title: Enhanced peroxynitrite decomposition protects against experimental obliterative bronchiolitis.
abstract: Obliterative bronchiolitis (OB) affects over half of all survivors following lung or heart-lung transplantation. Respiratory epithelial cell injury, peribronchial inflammation, and proliferation of fibrovascular tissue causing airway occlusion characterize the lesion. While peroxynitrite is known to participate in other models of acute lung injury, its role in the evolution of OB is unclear. Using a rat model of experimental OB, tracheas from Brown-Norway or Lewis rats were transplanted into Lewis recipients. Treated animals received FP-15, a peroxynitrite decomposition catalyst, at 1 mg/kg/day intraperitoneal for 14 days. Luminal obstruction, epithelial loss, and inflammatory infiltrate were examined, as was nitrotyrosine staining by immunohistochemistry in explanted tracheas. By postoperative day 14, control allografts demonstrated marked peribronchial inflammation, near complete loss of respiratory epithelium and extensive intraluminal proliferation of fibrovascular connective tissue, with a mean 83% reduction in airway cross-sectional area. Allograft recipients treated with FP-15 showed reduced nitrotyrosine formation, preservation of respiratory epithelium, limited peribronchial inflammation, and only 14% (P <.001) reduction in airway cross-sectional area. Peroxynitrite therefore appears to play a role in the development of obliterative bronchiolitis in rats. The peroxynitrite decomposition catalyst, FP-15, is protective when administered daily and warrants investigation into its potential clinical utility.
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, University of Washington, Box 356310, 1959 NE Pacific St., Seattle, WA 98195, USA.
authors.forename: Babu V
authors.initials: BV
authors.lastname: Naidu
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Farivar
authors.forename: Steven M
authors.initials: SM
authors.lastname: Woolley
authors.forename: Charles
authors.initials: C
authors.lastname: Fraga
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Salzman
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabo
authors.forename: John T
authors.initials: JT
authors.lastname: Groves
authors.forename: Michael S
authors.initials: MS
authors.lastname: Mulligan
mesh_terms: D000818:Animals; D001989:Bronchiolitis Obliterans / Q000503:physiopathology* / Q000517:prevention & control; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D023421:Models, Animal; D030421:Peroxynitrous Acid / Q000378:metabolism*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014132:Trachea / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: C471469:FeCl tetrakis-2-(triethyleneglycolmonomethylether)pyridylporphyrin; D008665:Metalloporphyrins; D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D014443:Tyrosine