Sulfur mustard (HD, mustard gas) is the most highly utilized chemical weapon in history, and currently it poses a serious threat to both military and civilian populations. In addition to stockpiles, HD remains one of the easiest chemical weapons to make in large quantities, and it is included in the list of likely choices for terrorist organizations. HD can be a severely debilitating agent for those exposed to it. The primary organs affected by HD are the lungs, skin and eyes. It results in acute airway edema, ARDS, bronchopneumonia, tracheobronchomalacia and/or airway stenosis, bronchiolitis obliterans, bronchiectasis, pulmonary fibrosis, asthma, and other respiratory complications. There are no specific treatments or antidotes for HD nor preventive medications to minimize its effects. Decontamination and supportive care are the only interventions recommended by current medical guidelines and more of these protect the airways. Decontamination is effective for skin and eyes only if enacted very early (< 5 minutes). Unfortunately, recognition of the problem usually does not occur within this timeframe. We hypothesize that supplementation or augmentation of airway mono- or dithiols will prevent or limit sulfur mustard toxicity. Using an animal model employing 2-chloroethyl ethyl sulfide (CEES, """"""""half-mustard""""""""), a less toxic analog of sulfur mustard, we will: 1) Determine airway inflammation, pro-inflammatory cytokines, and principal thiols following half-mustard aerosolization in rat, 2) evaluate effectiveness of oral and aerosolized mono- (GSH) and dithiols (lipoic acid, thioredoxin) in attenuating halfmustard lung injury (inflammation, cytokines, thiols), 3) develop novel compounds to stimulate mono- and dithiol efflux into lung epithelial lining fluid, and 4) examine the efficacy of these novel compounds in vivo. The latter studies will help us establish optimal compounds, route and mode of delivery, pharmacokinetics, bioavailability, and toxicology. Our laboratories have exceptional experience in measurement of the relevant, potentially protective thiol compounds to be evaluated. We anticipate these studies will lead to testing of the most effective compounds using authentic mustard gas at appropriate facilities. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
1U54ES015678-01
Application #
7225100
Study Section
Special Emphasis Panel (ZNS1-SRB-R (23))
Program Officer
Maull, Elizabeth A
Project Start
2006-09-29
Project End
2011-05-31
Budget Start
2006-09-29
Budget End
2007-05-31
Support Year
1
Fiscal Year
2006
Total Cost
$1,541,273
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
Rancourt, Raymond C; Rioux, Jacqueline S; Veress, Livia A et al. (2018) Methyl isocyanate inhalation induces tissue factor-dependent activation of coagulation in rats. Drug Chem Toxicol :1-7
McGraw, Matthew D; Osborne, Christopher M; Mastej, Emily J et al. (2017) Editor's Highlight: Pulmonary Vascular Thrombosis in Rats Exposed to Inhaled Sulfur Mustard. Toxicol Sci 159:461-469
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
Ghosh, Moumita; Ahmad, Shama; White, Carl W et al. (2017) Transplantation of Airway Epithelial Stem/Progenitor Cells: A Future for Cell-Based Therapy. Am J Respir Cell Mol Biol 56:1-10
McElroy, Cameron S; Min, Elysia; Huang, Jie et al. (2016) From the Cover: Catalytic Antioxidant Rescue of Inhaled Sulfur Mustard Toxicity. Toxicol Sci 154:341-353
White, Carl W; Rancourt, Raymond C; Veress, Livia A (2016) Sulfur mustard inhalation: mechanisms of injury, alteration of coagulation, and fibrinolytic therapy. Ann N Y Acad Sci 1378:87-95
Tewari-Singh, Neera; Agarwal, Rajesh (2016) Mustard vesicating agent-induced toxicity in the skin tissue and silibinin as a potential countermeasure. Ann N Y Acad Sci 1374:184-92
McElroy, Cameron S; Day, Brian J (2016) Antioxidants as potential medical countermeasures for chemical warfare agents and toxic industrial chemicals. Biochem Pharmacol 100:1-11
Houin, Paul R; Veress, Livia A; Rancourt, Raymond C et al. (2015) Intratracheal heparin improves plastic bronchitis due to sulfur mustard analog. Pediatr Pulmonol 50:118-26
Veress, Livia A; Anderson, Dana R; Hendry-Hofer, Tara B et al. (2015) Airway tissue plasminogen activator prevents acute mortality due to lethal sulfur mustard inhalation. Toxicol Sci 143:178-84

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