title: Nitrite therapy improves survival postexposure to chlorine gas.
abstract: Exposure to relatively high levels of chlorine (Cl₂) gas can occur in mass-casualty scenarios associated with accidental or intentional release. Recent studies have shown a significant postexposure injury phase to the airways, pulmonary, and systemic vasculatures mediated in part by oxidative stress, inflammation, and dysfunction in endogenous nitric oxide homeostasis pathways. However, there is a need for therapeutics that are amenable to rapid and easy administration in the field and that display efficacy toward toxicity after chlorine exposure. In this study, we tested whether nitric oxide repletion using nitrite, by intramuscular injection after Cl₂ exposure, could prevent Cl₂ gas toxicity. C57bl/6 male mice were exposed to 600 parts per million Cl₂ gas for 45 min, and 24-h survival was determined with or without postexposure intramuscular nitrite injection. A single injection of nitrite (10 mg/kg) administered either 30 or 60 min postexposure significantly improved 24-h survival (from ∼20% to 50%). Survival was associated with decreased neutrophil accumulation in the airways. Rendering mice neutropenic before Cl₂ exposure improved survival and resulted in loss of nitrite-dependent survival protection. Interestingly, female mice were more sensitive to Cl₂-induced toxicity compared with males and were also less responsive to postexposure nitrite therapy. These data provide evidence for efficacy and define therapeutic parameters for a single intramuscular injection of nitrite as a therapeutic after Cl₂ gas exposure that is amenable to administration in mass-casualty scenarios.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Jaideep
authors.initials: J
authors.lastname: Honavar
authors.affiliation: Department of Anesthesiology University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Stephen
authors.initials: S
authors.lastname: Doran
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Joo-Yeun
authors.initials: JY
authors.lastname: Oh
authors.affiliation: Department of Medicine University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Chad
authors.initials: C
authors.lastname: Steele
authors.affiliation: Department of Anesthesiology University of Alabama at Birmingham, Birmingham, Alabama; Center for Free Radical Biology and Lung Injury and Repair Center, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Sadis
authors.initials: S
authors.lastname: Matalon
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama; Center for Free Radical Biology and Lung Injury and Repair Center, University of Alabama at Birmingham, Birmingham, Alabama rakeshp@uab.edu.
authors.forename: Rakesh P
authors.initials: RP
authors.lastname: Patel
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D054360:Chemokine CXCL1 / Q000097:blood; D054426:Chemokine CXCL2 / Q000097:blood; D002713:Chlorine / Q000506:poisoning*; D005260:Female; D005739:Gas Poisoning / Q000188:drug therapy*; D005740:Gases / Q000633:toxicity; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D019570:Inhalation Exposure; D008168:Lung / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000008:administration & dosage*; D018384:Oxidative Stress; D012737:Sex Factors
chemical_list: D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D005740:Gases; D009573:Nitrites; D009569:Nitric Oxide; D002713:Chlorine
keywords: acute lung injury; halogen; inflammation; nitric oxide