title: Role of reactive oxygen and nitrogen species in olfactory epithelial injury by the sulfur mustard analogue 2-chloroethyl ethyl sulfide.
abstract: The inhalation of sulfur mustard (SM) causes substantial deposition in the nasal region. However, specific injury has not been characterized. 2-chloroethyl ethyl sulfide (CEES) is an SM analogue used to model injury and screen potential therapeutics. After the inhalation of CEES, damage to the olfactory epithelium (OE) was extensive. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells were present by 4 hours, and maximal at 18-72 hours. Cleaved caspase 3 immunohistochemistry (IHC) was maximal at 18 hours after the inhalation of 5% CEES. Olfactory marker protein (OMP)-positive olfactory neurons were markedly decreased at 18 hours. IHC-positive cells for 3-nitrotyrosine (3-NT) within epithelium were elevated by 8 hours, waning by 18 hours, and absent by 72 hours. AEOL 10150, a catalytic manganoporphyrin antioxidant, administered both subcutaneously (5 mg/kg) and intranasally (50 μM, "combined treatment"), decreased OE injury. CEES-induced increases in markers of cell death were decreased by combined treatment involving AEOL 10150. CEES-induced changes in OMP and 3-NT immunostaining were markedly improved by combined treatment involving AEOL 10150. The selective inducible nitric oxide synthase inhibitor 1400W (5 mg/kg, subcutaneous), administered 1 hour after inhalation and thereafter every 4 hours (five doses), also reduced OE damage with improved OMP and 3-NT staining. Taken together, these data indicate that reactive oxygen and nitrogen species are important mediators in CEES-induced nasal injury.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado at Denver Health Sciences Center, Denver, USA.
authors.forename: Heidi C
authors.initials: HC
authors.lastname: O'Neill
authors.forename: David J
authors.initials: DJ
authors.lastname: Orlicky
authors.forename: Tara B
authors.initials: TB
authors.lastname: Hendry-Hofer
authors.forename: Joan E
authors.initials: JE
authors.lastname: Loader
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Day
authors.forename: Carl W
authors.initials: CW
authors.lastname: White
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D007124:Immunoenzyme Techniques; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D009151:Mustard Gas / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D009296:Nasal Cavity / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D009831:Olfactory Mucosa / Q000187:drug effects* / Q000293:injuries* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: C472668:AEOL 10150; D000975:Antioxidants; D008665:Metalloporphyrins; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; C031278:2-chloroethyl ethyl sulfide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D009151:Mustard Gas