Accidental leaks from manufacturing plants are common and large groups of people may be exposed to high halogen (Cl2/Br2) concentrations. Use of halogen gases as chemical weapons is also on the rise. Victims of accidental bromine exposure experience respiratory distress, cardiac arrest and circulatory collapse. Studies evaluating acute and chronic sequelae of Br2 exposure are scant and treatment remains symptomatic as no effective countermeasures exist. Our studies have established that the heart is severely injured in animals that survive high dose halogen (Cl2/Br2) inhalation. The purpose of this application is to identify the biological mechanisms responsible for these events and develop appropriate countermeasures. Based on exciting preliminary data we propose that brominated reactants such as brominated lipids are produced in the lungs. Brominated reactants/lipids reach the heart along with oxygenated blood. These reactants inactivate important calcium pumps that regulate the heartbeats. Inactivity of calcium pumps causes calcium accumulation or ?calcium overload? in the heart cells. Calcium overload is a serious problem and can lead to sudden cardiac death. Increased calcium also activates destructive proteins, the calpains that destroy cardiac ultrastructure. We therefore hypothesize that Br2 inhalation produces highly reactive intermediates that activate Ca2+ sensitive calpains leading to cytoskeletal and mitochondrial damage and myocardial dysfunction and that calpain inhibition will mitigate Br2-induced cardiopulmonary dysfunction and death. These hypotheses will be tested by completing the experiments outlined in the following specific aims. SA#1: Characterize cardiac injury and death induced by Br2 inhalation. SA#2: Test the hypothesis that Br2 and Br2 reactants activate cardiac calpains and cause cytoskeletal and mitochondrial damage. SA#3: Test whether calpain inhibitor based countermeasures mitigate acute and chronic effects caused by Br2 inhalation. The outcome from this project will identify an effective antidote for bromine toxicity and enhance readiness for emergencies arising from accidental or intentional exposures.

Public Health Relevance

The proposed research is relevant to public health because new treatment strategies for halogen inhalation- induced toxicity are desperately needed. Halogen gases such as bromine are highly reactive, corrosive `inhalational' threat agent that can spread both as liquid and as fumes. Inhalation of bromine causes extensive injury to the lungs and the heart. Our goals are to identify the biochemical and molecular mechanisms responsible for these injuries and develop effective countermeasures.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01ES028182-02S1
Application #
9786606
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Nadadur, Srikanth
Project Start
2017-08-15
Project End
2020-07-31
Budget Start
2018-09-20
Budget End
2019-07-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294