Administration of nitrite after chlorine gas exposure prevents lung injury: Effect of administration modality

• Published in: Free radical biology & medicine 2012-10, Vol.53 (7), p.1431-1439
• Main Authors: Samal, Andrey A., Honavar, Jaideep, Brandon, Angela, Bradley, Kelley M., Doran, Stephen, Liu, Yanping, Dunaway, Chad, Steele, Chad, Postlethwait, Edward M., Squadrito, Giuseppe L., Fanucchi, Michelle V., Matalon, Sadis, Patel, Rakesh P.
• Format: Article
• Language: English
• Subjects: Acute Lung Injury - chemically induced; Acute Lung Injury - immunology; Acute Lung Injury - pathology; Acute Lung Injury - prevention & control; Animals; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid - cytology; Bronchoalveolar Lavage Fluid - immunology; Chlorine; epithelium; Free radicals; histology; Inflammation; Inhalation Exposure; Inhaled irritants; Injections, Intramuscular; Injections, Intraperitoneal; leukocytes; Lung; Lung - drug effects; Lung - immunology; Lung - pathology; Male; Methacholine Chloride - administration & dosage; Neutrophils - drug effects; Neutrophils - immunology; Neutrophils - pathology; Nitric oxide; Nitrite; nitrites; permeability; Rats; Rats, Sprague-Dawley; Sodium Nitrite - pharmacology; Sodium Nitrite - therapeutic use; surface proteins; therapeutics; toxicity; xanthine
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2012.08.007

Cl2 gas toxicity is complex and occurs during and after exposure, leading to acute lung injury (ALI) and reactive airway syndrome (RAS). Moreover, Cl2 exposure can occur in diverse situations encompassing mass casualty scenarios, highlighting the need for postexposure therapies that are efficacious and amenable to rapid and easy administration. In this study, we assessed the efficacy of a single dose of nitrite (1mg/kg) to decrease ALI when administered to rats via intraperitoneal (ip) or intramuscular (im) injection 30min after Cl2 exposure. Exposure of rats to Cl2 gas (400ppm, 30min) significantly increased ALI and caused RAS 6–24h postexposure as indexed by BAL sampling of lung surface protein and polymorphonucleocytes (PMNs) and increased airway resistance and elastance before and after methacholine challenge. Intraperitoneal nitrite decreased Cl2-dependent increases in BAL protein but not PMNs. In contrast im nitrite decreased BAL PMN levels without decreasing BAL protein in a xanthine oxidoreductase-dependent manner. Histological evaluation of airways 6h postexposure showed significant bronchial epithelium exfoliation and inflammatory injury in Cl2-exposed rats. Both ip and im nitrite improved airway histology compared to Cl2 gas alone, but more coverage of the airway by cuboidal or columnar epithelium was observed with im compared to ip nitrite. Airways were rendered more sensitive to methacholine-induced resistance and elastance after Cl2 gas exposure. Interestingly, im nitrite, but not ip nitrite, significantly decreased airway sensitivity to methacholine challenge. Further evaluation and comparison of im and ip therapy showed a twofold increase in circulating nitrite levels with the former, which was associated with reversal of post-Cl2 exposure-dependent increases in circulating leukocytes. Halving the im nitrite dose resulted in no effect in PMN accumulation but significant reduction of BAL protein levels, indicating a distinct nitrite dose dependence for inhibition of Cl2-dependent lung permeability and inflammation. These data highlight the potential for nitrite as a postexposure therapeutic for Cl2 gas-induced lung injury and also suggest that administration modality is a key consideration in nitrite therapeutics. [Display omitted] ► Chlorine causes postexposure acute lung injury (ALI) and airway hyperreactivity. ► Intraperitoneal or intramuscular nitrite therapy attenuates Cl2 gas-induced ALI but with distinct dose dependencies. ► The route