Novel Treatments of Acrolein-induced Cardiotoxicity The overall goal of this project is to develop new and improved countermeasures and therapeutics for preventing human mortality and morbidity associated with chemical threats. Such threats might be imposed by a terrorist attack, accidental leakage of chemicals used in industrial production, or those released during natural disasters and fires. The most common and abundant reactive chemicals, relevant to all these situations are reactive carbonyl compounds (RCCs). A prototypical member of this class is acrolein. Acrolein and related RCCs are the most abundant and toxic constituents generated in lethal amounts (600 ppm) during forest and structural fires. Profound respiratory and cardiovascular effects of exogenous and endogenous RCCs have also been described;however, neither the toxicological effects of RCCs nor their mechanisms of toxicity have been systematically delineated. Similarly, the specific vulnerability of young, old and women to RCC exposure has not been assessed. Most importantly, no effective countermeasures or therapeutic interventions are currently available. Possible therapeutic interventions include treatment with inhibitors of RCC receptors known as transient receptor potential (TRP) channels. These antagonists including TRPV1 and TRPA1 inhibitors hold promise to diminish the pain and inflammation in the cardiovascular and pulmonary systems associated with high dose exposure to RCC. Evaluation of mitigation therapies following high level RCC exposure will provide the first step in judging their relative efficacy for use in the case of a chemical emergency threat in humans.

Public Health Relevance

Profound respiratory and cardiovascular effects of exogenous and endogenous reactive carbonyl compounds (RCCs), such as acrolein, have been described;yet, neither the toxicological effects of RCCs nor their mechanisms of toxicity have been systematically delineated. Moreover, the specific vulnerability of the young, old, and females to inhaled RCCs, including acrolein, has not been assessed. Possible therapeutic interventions include treatment with known transient receptor potential (TRP) channel inhibitors including TRPA1 and TRPV1 antagonists, and evaluation of mitigation therapy following high level RCC exposure will provide the first step in judging their efficacy in the case of a chemical emergency threat in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21ES024030-01
Application #
8610016
Study Section
Special Emphasis Panel (ZRG1-MDCN-B (55))
Program Officer
Nadadur, Srikanth
Project Start
2013-09-24
Project End
2015-08-31
Budget Start
2013-09-24
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$375,000
Indirect Cost
$125,000
Name
University of Louisville
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
O'Toole, Timothy E; Abplanalp, Wesley; Li, Xiaohong et al. (2014) Acrolein decreases endothelial cell migration and insulin sensitivity through induction of let-7a. Toxicol Sci 140:271-82