The Cytoskeleton and ATP in Sulfur Mustard-Medicated Injury to Endothelial Cells and Keratinocytes.
Abstract
The major goal of this project is to test the hypothesis that sulfur mustard (SM)-mediated cell death in keratinocytes and endothelial cells is primarily apoptotic in nature, and that several factors (e.g., cellular levels of adenosine triphosphate (ATP), reactive oxygen species ROS) help define this process. Using biochemical and fluorescence microscopic techniques to measure several parameters of cell death over a 72 hour time course of SM injury, we found that keratinocytes develop mixed features of both apoptosis and necrosis, but more slowly than endothelial cells which exhibit a more classical pattern of apoptosis. Caspase-3, a protease which plays a central role in programmed cell death was activated in both cell types by SM. In a model of moderate ATP depletion (approx. 50% of control) endothelial cell progression into apoptosis was suppressed after SM injury followed by later increases in necrosis at higher SM concentrations. Protective effects of N-acetyl-l-cysteine (NAC) on SM-injured endothelial cells were found to be glutathione (GSH)-dependent but other studies assaying for ROS within SM-injured cells were as yet inconclusive. Our results thus far suggest that cell death induced by SM may represent a continuum between the extremes of apoptosis and necrosis. Caspase activation appears to be a critical element common to SM-induced endothelial cell and keratinocyte death and thus may be an important target for therapeutic intervention.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 1998
- Accession Number
- ADA378102
Entities
People
- Daniel B. Hinshaw