This proposal presents a translational research strategy to develop a countermeasure to acrolein- induced acute lung injury. Acrolein, an electrophile, is a chemical of high concern due to its pulmonary toxicity and industrial usage. Lethal acrolein exposures have resulted from smoke inhalation and accidental release during transportation. At sites of injury, acrolein adducted proteins and past studies have examined whether nucleophiles could scavenge free acrolein within the cell, thereby preventing macromolecular adduction and the accompanying toxicity. Such acrolein scavengers have been investigated in vitro; while effective before or during acrolein exposure, they have not been successful in post-exposure attempts. In contrast, nucleophilic compounds that trap acrolein carbonyls while adducted to proteins are emerging as effective protection following acrolein exposure in vitro and in vivo. One compound that is a strong nucleophile in clinical use is hydralazine. We present preliminary data that support the use of carbonyl trapping with hydralazine to improve survival and diminish bronchoalveolar lavage protein when administered after acrolein exposure in mice. Hypothesis: Carbonyl trapping of acrolein-protein adducts will impart resistance to acrolein- induced acute lung injury by maintaining epithelial integrity and signaling events that promote epithelial cell function.
Aim 1. To determine the efficacy of the lead compound, hydralazine in vivo.
Aim 2. To assess hydralazine lung pharmacokinetics and safety profiles.
Aim 3. To determine mode of action in vivo Inasmuch as acrolein is a primary mediator of acute lung injury, and there are no mechanism- based therapies available, developing effective therapeutics that can reduce lung injury would have considerable value as a countermeasure. At the successful completion of these studies, we will have developed scientific evidence that supports or refutes the capabilities of the carbonyl trapping for use in protection in delayed pulmonary edema.
Acrolein exposure can be the result of intentional release by terrorists following railroad car derailment, transport truck hijacking, or chemical plant detonation. It is also the major toxic component of smoke that leads to lung injury. Such exposure can lead to delayed pulmonary edema and death. This proposal seeks to advance the development of a drug that can be used to treat victims of acrolein exposure and thereby reduce mortality.
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