Nitrite therapy prevents chlorine gas toxicity in rabbits

•Chlorine gas induces acute lung injury and death in rabbits.•Post-chlorine exposure administration of IM nitrite improves 18 h survival.•Post-chlorine exposure administration of IM nitrite prevents lung leak and airway accumulation of neutrophils.

Chlorine (Cl2) gas exposure and toxicity remains a concern in military and industrial sectors. While post-Cl2 exposure damage to the lungs and other tissues has been documented and major underlying mechanisms elucidated, no targeted therapeutics that are effective when administered post-exposure, and which are amenable to mass-casualty scenarios have been developed. Our recent studies show nitrite administered by intramuscular (IM) injection post-Cl2 exposure is effective in preventing acute lung injury and improving survival in rodent models. Our goal in this study was to develop a rabbit model of Cl2 toxicity and test whether nitrite affords protection in a non-rodent model. Exposure of New Zealand White rabbits to Cl2 gas (600 ppm, 45 min) caused significant increases in protein and neutrophil accumulation in the airways and ∼35% mortality over 18 h. Nitrite administered 30 min post Cl2 exposure by a single IM injection, at 1 mg/kg or 10 mg/kg, prevented indices of acute lung injury at 6 h by up to 50%. Moreover, all rabbits that received nitrite survived over the study period. These data provide further rationale for developing nitrite as post-exposure therapeutic to mitigate against Cl2 gas exposure injury.