Sulfur Mustard Induces Apoptosis in Cultured Normal Human Airway Epithelial Cells: Evidence of a Dominant Caspase-8-Mediated Pathway and Differential Cellular Responses
Abstract
We have shown that sulfur mustard (SM; bis-(2-chloroethyl) sulfide), an alkylating, vesicating chemical warfare agent, causes dermal toxicity, including skin microblisters, via the induction of both death receptor (DR) and mitochondrial pathways of apoptosis in human epidermal keratinocytes. While SM is known for its skin-vesicating properties, respiratory tract lesions are the main source of morbidity and mortality after inhalation exposure. We, therefore, investigated whether SM induces apoptotic cell death in normal human bronchial epithelial (NHBE) cells and small airway epithelial cells (SAEC) in vitro. Cells were exposed to various concentrations of SM (0, 50, 100, and 300 micron for 16 h) in the culture medium and then tested for the activation of apoptotic executioner caspase-3 and initiator caspases-8 and -9. Caspases-8 and -3 were activated by SM in both airway cell types, indicating the induction of a DR pathway of apoptosis in these cells; however, the levels of enzyme activation were different, depending on the cell type and the SM concentrations used. Consistent with enzyme activity results, immunoblot analyses revealed the proteolytic processing of the proenzymes to the active forms of caspases-8 and -3 in these cells after SM exposure. Interestingly, NHBE cells were found to be exquisitely sensitive to SM, compared to SAEC, with caspase-3 activities in SM-exposed NHBE cells ~2-fold higher and caspase-8 activities ~10-fold higher than in SAEC. Furthermore, SM activated caspase-9 in NHBE cells, but not in SAEC, indicating a possible role of the mitochondrial pathway only in the NHBE cells. The present study shows that both upper airway (NHBE cells) and deep lung (SAEC) epithelial cells undergo SM-induced apoptotic death in vitro, but distinct cell-type specific responses can be elicited, which may be attributed to intrinsic properties that characterize the response of these cells to SM.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2008
- Accession Number
- ADA501707
Entities
People
- Ahmad Daher
- Betty Benton
- Brian Keyser
- Cynthia M. Simbulan-rosenthal
- Dean S. Rosenthal
- Radharaman Ray
Organizations
- United States Army Medical Research Institute of Chemical Defense