Sulfur Mustard Aerosol Inhalation Injury in Rat Lungs via Fas‐mediated Apoptosis

Abstract

We have focused on the Fas (death receptor)‐mediated pathway of apoptosis as a major mechanism of sulfur mustard (SM) inhalation injury. We examined the changes in caspase−8, −9, −3 and −6 activities in bronchoalveolar lavage fluid (BALF) cells and in soluble Fas ligand (sFasL) in BALF at 24 hours following SM exposure (3.0 mg/kg SM, 10 minutes) using a ventilated SM aerosol inhalation rat model. We observed that SM inhalation increased all four caspases in BALF cells as well as the level of sFasL in BALF. Caspase−8, −9, −3, and −6 increased 7‐, 10‐, 2‐ and 4‐fold, respectively, compared to their respective sham controls at 24 hours after SM exposure. Immunohistochemical staining in whole lung tissue showed the presence of activated caspase‐3 in SM inhalation‐exposed rat airway and the lung. These findings suggest that SM inhalation causes apoptosis in the airways and the lungs in this rat model. Observed increases in caspase‐8 and sFasL suggest their involvement in the caspase cascade signaling sequence and the Fas‐mediated pathway as seen in vitro in cultured human AEC. However, these observations need to be validated by studying the relationships between caspase‐3 and the other caspases. In conclusion, these results should be useful in determining the pathogenic mechanisms as well as therapeutic targets for SM inhalation injury. Research was funded by DTRA – Joint Science and Technology Office, Medical S&T Division.