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Principal Investigator: Leikauf, George Douglas
Institute Receiving Award University Of Pittsburgh At Pittsburgh
Location Pittsburgh, PA
Grant Number U01ES015675
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 29 Sep 2006 to 30 Jun 2022
DESCRIPTION (provided by applicant): 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.
Science Code(s)/Area of Science(s) Primary: 37 - Counter-Terrorism
Secondary: 01 - Basic Cellular or Molecular processes
Publications See publications associated with this Grant.
Program Officer Srikanth Nadadur
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