title: 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.affiliation: Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, North Carolina 27709, USA. bonnerj@niehs.nih.gov
authors.forename: James C
authors.initials: JC
authors.lastname: Bonner
authors.forename: Annette B
authors.initials: AB
authors.lastname: Rice
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Ingram
authors.forename: Cindy R
authors.initials: CR
authors.lastname: Moomaw
authors.forename: Abraham
authors.initials: A
authors.lastname: Nyska
authors.forename: Alyce
authors.initials: A
authors.lastname: Bradbury
authors.forename: Alisha R
authors.initials: AR
authors.lastname: Sessoms
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Chulada
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Morgan
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.forename: Robert
authors.initials: R
authors.lastname: Langenbach
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D005260:Female; D020022:Genetic Predisposition to Disease; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011451:Prostaglandin-Endoperoxide Synthases / Q000172:deficiency / Q000235:genetics*; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000235:genetics*; D015854:Up-Regulation; D017968:Vanadium Compounds / Q000633:toxicity
chemical_list: D007527:Isoenzymes; D017968:Vanadium Compounds; C066075:vanadium pentoxide; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone