One of the primary concerns with exposure to sulfur mustard or chlorine gas is acute damage to upper and lower respiratory tract, particulariy the epithelia of the upper respiratory mucus membranes. The acute damage can lead to severe pulmonary edema, pneumonia, hyaline membrane formation, multiple pulmonary thromboses, and ulcerative tracheobronchitis. Currently there is a lack of effective therapies to mitigate either sulfur mustard or chlorine gas-induced lung injury. Reactive oxygen species (ROS) play an important role in this chemical warfare agent-induced acute lung injury. My laboratory has extensively studied manganese porphyrins and demonstrated them to be efficient scavengers of superoxide (O2'), hydrogen peroxide (H2O2), lipid peroxides (LOOH) and peroxynitrite (ONOO). Manganese porphyrins are highly effective against a variety of intracellular oxidative stress models and particulariy effective in the mitochondria. Our previous work during the last 5 years has provided a lead manganese porphyrin candidate, AEOL 10150, with some preliminary proof of principle studies showing its ability to mitigate acute lung injury in sulfur mustard and chlorine lung injury models. Another attractive feature of AEOL 10150 is its safety profile with completed GLP chronic safety studies in mice and monkeys and is presently in phase I clinical safety trials in humans. Another attractive feature is its ability to be a broad use lung mitigation agent against two inhaled chemicals and radiation. In the previous funding cycle, we used the sulfur mustard analog CEES to develop a rat lung injury model and identify a lead catalytic antioxidant candidate. In addition, from the use of supplements we were able to obtain preliminary data indicating possible efficacy of AEOL 10150 in sulfur mustard and chlorine gas-induced lung injury. A number of remaining issues need to be examined in the next cycle including: 1) optimizing the dose and dose regimen of AEOL 10150 in sulfur mustard and chlorine gas-induced lung injury;2) establishing the window of opportunity for AEOL 10150 treatment in these models;3) determining the effective length of treatment with AEOL 10150 in these models;and 4) clearly establishing a mechanism of oxidative stress in the pathophysiologic processes associated with the acute lung injury in these animal models. The next five years will be devoted to these studies that will set the stage for pivotal efficacy studies needed for regulatory FDA approval using the two animal mle.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
3U54ES015678-08W1
Application #
8737372
Study Section
Special Emphasis Panel (ZRG1-MDCN-J)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
8
Fiscal Year
2013
Total Cost
$23,921
Indirect Cost
$2,276
Name
University of Colorado-Denver
Department
Type
DUNS #
City
State
Country
Zip Code
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
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
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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
Ahmad, Shama; Ahmad, Aftab; Hendry-Hofer, Tara B et al. (2015) Sarcoendoplasmic reticulum Ca(2+) ATPase. A critical target in chlorine inhalation-induced cardiotoxicity. Am J Respir Cell Mol Biol 52:492-502
Kumar, Dileep; Tewari-Singh, Neera; Agarwal, Chapla et al. (2015) Nitrogen mustard exposure of murine skin induces DNA damage, oxidative stress and activation of MAPK/Akt-AP1 pathway leading to induction of inflammatory and proteolytic mediators. Toxicol Lett 235:161-71
Goswami, Dinesh G; Kumar, Dileep; Tewari-Singh, Neera et al. (2015) Topical nitrogen mustard exposure causes systemic toxic effects in mice. Exp Toxicol Pathol 67:161-70
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
Jain, Anil K; Tewari-Singh, Neera; Inturi, Swetha et al. (2015) Flavanone silibinin treatment attenuates nitrogen mustard-induced toxic effects in mouse skin. Toxicol Appl Pharmacol 285:71-8

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