Susceptibility of cyclooxygenase-2-deficient mice to pulmonary fibrogenesis

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 wildtype and COX-1(-/-) terminal bronchioles and was strongly induced 24 hours after V2O5 exposure. Prostaglandin (PG) E-2 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 PGE(2) 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 PGE(2) is an important factor in resolving inflammation.