclooxygenase (COX)-2 enzyme has been implicated as an important mediator of pulmonary fibrosis. In this study, the lung fibrotic responses were investigated in COX-1 or COX-2-deficient (-/-) mice following vanadium pentoxide (V2O5) exposure. Lung histology was normal in saline-instilled wild-type and COX-deficient mice. COX-2-/-, but not COX-1-/- or wild-type mice, exhibited severe inflammatory responses by 3 days following V2O5 exposure and developed pulmonary fibrosis 2 weeks post-V2O5 exposure. Western blot analysis and immunohistochemistry showed that COX-1 protein was present in type 2 epithelial cells, bronchial epithelial cells, and airway smooth muscle cells of saline or V2O5-exposed wild-type and COX-2-/- mice. COX-2 protein was present in Clara cells of wild-type and COX-1-/- terminal bronchioles and was strongly induced 24 hours after V2O5 exposure. Prostaglandin (PG) E2 levels in the bronchoalveolar lavage (BAL) fluid from wild-type and COX-1-/- mice were significantly up-regulated by V2O5 exposure within 24 hours, whereas PGE2 was not up-regulated in COX-2-/- BAL fluid. Tumor necrosis factor-{alpha} was elevated in the BAL fluid from all genotypes after V2O5 exposure, but was significantly and chronically elevated in the BAL fluid from COX-2-/- mice above wild-type or COX-1-/- mice. These findings indicate that the COX-2 enzyme is protective against pulmonary fibrogenesis, and we suggest that COX-2 generation of PGE2 is an important factor in resolving inflammation.




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