Cl(2) gas toxicity is complex and occurs during and after exposure, leading to
acute lung injury (ALI) and reactive airway syndrome (RAS). Moreover, Cl(2) 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 (1 mg/kg) to decrease ALI when administered to rats via intraperitoneal (ip) or intramuscular (im) injection 30 min after Cl(2) exposure. Exposure of rats to Cl(2) gas (400 ppm, 30 min) 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 Cl(2)-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 Cl(2)-exposed rats. Both ip and im
nitrite improved airway histology compared to Cl(2) 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 Cl(2) 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-Cl(2) 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 Cl(2)-dependent lung permeability and
inflammation. These data highlight the potential for
nitrite as a postexposure therapeutic for Cl(2) gas-induced
lung injury and also suggest that administration modality is a key consideration in
nitrite therapeutics.