Abstract

Sulfur mustard (SM) is highly toxic to the lung inducing both acute and chronic effects including upper and lower obstructive disease, airway inflammation, and acute respiratory distress syndrome, and with time, tracheobronchial stenosis, bronchitis, and bronchiolitis obliterans. Thus it is essential to identify effective strategies to mitigate the toxicity of SM and related vesicants. Studies in animals and in cell culture models have identified key mechanistic pathways mediating their toxicity, which may be relevant targets for the development of countermeasures. For example, following SM poisoning, DNA damage, apoptosis, and autophagy are observed in the lung, along with increased expression of activated caspases and DNA repair enzymes, biochemical markers of these activities. This is associated with inflammatory cell accumulation in the respiratory tract and increased expression of tumor necrosis factor-α and other proinflammatory cytokines, as well as reactive oxygen and nitrogen species. Matrix metalloproteinases are also upregulated in the lung after SM exposure, which are thought to contribute to the detachment of epithelial cells from basement membranes and disruption of the pulmonary epithelial barrier. Findings that production of inflammatory mediators correlates directly with altered lung function suggests that they play a key role in toxicity. In this regard, specific therapeutic interventions currently under investigation include anti-inflammatory agents (e.g., steroids), antioxidants (e.g., tocopherols, melatonin, N-acetylcysteine, nitric oxide synthase inhibitors), protease inhibitors (e.g., doxycycline, aprotinin, ilomastat), surfactant replacement, and bronchodilators. Effective treatments may depend on the extent of lung injury and require a multi-faceted pharmacological approach.

Original languageEnglish (US)
Pages (from-to)92-99
Number of pages8
JournalPulmonary Pharmacology and Therapeutics
Volume24
Issue number1
DOIs
StatePublished - Feb 1 2011

Fingerprint

Mustard Gas
Lung Injury
Toxicity
Lung
DNA Repair Enzymes
Reactive Nitrogen Species
Aprotinin
Tocopherols
Doxycycline
Irritants
Poisons
Bronchodilator Agents
Acetylcysteine
Bronchiolitis Obliterans
Melatonin
Therapeutics
Caspases
Protease Inhibitors
Matrix Metalloproteinases
Cell culture

All Science Journal Classification (ASJC) codes

  • Biochemistry, medical
  • Pharmacology (medical)
  • Pulmonary and Respiratory Medicine

Keywords

  • Lung
  • Sulfur mustard
  • Toxicity
  • Vesicants

Cite this

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title = "Sulfur mustard-induced pulmonary injury: Therapeutic approaches to mitigating toxicity",
abstract = "Sulfur mustard (SM) is highly toxic to the lung inducing both acute and chronic effects including upper and lower obstructive disease, airway inflammation, and acute respiratory distress syndrome, and with time, tracheobronchial stenosis, bronchitis, and bronchiolitis obliterans. Thus it is essential to identify effective strategies to mitigate the toxicity of SM and related vesicants. Studies in animals and in cell culture models have identified key mechanistic pathways mediating their toxicity, which may be relevant targets for the development of countermeasures. For example, following SM poisoning, DNA damage, apoptosis, and autophagy are observed in the lung, along with increased expression of activated caspases and DNA repair enzymes, biochemical markers of these activities. This is associated with inflammatory cell accumulation in the respiratory tract and increased expression of tumor necrosis factor-α and other proinflammatory cytokines, as well as reactive oxygen and nitrogen species. Matrix metalloproteinases are also upregulated in the lung after SM exposure, which are thought to contribute to the detachment of epithelial cells from basement membranes and disruption of the pulmonary epithelial barrier. Findings that production of inflammatory mediators correlates directly with altered lung function suggests that they play a key role in toxicity. In this regard, specific therapeutic interventions currently under investigation include anti-inflammatory agents (e.g., steroids), antioxidants (e.g., tocopherols, melatonin, N-acetylcysteine, nitric oxide synthase inhibitors), protease inhibitors (e.g., doxycycline, aprotinin, ilomastat), surfactant replacement, and bronchodilators. Effective treatments may depend on the extent of lung injury and require a multi-faceted pharmacological approach.",
keywords = "Lung, Sulfur mustard, Toxicity, Vesicants",
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Sulfur mustard-induced pulmonary injury : Therapeutic approaches to mitigating toxicity. / Weinberger, Barry; Laskin, Jeffrey; Sunil, Vasanthi R.; Sinko, Patrick; Heck, Diane E.; Laskin, Debra.

In: Pulmonary Pharmacology and Therapeutics, Vol. 24, No. 1, 01.02.2011, p. 92-99.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Sulfur mustard-induced pulmonary injury

T2 - Therapeutic approaches to mitigating toxicity

AU - Weinberger, Barry

AU - Laskin, Jeffrey

AU - Sunil, Vasanthi R.

AU - Sinko, Patrick

AU - Heck, Diane E.

AU - Laskin, Debra

PY - 2011/2/1

Y1 - 2011/2/1

N2 - Sulfur mustard (SM) is highly toxic to the lung inducing both acute and chronic effects including upper and lower obstructive disease, airway inflammation, and acute respiratory distress syndrome, and with time, tracheobronchial stenosis, bronchitis, and bronchiolitis obliterans. Thus it is essential to identify effective strategies to mitigate the toxicity of SM and related vesicants. Studies in animals and in cell culture models have identified key mechanistic pathways mediating their toxicity, which may be relevant targets for the development of countermeasures. For example, following SM poisoning, DNA damage, apoptosis, and autophagy are observed in the lung, along with increased expression of activated caspases and DNA repair enzymes, biochemical markers of these activities. This is associated with inflammatory cell accumulation in the respiratory tract and increased expression of tumor necrosis factor-α and other proinflammatory cytokines, as well as reactive oxygen and nitrogen species. Matrix metalloproteinases are also upregulated in the lung after SM exposure, which are thought to contribute to the detachment of epithelial cells from basement membranes and disruption of the pulmonary epithelial barrier. Findings that production of inflammatory mediators correlates directly with altered lung function suggests that they play a key role in toxicity. In this regard, specific therapeutic interventions currently under investigation include anti-inflammatory agents (e.g., steroids), antioxidants (e.g., tocopherols, melatonin, N-acetylcysteine, nitric oxide synthase inhibitors), protease inhibitors (e.g., doxycycline, aprotinin, ilomastat), surfactant replacement, and bronchodilators. Effective treatments may depend on the extent of lung injury and require a multi-faceted pharmacological approach.

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