Genomic Analysis of Rodent Pulmonary Tissue Following Bis-(2-chloroethyl) Sulfide Exposure

Dillman, James F.; Phillips, Christopher S.; Dorsch, Linda M.; Croxton, Matthew D.; Hege, Alison I.; Sylvester, Albert J.; Moran, Theodore S.; Sciuto, Alfred M.

doi:10.1021/tx049745z

Cited by 54 publications

(46 citation statements)

References 40 publications

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“…The increased ROS we have seen in mitochondria may be because of mitochondrial dysfunctional, which we have seen in our CEES model and what others have seen after SM exposure (Sourdeval et al, 2006). The mitochondrion, specifically the respiratory chain, can produce a substantial amount of endogenous ROS (Fridovich, 1978;Drose and Brandt, 2008), and, if CEES causes mitochondrial uncoupling, this could explain oxidation products seen in other areas of the cell and markers of apoptosis (Dillman et al, 2005;Sourdeval et al, 2006). This idea is supported by recent findings that suggest sulfur and nitrogen mustards can react with cellular reductases and increase free radical production (Brimfield et al, 2009).…”

Section: Discussionsupporting

confidence: 68%

“…More recent work with SM on DNA has characterized genomic changes that show increases in markers of apoptosis, cell cycle regulation, and various other response genes (Dillman et al, 2005). Furthermore, exploring the role of oxidative stress in CEES-mediated injury and supplementation with antioxidants as a treatment has been a major area of interest.…”

Section: Discussionmentioning

confidence: 99%

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A Role for Mitochondrial Oxidative Stress in Sulfur Mustard Analog 2-Chloroethyl Ethyl Sulfide-Induced Lung Cell Injury and Antioxidant Protection

Gould¹,

White²,

Day³

2008

J Pharmacol Exp Ther

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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.Bis(2-chloroethyl sulfide) or sulfur mustard (SM) was first synthesized in the late 1880s and since has been used as a warfare agent on a number of occasions. SM was first used in World War I and has been used in warfare as recently as the Iran-Iraq conflict of the late 1980s (Blanc, 1999). Although SM is less of a threat in warfare as it once was, it still posses a threat to military and civilian personnel because of current concerns for its deployment in a terrorist attack.Sulfur mustards are classic vesicating agents that mainly affect the skin, eyes, and respiratory system. There is no known antidote or specific treatment for SM exposure, and the current therapy is largely supportive. SM on the skin can be decontaminated with soap and water or a dilute bleach solution, but internal exposure, such as the respiratory system, is considerably more difficult to treat (Munro et al., 1990;Watson and Griffin, 1992). SM produces airway damage that includes necrosis, inflammation, and edema (Kehe and Szinicz, 2005). The exact mechanism of SM toxicity is unknown. 2-Chloroethyl ethyl sulfide (CEES; half mustard) is a monofunctional analog of SM (Fig. 1) that provides a useful model for SM injury without the need for a specialized containment facility. CEES, like SM, is an alkylating agent that can bind DNA and other macromolecules within the cell. Recent research into counteragents has focused on bolstering the endogenous antioxidant defenses by supplementation with N-acetyl-cysteine (McClintock et al

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

A Role for Mitochondrial Oxidative Stress in Sulfur Mustard Analog 2-Chloroethyl Ethyl Sulfide-Induced Lung Cell Injury and Antioxidant Protection

Gould¹,

White²,

Day³

2008

J Pharmacol Exp Ther

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“…However, p53 is also activated in SM injury [10,[23][24][25]. Given that SM is known to damage DNA and the classical role of p53 is in cell cycle arrest and apoptosis, p53 has been widely implicated in SM-induced cell death [10,23,24,26,27].…”

Section: Introductionmentioning

confidence: 99%

Sulfur mustard induced cytokine production and cell death: Investigating the potential roles of the p38, p53, and NF‐κB signaling pathways with RNA interference

Ruff

Dillman

2010

J Biochem & Molecular Tox

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Cutaneous and ocular injuries caused by sulfur mustard (SM; bis-(2-chloroethyl) sulfide) are characterized by severe inflammation and death of exposed cells. Given the known roles of p38MAPK and NF-kappaB in inflammatory cytokine production, and the known roles of NF-kappaB and p53 in cell fate, these pathways are of particular interest in the study of SM injury. In this study, we utilized inhibitory RNA (RNAi) targeted against p38 alpha, the p50 subunit of NF-kappaB, or p53 to characterize their role in SM-induced inflammation and cell death in normal human epidermal keratinocytes (NHEK). Analysis of culture supernatant from 200 microM SM-exposed cells showed that inflammatory cytokine production was inhibited by p38 alpha RNAi but not by NF-kappaB p50 RNAi. These findings further support a critical role for p38 in SM-induced inflammatory cytokine production in NHEK and suggest that NF-kappaB may not play a role in the SM-induced inflammatory response of this cell type. Inhibition of NF-kappaB by p50 RNAi did, however, partially inhibit SM-induced cell death, suggesting a role for NF-kappaB in SM-induced apoptosis or necrosis. Interestingly, inhibition of p53 by RNAi potentiated SM-induced cell death, suggesting that the role of p53 in SM injury, may be complex and not simply prodeath.

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“…Thus, one clear benefit of microarray analysis is the potential to identify thousands of genes dysregulated in response to HD and, using mapping software, to characterize significantly altered pathways. Early microarray studies identified pathways such as inflammation, apoptosis, protein catabolism, and cell cycle as involved in HD-induced toxicity (Rogers et al, 2004;Dillman et al, 2005). Likewise, genomics efforts from our group are now focused on assessing how HD exposure dose and time affect these signaling pathways.…”

Section: Genomics Applications To Cwasmentioning

confidence: 99%

Genomics and proteomics in chemical warfare agent research: Recent studies and future applications

Everley¹,

Dillman²

2010

Toxicology Letters

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a b s t r a c tMedical research on the effects of chemical warfare agents (CWAs) has been ongoing for nearly 100 years, yet these agents continue to pose a serious threat to deployed military forces and civilian populations. CWAs are extremely toxic, relatively inexpensive, and easy to produce, making them a legitimate weapon of choice for terrorist organizations. While the mechanisms of action for many CWAs have been known for years, questions about their molecular effects following acute and chronic exposure remain largely unanswered. Global approaches that can pinpoint which cellular pathways are altered in response to CWAs and characterize long-term toxicity have not been widely used. Fortunately, innovations in genomics and proteomics technologies now allow for thousands of genes and proteins to be identified and subsequently quantified in a single experiment. Advanced bioinformatics software can also help decipher large-scale changes observed, leading to mapping of signaling pathways, functional characterization, and identification of potential therapeutic targets. Here we present an overview of how genomics and proteomics technologies have been applied to CWA research and also provide a series of questions focused on how these techniques could further our understanding of CWA toxicity.

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Genomic Analysis of Rodent Pulmonary Tissue Following Bis-(2-chloroethyl) Sulfide Exposure

Cited by 54 publications

References 40 publications

A Role for Mitochondrial Oxidative Stress in Sulfur Mustard Analog 2-Chloroethyl Ethyl Sulfide-Induced Lung Cell Injury and Antioxidant Protection

A Role for Mitochondrial Oxidative Stress in Sulfur Mustard Analog 2-Chloroethyl Ethyl Sulfide-Induced Lung Cell Injury and Antioxidant Protection

Sulfur mustard induced cytokine production and cell death: Investigating the potential roles of the p38, p53, and NF‐κB signaling pathways with RNA interference

Genomics and proteomics in chemical warfare agent research: Recent studies and future applications

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