Oxidative damage to lung mitochondrial DNA is a key contributor to the development of chemical lung injury

Abstract

Humans exposed to chlorine (Cl₂) due to industrial accidents or acts of terrorism may develop lung injury culminating to Acute Respiratory Distress syndrome and death from respiratory failure. Early molecular targets of inhaled oxidant gases suitable for pharmacologic modulation have not been established. Because the mitochondrial genome is highly sensitive to oxidant stress, we tested the hypothesis that mice exposure to Cl₂ gas causes oxidative damage to the mitochondrial DNA (mtDNA) that triggers the development of acute and chronic lung injury. Cl₂ gas-exposed C57BL/6 mice and returned to room air, developed progressive loss of lung DNA glycosylase OGG1, followed by oxidative mtDNA damage. This resulted in activation of inflammatory pathways by circulating DNA, progressive increased airway resistance, alveolar injury and acute pulmonary edema due to loss of epithelial amiloride-sensitive sodium channels. Mice not succumbing acutely displayed a delayed syndrome of progressive increase in airway resistance and emphysematous-like changes in lung morphology. Global proteomics of lungs harvested 24 h post Cl₂ exposure revealed alterations in over 1500 lung proteins, including 14 key mitochondrial proteins. Intranasal instillation of a recombinant protein targeting OGG1 to mitochondria (mitoOGG1) at 1 h post exposure decreased oxidized lung mtDNA, alterations to the lung and mitochondrial proteomes, severity of the acute and delayed lung injury and increased survival. These data show that injury to the mt-genome is a key contributor to the development of acute and chronic lung injury after Cl₂ gas exposure and point to mtDNA oxidation as a target for pharmacologic intervention.