A Role for Mitochondrial Oxidative Stress in Sulfur Mustard Analog 2-Chloroethyl Ethyl Sulfide-Induced Lung Cell Injury and Antioxidant Protection
- Departments of Pharmaceutical Sciences (N.S.G., C.W.W., B.J.D.), Medicine (B.J.D.), and Immunology (B.J.D.), University of Colorado Health Sciences Center, Denver, Colorado; and Departments of Pediatrics (C.W.) and Medicine (B.J.D.), National Jewish Health, Denver, Colorado
- Address correspondence to:
Dr. Brian J. Day, National Jewish Health, 1400 Jackson Street, Denver, CO 80206. E-mail: dayb{at}njc.org
Abstract
Sulfur mustards (SMs) have been used as warfare agents since World War I and still pose a significant threat against civilian and military personnel. SM exposure can cause significant blistering of the skin, respiratory injury, and fibrosis. No antidote currently exists for SM exposure, but recent studies, using the SM analog 2-chloroethyl ethyl sulfide (CEES), have focused on the ability of antioxidants to prevent toxicity. Although antioxidants can prevent CEES-induced toxicity, the mechanisms by which these compounds are effective against SM agents are largely unknown. Using human bronchial epithelial (16HBE) cells and primary small airway epithelial cells, we show that CEES causes a significant increase in mitochondrial dysfunction as early as 4 h, which is followed by increases in mitochondrial reactive oxygen species (ROS), peaking 12 h after exposure. We also have identified a catalytic antioxidant metalloporphyrin that can rescue airway cells from CEES-induced toxicity when added 1 h after CEES exposure. In addition, the cytoprotective effects of the catalytic antioxidant are associated with correcting mitochondrial dysfunction ROS, DNA oxidation, and decreases in intracellular GSH. These findings suggest a role for oxidative stress in CEES toxicity and provide a rationale to investigate antioxidants as rescue agents in SM exposures.
Footnotes
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This work was supported by the National Institutes of Health [Grant U54-ES015678]; and Aeolus Pharmaceuticals [Research Grant].
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B.J.D. is a consultant for and holds equity in Aeolus Pharmaceuticals, which is commercially developing catalytic antioxidant mimetics as therapeutic agents.
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doi:10.1124/jpet.108.145037.
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ABBREVIATIONS: SM, sulfur mustard; CEES, 2-chloroethyl ethyl sulfide; SOD, superoxide dismutase; ROS, reactive oxygen species; AEOL 10150 or MnTDE-1,3-IP5+, manganese(III) meso-tetrakis(N,N′-diethylimidazolium-2-yl)porphyrin; SAE, small airway epithelial; DMSO, dimethyl sulfoxide; AM, acetoxymethyl ester; PBS, phosphate-buffered saline; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; Rho 123, Rhodamine 123; 8OHdG, 8-hydroxy-2-deoxyguanosine; 2dG, 2-deoxyguanosine; ANOVA, analysis of variance; AEOL 10113 or MnTE-2-PyP5+, manganese(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin; AEOL 10303, manganese(III) meso-[5-(4-carboxy-3-hydroxyphenyl)-10,15,20-tris(4-carboxymethyl-3-hydroxyphenyl) porphyrin; MnTBAP, manganese(III) meso-tetrakis(4-benozic acid) porphyrin or manganese(III) meso-tetrakis(4-carboxyphenyl)porphyrin.
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- Received August 18, 2008.
- Accepted December 5, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
