Susceptibility of cyclooxygenase-2-deficient mice to pulmonary fibrogenesis.

Abstract

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 (V(2)O(5)) 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 V(2)O(5) exposure and developed pulmonary fibrosis 2 weeks post-V(2)O(5) 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 V(2)O(5)-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 V(2)O(5) exposure. Prostaglandin (PG) E(2) levels in the bronchoalveolar lavage (BAL) fluid from wild-type and COX-1(-/-) mice were significantly up-regulated by V(2)O(5) 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 V(2)O(5) 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.

• Authors: James C Bonner, Annette B Rice, Jennifer L Ingram, Cindy R Moomaw, Abraham Nyska, Alyce Bradbury, Alisha R Sessoms, Patricia C Chulada, Daniel L Morgan, Darryl C Zeldin, Robert Langenbach
• Journal: The American journal of pathology (Am J Pathol) Vol. 161 Issue 2 Pg. 459-70 (Aug 2002) ISSN: 0002-9440 [Print] United States
• PMID: 12163371 (Publication Type: Journal Article)

Chemical References

• Isoenzymes
• Vanadium Compounds
• vanadium pentoxide
• Cyclooxygenase 2
• Prostaglandin-Endoperoxide Synthases
• Dinoprostone

Topics

• Animals
• Cyclooxygenase 2
• Dinoprostone (biosynthesis)
• Female
• Genetic Predisposition to Disease
• Immunohistochemistry
• Isoenzymes (deficiency, genetics)
• Male
• Mice
• Mice, Knockout
• Prostaglandin-Endoperoxide Synthases (deficiency, genetics)
• Pulmonary Fibrosis (etiology, genetics)
• Up-Regulation
• Vanadium Compounds (toxicity)