Mitigation of Chlorine Injury to Mitochondria

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Chlorine (Cl2) is an irritant and reactive gas produced in large quantities throughout the world. Humans and animals exposed to Cl2 from industrial accidents or acts of terrorism, develop severe reactive airway disease, pulmonary edema and even death from respiratory failure. Those that survive are at risk of developing chronic lung diseases, such as pulmonary fibrosis and emphysema and be susceptive to infections. However, the mechanism(s) involved and the countermeasures required to ameliorate acute and chronic lung injury remain elusive. Herein we show that exposure of mice to Cl2 damages their mitochondria DNA (mtDNA) that administration of the DNA repair enzyme, 8-oxoguanine-DNA glycosylase 1 (OGG1), attached to the mitochondrial targeting signal (mitoOGG1 or OGG1 fusion protein) ameliorated mitochondrial dysfunction and Cl2-induced acute and chronic lung injury. The goals of our R21 application are: (1) to establish that exposure of mice to Cl2 damages their mtDNA; (2) administration of mitoOGG1 post Cl2 exposure decrease acute and chronic lung injury and mortality by repairing mtDNA and (3) that mitoOGG1 repairs the mitochondria bioenergetics in vitro. These hypotheses will be tested by completing the comprehensive set of experiments outlined in the following two Specific Aims: 1. Assess the efficacy of mitoOGG1 administered in mice post Cl2 exposure to decreases acute lung injury, mortality and the development of pulmonary fibrosis in vivo. 2. To demonstrate that mitoOGG1, administered to lung cells post Cl2 exposure in vitro, reverses, or at least mitigates, mitochondria bioenergetics and cell injury by repairing their mtDNA. Injury to mtDNA will compromise mitochondria respiration and membrane potential resulting in apoptosis and necrosis. mitoOGG1, administered post-heme, will reverse, or at least mitigate, these effects by repairing mtDNA. Previous studies have shown that injury to mtDNA plays a key role in the development of acute lung injury. Overexpression of mitoOGG1 attenuated mtDNA damage and preserved cardiac function in heart failure), protected against ventilator-induced lung injury in intact mice and limited human lung injury after circulatory death. Thus, these published studies, in addition to our highly exciting preliminary data, indicated that mitoOGG1 may prove to be a therapeutic for acute and chronic lung injury in patients exposed to Cl2, as well as other halogens (such as Bromine) and chlorine-containing compounds (such as Phosgene). These studies combine the expertise of two senior investigators (Drs. Matalon and Gillespie) with significant expertise in Cl2 induced lung injury and repair and mitochondrial function.