A Preliminary Study of Chronic Lung Toxicity in Rats Following a Single Inhalation Challenge to Sulfur Mustard: Assessment of the Effect of Mesenchymal Stem Cell Treatment
Abstract
Sulfur mustard (SM) is a blistering agent (vesicant) that causes severe chemical burns to the skin, eyes and airways. SM was used as a chemical warfare agent (CWA) in the Iran/Iraq conflict, and more than half of surviving SM-exposed casualties continue to suffer from permanent lung injuries. SM remains a serious threat with no effective antidote. Despite over 90 years of study since SM was developed as a CWA, the mechanisms and timing of the development of these pathologies remain poorly defined. To model the mouth-breathing human, rats were intubated and ventilated for 10 min with nebulized SM or a vehicle to achieve total doses of 0, 0.5, 1.75, 2.25, and 3 mg/kg (335-402 mg/m3). Pulmonary function was analyzed by whole-body plethysmography. Rats were euthanized at various time points < or = 6 months post-exposure, blood chemistry was analyzed, and lungs were subjected to pathologic analysis. Mid-study data showed elevated pCO2 and lowered blood pH and pO2, which correlated with upper airway necrosis and measurements of pulmonary function in the 24-48 hrs after 3 mg/kg SM exposure. For the 6-month animals, the period between 3 and 7 weeks presented a significant challenge because approximately 60-70% of the high exposure dose group (3 mg/kg) and 40-50% of the 2.25 mg/kg group either died or required withdrawal from the study during this timeframe. Over time, blood gas chemistries, antioxidant response elements, inflammatory markers and histopathology revealed that SM inhalation resulted in a range of physiological and toxicological decrements consistent with the progression of severe lung injury observed in humans. In addition, alveolar exudates, edema, and inflammation peaked early in the acute phase of injury and correlated with compensatory changes in pulmonary function and/or respiratory distress.
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2017
- Accession Number
- AD1055436
Entities
People
- Alfred M. Sciuto
- Ashley M. Rodriguez
- Dorian S. Olivera
- Jannitt B. Simons
- Jennifer L. Collins
- Timothy R. Varney
Organizations
- United States Army Medical Research Institute of Chemical Defense