Exposure–response effects of inhaled sulfur mustard in a large porcine model: a 6-h study

Abstract

Context: Inhalation of sulfur mustard (HD) vapor can cause life-threatening lung injury for which there is no specific treatment. A reproducible, characterized in vivo model is required to investigate novel therapies targeting HD-induced lung injury.

Materials and methods: Anesthetized, spontaneously breathing large white pigs (∼50 kg) were exposed directly to the lung to HD vapor at 60, 100, or 150 µg/kg, or to air, for ∼10 min, and monitored for 6 h. Cardiovascular and respiratory parameters were recorded. Blood and bronchoalveolar lavage fluid (BALF) were collected to allow blood gas analysis, hematology, and to assay for lung inflammatory cells and mediators. Urine was collected and analyzed for HD metabolites. Histopathology samples were taken postmortem (PM).

Results: Air-exposed animals maintained normal lung physiology whilst lying supine and spontaneously breathing. There was a statistically significant increase in shunt fraction across all three HD-exposed groups when compared with air controls at 3–6 h post-exposure. Animals were increasingly hypoxemic with respiratory acidosis. The monosulfoxide β-lyase metabolite of HD (1-methylsulfinyl-2-[2(methylthio)ethylsulfonyl)ethane], MSMTESE), was detected in urine from 2 h post-exposure. Pathological examination revealed necrosis and erosion of the tracheal epithelium in medium and high HD-exposed groups.

Conclusion: These findings are consistent with those seen in the early stages of acute lung injury (ALI).

Keywords::

• Acute lung injury
• histopathology
• inflammation
• inhalation
• monosulfoxide
• physiology
• porcine
• sulfur mustard (HD)

Acknowledgements

The authors would like to thank the following for their contributions to this work: R. Brown for technical expertise; C. Masey for surgical preparation of the subjects; R. Perrott for technical assistance, the Animal Services Staff for animal husbandry; and J. Platt and C. Taylor for histopathological analyzes.

Declaration of interest

This work was supported by the Defense Threat Reduction Agency (US Department of Defense) under Contract W91ZLK-05-P-1328.