A role for mitochondrial oxidative stress in sulfur mustard analog 2-chloroethyl ethyl sulfide-induced lung cell injury and antioxidant protection.
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.
Gould
Neal S
NS
Department of Pharmaceutical Sciences, University ofColorado Health Sciences Center, Denver, Colorado, USA.
White
Carl W
CW
Day
Brian J
BJ
D000975:Antioxidants / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D055370:Lung Injury / Q000139:chemically induced / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology*; D009151:Mustard Gas / Q000031:analogs & derivatives* / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species
D000975:Antioxidants; D017382:Reactive Oxygen Species; C031278:2-chloroethyl ethyl sulfide; D009151:Mustard Gas