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 #
5U54ES015678-08
Application #
8535759
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
$333,525
Indirect Cost
$149,746
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Day, Brian J (2014) Antioxidant therapeutics: Pandora's box. Free Radic Biol Med 66:58-64
Tewari-Singh, Neera; Inturi, Swetha; Jain, Anil K et al. (2014) Catalytic antioxidant AEOL 10150 treatment ameliorates sulfur mustard analog 2-chloroethyl ethyl sulfide-associated cutaneous toxic effects. Free Radic Biol Med 72:285-95
Jain, Anil K; Tewari-Singh, Neera; Inturi, Swetha et al. (2014) Myeloperoxidase deficiency attenuates nitrogen mustard-induced skin injuries. Toxicology 320:25-33

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