Chlorine gas is a highly toxic respiratory irritant that is considered a chemical threat agent because of the possibility that it could be released in industrial accidents or terrorist attacks. Acute effects of chlorine inhalation include dyspnea, hypoxemia, pneumonitis, and pulmonary edema. Longer term consequences of chlorine inhalation include pulmonary function impairment and airway structural changes that have been observed in some exposed individuals. We have developed a mouse chlorine inhalation model in which animals develop pulmonary edema, inflammation, airway obstruction, and airway hyperreactivity within one day after exposure. In new studies related to the current application, we have characterized injury and repair of the lung at longer times after chlorine inhalation. We have observed that airways with a partial loss of epithelium are repaired quickly by the proliferation and differentiation of epithelial cells that survive chlorine exposure. In contrast, portions of airways with few surviving epithelial cells are repaired inefficiently, and fibroproliferative lesions develop at such sites within a week after chlorine exposure. This development of airway fibrosis is associated with impaired lung function, including increased respiratory system resistance and airway hyperreactivity to inhaled methacholine. In the current application, we propose to develop countermeasures that can be administered following a chemical attack or accidental release to prevent chlorine-induced airway disease. The hypothesis to be tested in the proposed studies is that inefficient repair of airway epithelium following chlorine lung injury leads to airway fibrosis and impaired lung function;agents that mimic anti-fibrotic effects of airway epithelium or stimulate airway repair will ameliorate chlorin- induced airway disease.
Specific Aim 1 will characterize airway epithelial repair, airway fibrosis, and lung function impairment following chlorine exposure in mice.
Specific Aims 2 -5 will evaluate the efficacy of the following potential countermeasures for the treatment of chlorine-induced airway disease: the prostanoid receptor agonists butaprost and iloprost;the long-lasting ss-agonist formoterol and the type 4 phosphodiesterase inhibitor rolipram;stimulation of plasminogen activation with urokinase-type plasminogen activator or the plasminogen activator inhibitor-1 inhibitor tiplaxtinin;and manipulation of Wnt/ss-catenin signaling with lithium chlorie or pyrvinium.
Specific Aim 6 will involve development of a ferret model of chlorine-induced airway disease and testing of countermeasures in this non-rodent species. The proposed studies are expected to identify a countermeasure for prevention of chronic airway disease that develops as a result of an acute high level exposure to chlorine.

Public Health Relevance

The goal of the proposed experiments is to develop novel ways to treat chronic airway disease caused by acute high level exposure to chlorine gas. This type of research is important because of concerns that U.S. civilians could be adversely affected by the accidental or intentional release of highly toxic chemicals such as chlorine.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZRG1-MDCN-J (50))
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Nadadur, Srikanth
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University of Louisville
Public Health & Prev Medicine
Schools of Public Health
United States
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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
Hoyle, Gary W; Svendsen, Erik R (2016) Persistent effects of chlorine inhalation on respiratory health. Ann N Y Acad Sci 1378:33-40
Mo, Yiqun; Chen, Jing; Humphrey Jr, David M et al. (2015) Abnormal epithelial structure and chronic lung inflammation after repair of chlorine-induced airway injury. Am J Physiol Lung Cell Mol Physiol 308:L168-78
Mo, Yiqun; Chen, Jing; Schlueter, Connie F et al. (2013) Differential susceptibility of inbred mouse strains to chlorine-induced airway fibrosis. Am J Physiol Lung Cell Mol Physiol 304:L92-102
Musah, Sadiatu; Chen, Jing; Hoyle, Gary W (2012) Repair of tracheal epithelium by basal cells after chlorine-induced injury. Respir Res 13:107