Attenuation of half sulfur mustard gas-induced acute lung injury in rats

Abstract

Airway instillation into rats of 2-chloroethyl ethyl sulfide (CEES), the half molecule of sulfur mustard compound, results in acute lung injury, as measured by the leak of plasma albumin into the lung. Morphologically, early changes in the lung include alveolar hemorrhage and fibrin deposition and the influx of neutrophils. Following lung contact with CEES, progressive accumulation of collagen occurred in the lung, followed by parenchymal collapse. The co-instillation with CEES of liposomes containing pegylated (PEG)-catalase (CAT), PEG-superoxide dismutase (SOD), or the combination, greatly attenuated the development of lung injury. Likewise, the co-instillation of liposomes containing the reducing agents, N-acetylcysteine (NAC), glutathione (GSH), or resveratrol (RES), significantly reduced acute lung injury. The combination of complement depletion and airway instillation of liposomes containing anti-oxidant compounds maximally attenuated CEES-induced lung injury by nearly 80%. Delayed airway instillation of anti-oxidant-containing liposomes (containing NAC or GSH, or the combination) significantly diminished lung injury even when instillation was delayed as long as 1 h after lung exposure to CEES. These data indicate that CEES-induced injury of rat lungs can be substantially diminished by the presence of reducing agents or anti-oxidant enzymes delivered via liposomes.

Airway Obstruction Due to Bronchial Vascular Injury after Sulfur Mustard Analog Inhalation

“…Gaps or voids within the epithelial layer were never found after ethanol exposure. When naive rat airways were examined, we found occasional single EthD-1-positive cells within all distal pathways (generations [22][23][24][25], but none within the proximal pathways ( Figure 8A). No defects within the epithelial layer were seen in naive rats.…”

“…2-Chloroethyl ethyl sulfide (CEES) is a surrogate agent used to mimic SM injury in laboratories (22,23). It is less toxic than SM because of the absence of one of two terminal chloride groups (that cross-link DNA and proteins), and because of its considerably shorter half-life in aqueous solution.…”

“…It is less toxic than SM because of the absence of one of two terminal chloride groups (that cross-link DNA and proteins), and because of its considerably shorter half-life in aqueous solution. Although safer to handle than SM, CEES possesses many of the same damaging properties as an alkylating agent (22,23) as does SM, making it suitable for use in experiments to mimic SM-induced respiratory tract injury without the need for a specialized containment facility. In this article, we provide an animal model for potentially fatal airway obstruction seen acutely after SM…”

Ebselen Analogues Reduce 2-chloroethyl Ethyl Sulphide Toxicity in A-431 Cells

“…RES has been found in at least one in vivo study to protect the lungs from mustard injury (8). This discrepancy may be due to the cell type tested here or to not having used a high enough concentration of the stilbene.…”

“…Oxidative stress can lead to cell death when the production of reactive oxygen (ROS) and/or reactive nitrogen oxide species (RNOS) exceeds the capacity of cellular antioxidant defence mechanisms (5,6). In recent years, the idea of using antioxidants to decrease the toxicity of vesicants has gained momentum through results obtained from in vivo (7,8) and in vitro studies (9)(10)(11)(12). While these antioxidants may serve as effective countermeasures to mustard toxicity in various experimental models, none of them have evolved into an effective therapy to date.…”