Chlorine (Cl2) is a highly irritant and reactive gas produced in large quantities throughout the world and used extensively for pulp bleaching, waste sanitation and in the manufacturing of various pharmaceuticals. It also poses a significant threat to public health when inhaled. Exposure to Cl2, released into the atmosphere during transportation and industrial accidents, as well as acts of terrorism resulted in significant morbidity and mortality to both humans and animals. There is no safe exposure to Cl2: Even domestic exposure to low levels of Cl2 may result in wheezing and exacerbate the clinical outcome of asthma and chronic obstructive pulmonary disease. When inhaled, Cl2 first reacts with antioxidants in the lung epithelial lining fluid (ELF);when antioxidants are depleted, it fors relatively stable adducts with proteins, components of the extracellular matrix and unsaturated fatty acids which then proceed to prolong the toxicity of the initial Cl2 exposure and contribute t the long term pathology. In this proposal we will test the hypothesis that these secondary reactive species target the mitochondrion and so decrease mitochondrial quality and cause bioenergetic dysfunction which delays tissue recovery and repair. Based upon these data we hypothesize that mitochondria are a critical target for Cl2 toxicity in lung epithelial cells and te combined strategy of preventing mitochondrial oxidative damage by mitochondrial targeted antioxidants (such as MitoQ) with enhancing mitophagy (by rapamycin and trehalose), will be beneficial in ameliorating Cl2 toxicity. This hypothesis will be tested by completing the in vitro and in vivo studies highlighted in these two highly integrated specific aims: SA-1: Determine the mechanisms and physiological sequelae of mitochondria injury and autophagy following exposure of human airway cells to Cl2 in vitro. SA-2: Determine if post Cl2 administration of MitoQ, rapamycin and trehalose in mice decreases Cl2 induced mortality and lung injury and improves mitochondrial bioenergetics function. Completion of these experiments will provide the rational basis for additional studies to establish effective therapies for a major environmental and public health threat to humans.

Public Health Relevance

Chlorine (Cl2) is a highly irritant and reactive gas which poses significant threat to public health when inhaled. We found that chlorine damages the mitochondria which are responsible for generating ATP, the fuel that is necessary for all metabolic functions. We propose to use three treatments to limit injury to the mitochondria thus decreasing the toxicity of chlorine to humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21ES024027-01
Application #
8608361
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
$367,500
Indirect Cost
$117,500
Name
University of Alabama Birmingham
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Aggarwal, Saurabh; Lam, Adam; Bolisetty, Subhashini et al. (2016) Heme Attenuation Ameliorates Irritant Gas Inhalation-Induced Acute Lung Injury. Antioxid Redox Signal 24:99-112
Bali, Vedrana; Lazrak, Ahmed; Guroji, Purushotham et al. (2016) A synonymous codon change alters the drug sensitivity of ?F508 cystic fibrosis transmembrane conductance regulator. FASEB J 30:201-13
Lam, Adam; Vetal, Nilam; Matalon, Sadis et al. (2016) Role of heme in bromine-induced lung injury. Ann N Y Acad Sci 1374:105-10
Carlisle, Matthew; Lam, Adam; Svendsen, Erik R et al. (2016) Chlorine-induced cardiopulmonary injury. Ann N Y Acad Sci 1374:159-67
Bali, Vedrana; Lazrak, Ahmed; Guroji, Purushotham et al. (2016) Mechanistic Approaches to Improve Correction of the Most Common Disease-Causing Mutation in Cystic Fibrosis. PLoS One 11:e0155882
Surolia, Ranu; Karki, Suman; Kim, Hyunki et al. (2015) Heme oxygenase-1-mediated autophagy protects against pulmonary endothelial cell death and development of emphysema in cadmium-treated mice. Am J Physiol Lung Cell Mol Physiol 309:L280-92
Song, Weifeng; Yu, Zhihong; Doran, Stephen F et al. (2015) Respiratory syncytial virus infection increases chlorine-induced airway hyperresponsiveness. Am J Physiol Lung Cell Mol Physiol 309:L205-10
Matalon, Sadis; Bartoszewski, Rafal; Collawn, James F (2015) Role of epithelial sodium channels in the regulation of lung fluid homeostasis. Am J Physiol Lung Cell Mol Physiol 309:L1229-38
Lazrak, Ahmed; Creighton, Judy; Yu, Zhihong et al. (2015) Hyaluronan mediates airway hyperresponsiveness in oxidative lung injury. Am J Physiol Lung Cell Mol Physiol 308:L891-903
Jurkuvenaite, Asta; Benavides, Gloria A; Komarova, Svetlana et al. (2015) Upregulation of autophagy decreases chlorine-induced mitochondrial injury and lung inflammation. Free Radic Biol Med 85:83-94

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