Chlorine is a potent respiratory and pulmonary irritant that causes concentration-dependent injury after exposure. It is one of the most common substances involved in toxic inhalation. The clinical picture associated with acute chlorine inhalation includes eye and throat irritation in mild exposures, with escalating cardiopulmonary symptoms at higher concentrations. Exposure to massive amounts of chlorine results in profound hypoxemia, dyspnea, bronchoconstriction, acute lung injury, cardiomegaly, and may result in death. Current treatment of acute chlorine gas injury after prompt decontamination is merely symptomatic. The mechanism(s) of injury causing acute mortality after chlorine inhalation are poorly understood and scarcely studied. Injury to the respiratory tract after exposure occurs when inhaled chlorine reacts with water on the surface of mucus membranes and airways, forming hydrochloric acid (HCl) and hypochlorous acid (HOCl), a powerful oxidant. Chlorine also reacts with proteins to form chlorinated derivatives (chloramines), which are long-lived products with considerable oxidizing potential. It is believed that chlorine exerts its toxic effects on human tissue via oxidative properties of chlorine itself, HOCl and chloramines, and also from acidification of respiratory mucosa. However, the mechanism as to how all this would lead to death within minutes to hours of exposure is not known. Recent studies have suggested the involvement of airway irritant sensory receptors, i.e. transient receptor potential (TRP) channels, in propagating injury. New research into the effects of HOCl and chloramines uncovered their potential to modify several vital enzymatic functions, including the inactivation o acetylcholinesterase (AChE). AChE inhibition results in sustained activation of muscarinic receptors, causing symptoms of cholinergic overstimulation, consisting of bronchorrhea, bronchoconstriction, bradycardia, poor cardiac contractility, pulmonary hypertension, systemic vasodilation, and potential for cardiopulmonary failure. All these symptoms have been reported in victims after massive chlorine exposure. Preliminary data from our laboratory confirmed severe AChE inhibition after high dose chlorine exposure in rats, with concurrent signs of `cholinergic toxidrome, often followed by death. Therefore, in addition to oxidative damage from HOCl and chloramines, the inactivation of the AChE enzyme and the resultant parasympathetic/ cholinergic/ muscarinic pathway overstimulation could play a major role in chlorine-induced mortality and morbidity. Our hypothesis is that atropine, an FDA-approved anticholinergic rescue drug, will improve survival and reverse serious morbidity associated with high dose chlorine exposure, with particular improvement in cardiopulmonary function. To test its potential as a single rescue agent, atropine will be given intramuscularly after exposure. We will also evaluate possible underlying mechanisms by which atropine may exert its efficacy in this model. This application will develop practical agent(s) for field rescue after significant chlorine inhalation.

Public Health Relevance

Current treatment plan for high dose chlorine gas inhalation injury is supportive therapy measures, with administration of oxygen, fluids, and bronchodilators. No rescue therapy exists to prevent death from high dose chlorine inhalation, or to improve serious sequelae after exposure. In this project, I propose to study the anticholinergic drug Atropine as rescue therapy in a rat model of high dose chlorine inhalation, administered intramuscularly after exposure, with the goal of improving survival and decreasing morbidity in the acute setting.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-MDCN-B (55))
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Nadadur, Srikanth
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University of Colorado Denver
Schools of Medicine
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Okponyia, Obiefuna C; McGraw, Matthew D; Dysart, Marilyn M et al. (2018) Oxygen Administration Improves Survival but Worsens Cardiopulmonary Functions in Chlorine-exposed Rats. Am J Respir Cell Mol Biol 58:107-116
Summerhill, Eleanor M; Hoyle, Gary W; Jordt, Sven-Eric et al. (2017) An Official American Thoracic Society Workshop Report: Chemical Inhalational Disasters. Biology of Lung Injury, Development of Novel Therapeutics, and Medical Preparedness. Ann Am Thorac Soc 14:1060-1072