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Inflammatory effects of inhaled sulfur mustard in rat lung
Rama Malaviya1, Vasanthi R Sunil, Jessica Cervelli
1Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA.
Abstract:
Inhalation of sulfur mustard (SM), a bifunctional alkylating agent that causes severe lung damage, is a significant threat to both military and civilian populations. The mechanisms mediating its cytotoxic effects are unknown and were investigated in the present studies. Male rats Crl:CD(SD) were anesthetized, and then intratracheally intubated and exposed to 0.7-1.4mg/kg SM by vapor inhalation. Animals were euthanized 6, 24, 48h or 7days post-exposure and bronchoalveolar lavage fluid (BAL) and lung tissue collected. Exposure of rats to SM resulted in rapid pulmonary toxicity, including focal ulceration and detachment of the trachea and bronchial epithelia from underlying mucosa, thickening of alveolar septal walls and increased numbers of inflammatory cells in the tissue. There was also evidence of autophagy and apoptosis in the tissue. This was correlated with increased BAL protein content, a marker of injury to the alveolar epithelial lining. SM exposure also resulted in increased expression of markers of inflammation including cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNFα), inducible nitric oxide synthase (iNOS), and matrix metalloproteinase-9 (MMP-9), each of which has been implicated in pulmonary toxicity. Whereas COX-2, TNFα and iNOS were mainly localized in alveolar regions, MMP-9 was prominent in bronchial epithelium. In contrast, expression of the anti-oxidant hemeoxygenase, and the anti-inflammatory collectin, surfactant protein-D, decreased in the lung after SM exposure. These data demonstrate that SM-induced oxidative stress and injury are associated with the generation of cytotoxic inflammatory proteins which may contribute to the pathogenic response to this vesicant.
Insights
Sulfur mustard (SM) inhalation causes rapid lung damage through inflammation and cell death. This study reveals SM triggers cytotoxic inflammatory proteins, contributing to its severe pulmonary toxicity.
Area of Science:
- Toxicology
- Pulmonary Medicine
- Chemical Warfare Agents
Background:
- Sulfur mustard (SM) is a potent chemical warfare agent causing severe lung damage.
- The precise mechanisms of SM-induced pulmonary toxicity remain largely unknown.
- Understanding these mechanisms is crucial for developing effective countermeasures.
Purpose of the Study:
- To investigate the mechanisms of cytotoxic effects following sulfur mustard inhalation.
- To identify key inflammatory and cellular responses in the lungs post-SM exposure.
- To correlate molecular changes with observed lung injury.
Main Methods:
- Male rats were exposed to varying doses of sulfur mustard vapor via intratracheal intubation.
- Lung tissue and bronchoalveolar lavage fluid were collected at multiple time points post-exposure (6h to 7 days).
- Analysis included histological examination, protein content measurement, and assessment of inflammatory marker expression (COX-2, TNFα, iNOS, MMP-9).
Main Results:
- SM exposure induced rapid pulmonary toxicity, including epithelial damage, inflammation, autophagy, and apoptosis.
- Increased bronchoalveolar lavage fluid protein indicated alveolar epithelial lining injury.
- Expression of inflammatory markers (COX-2, TNFα, iNOS, MMP-9) was significantly upregulated, while antioxidant (hemeoxygenase) and anti-inflammatory (surfactant protein-D) markers decreased.
Conclusions:
- Sulfur mustard inhalation triggers significant pulmonary inflammation and cellular damage.
- Oxidative stress and the generation of cytotoxic inflammatory proteins are key contributors to SM-induced lung injury.
- These findings provide insights into the pathogenesis of sulfur mustard toxicity.
