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

Abstract

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.

Hyaluronan mediates airway hyperresponsiveness in oxidative lung injury

“…There are of course significant differences between Cl 2 and ozone gas toxicity, with respect to acute symptoms, airway penetration, and sequelae (70,73). Nevertheless, both agents cause significant oxidative injury to airway epithelium and increase airway resistance and hyperresponsiveness to methacholine, which last for days postexposure (2,15,21,23,30,60,65,67); furthermore, workers exposed to ozone or chlorine both report a significant increase in acute wheezing episodes (27). In both cases there is increased generation of reactive intermediates, which lasts after the cessation of exposure.…”

Formation of chlorinated lipids post-chlorine gas exposure

“…From 20 s up to 3 min after each aerosol challenge, resistance (centimeters of water per milliliter per second) and elastance (centimeters of water per milliliter) were recorded continuously, as previously described (38).…”

Nitrite therapy improves survival postexposure to chlorine gas

“…This is followed by a postexposure injury phase occurring over a time span ranging from days to months, which affects the airways and pulmonary and systemic vasculature (9,11,20,25,26,30,37). Clinically, this presents as reactive airway syndrome, hypoxemia, noncardiogenic edema leading to acute lung injury, and development of acute respiratory distress syndrome, which chronically leads to reactive airway disease, increased sensitivity to pulmonary infections, fibrosis, and bronchiolitis obliterans, as well as dermal injury (9,10,12,17,24,26,28,30). Exciting recent studies are providing insights into the postexposure mechanisms that include increased oxidative stress, neurogenic and airway inflammation, fibrosis, loss of nitric oxide (NO) signaling homeostasis, and loss of endogenous airway repair mechanisms (2, 9 -11, 15, 20, 22, 25, 26, 36).…”

“…Exciting recent studies are providing insights into the postexposure mechanisms that include increased oxidative stress, neurogenic and airway inflammation, fibrosis, loss of nitric oxide (NO) signaling homeostasis, and loss of endogenous airway repair mechanisms (2, 9 -11, 15, 20, 22, 25, 26, 36). This information has led to the testing and demonstration of efficacy for antioxidant therapy (9,16,22,23,37), anti-inflammatory (using corticosteroids) treatment (5), ␤2-agonists (29), phosphodiesterase inhibitors (4), transient receptor potential channel inhibitors (1,2), and strategies that improve NO bioavailability (28,36).…”