Yadav AK, Doran SF, Samal AA, Sharma R, Vedagiri K, Postlethwait EM, Squadrito GL, Fanucchi MV, Roberts LJ 2nd, Patel RP, Matalon S. Mitigation of chlorine gas lung injury in rats by postexposure administration of sodium nitrite.

Chlorine gas (Cl 2 ) exposure during accidents or in the military setting results primarily in injury to the lungs. However, the potential for Cl 2 exposure to promote injury to the systemic vasculature leading to compromised vascular function has not been studied. We hypothesized that Cl 2 promotes extrapulmonary endothelial dysfunction characterized by a loss of endothelial nitric oxide synthase (eNOS)-derived signaling. Male Sprague Dawley rats were exposed to Cl 2 for 30 minutes, and eNOS-dependent vasodilation of aorta as a function of Cl 2 dose (0-400 ppm) and time after exposure (0-48 h) were determined. Exposure to Cl 2 (250-400 ppm) significantly inhibited eNOS-dependent vasodilation (stimulated by acetycholine) at 24 to 48 hours after exposure without affecting constriction responses to phenylephrine or vasodilation responses to an NO donor, suggesting decreased NO formation. Consistent with this hypothesis, eNOS protein expression was significantly decreased (z 60%) in aorta isolated from Cl 2 -exposed versus airexposed rats. Moreover, inducible nitric oxide synthase (iNOS) mRNA was up-regulated in circulating leukocytes and aorta isolated 24 hours after Cl 2 exposure, suggesting stimulation of inflammation in the systemic vasculature. Despite decreased eNOS expression and activity, no changes in mean arterial blood pressure were observed. However, injection of 1400W, a selective inhibitor of iNOS, increased mean arterial blood pressure only in Cl 2 -exposed animals, suggesting that iNOS-derived NO compensates for decreased eNOS-derived NO. These results highlight the potential for Cl 2 exposure to promote postexposure systemic endothelial dysfunction via disruption of vascular NO homeostasis mechanisms.

Cl2 gas toxicity is complex and occurs during, and post exposure leading to acute lung injury (ALI) and reactive airway syndrome (RAS). Moreover, Cl2 exposure can occur in diverse situations encompassing mass casualty scenarios underscoring the need for post-exposure therapies that are efficacious and amenable to rapid and easy administration. In this study, we compared the efficacy of a single dose, post (30min) Cl2 exposure administration of nitrite (1mg/kg) via intraperitoneal (IP) or intramuscular (IM) injection in rats, to decrease ALI. Exposure of rats to Cl2 gas (400ppm, 30min) significantly increased ALI and caused RAS 6–24h post exposure as indexed by BAL sampling of lung surface protein, PMN and increased airway resistance and elastance prior to and post methacholine challenge. IP nitrite decreased Cl2 - dependent increases in BAL protein but not PMN. In contrast IM nitrite decreased BAL PMN levels without decreasing BAL protein in a xanthine oxidoreductase independent manner. Histological evaluation of airways 6h post exposure 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 two-fold 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 of BAL protein levels indicating distinct nitrite dose dependence for inhibition of Cl2 dependent lung permeability and inflammation. These data highlight the potential for nitrite as a post-exposure therapeutic for Cl2 gas induced lung injury and also suggest that administration modality is a key consideration in nitrite therapeutics.

Exposure to chlorine gas (Cl(2)) primarily causes injury to the lung and is characterized by inflammation and oxidative stress mediated by reactive chlorine species. Reducing lung injury and improving respiratory function are the principal therapeutic goals in treating individuals exposed to Cl(2) gas. Less is known on the potential for Cl(2) gas exposure to cause injury to extrapulmonary tissues and specifically to mediate endothelial dysfunction. This concept is forwarded in this article on the basis that (1) many irritant gases whose reactivity is limited to the lung have now been shown to have effects that promote endothelial dysfunction in the systemic vasculature, and as such lead to the acute and chronic cardiovascular disease events (e.g., myocardial infarctions and atherosclerosis); and (2) that endogenously produced reactive chlorine species are now considered to be central in the development of cardiovascular diseases. This article discusses these two areas with the view of providing a framework in which potential extrapulmonary toxic effects of Cl(2) gas exposure may be considered.

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