Nitrite dependent protection against Cl2 gas toxicity_role of chlorinated lipids

University Of Alabama At Birmingham, Birmingham AL

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Abstract

DESCRIPTION (provided by applicant): Chlorine (Cl2) gas mediated injury is complex involving a direct toxicity that occurs during the exposure and a robust post exposure toxicity that occurs over hrs-days to the airways, pulmonary and systemic vasculature. Preliminary data and our recently published studies show that injury post Cl2 exposure includes significant decreases in NO-bioavailability as indexed by diminution of eNOS-dependent vasodilation in the pulmonary and extrapulmonary vasculature and demonstration that post Cl2 exposure administration of nitrite (an NO- repleting strategy) by a single IM injection, protects against acute lung injury, airway hyper-reactivity and importantly, mortality. In this proposal we will i) establish a therapeutic framework for the development for the use of nitrite as a post exposure therapeutic that can be administered in mass casualty scenarios. How post- Cl2 gas injury occurs is unclear. We show novel data that Cl2 gas increases lung and circulating chlorinated lipids (Cl-lip), which are ?-chloro fatty acids derived from plasmalogens. Cl-lip may serve as novel biomarkers for Cl2 exposure, but we also provide evidence that these species can themselves cause acute lung injury and airway epithelial cell dysfunction. Importantly, Cl-lip dependent toxicity can also be prevented by post-exposure nitrite therapy. Taken together, we hypothesize that Cl-lip are novel biomarkers and mediators of post Cl2 gas toxicity and that post-exposure nitrite therapy will attenuate Cl2 gas and Cl-lip dependent toxicity and will test this via the following Specific Aims: 1. Determine the role of Cl-lip in mediating Cl2 gas induced toxicity, 2. Determine optimal nitrite therapeutic conditions for attenuating lethal and sub-lethal Cl2 gas toxicity, 3. Determine safety / toxicology profiles for IM nitrite administration under GLP conditions. A combination of in vivo Cl2 gas exposure with ex vivo studies is proposed. We feel this research is both timely and important and anticipate will yield novel insights into molecular mechanisms of Cl2 gas toxicity and identify and develop therapeutic (countermeasure) strategies.