Accession Number:

ADA574486

Title:

Postexposure Application of Fas Receptor Small-Interfering RNA to Suppress Sulfur Mustard-Induced Apoptosis in Human Airway Epithelial Cells: Implication for a Therapeutic Approach

Descriptive Note:

Journal article

Corporate Author:

ARMY MEDICAL RESEARCH INST OF CHEMICAL DEFENSE ABERDEEN PROVING GROUND MD

Report Date:

2013-01-01

Pagination or Media Count:

10.0

Abstract:

Sulfur mustard SM is a vesicant chemical warfare and terrorism agent. Besides skin and eye injury, respiratory damage has been mainly responsible for morbidity and mortality after SM exposure. Previously, it was shown that suppressing the death receptor DR response by the dominant-negative Fas-associated death domain protein prior to SM exposure blocked apoptosis and microvesication in skin. Here, we studied whether antagonizing the Fas receptor FasR pathway by small-interfering RNA siRNA applied after SM exposure would prevent apoptosis and, thus, airway injury. Normal human bronchialtracheal epithelial NHBE cells were used as an in vitro model with FasR siRNA, FasR agonistic antibody CH11, and FasR antagonistic antibody ZB4 as investigative tools. In NHBE cells, both SM 300 mM and CH11 100 ngml induced caspase-3 activation, which was inhibited by FasR siRNA and ZB4, indicating that SM-induced apoptosis was via the Fas response. FasR siRNA inhibited SM-induced caspase-3 activation when added to NHBE cultures up to 8 hours after SM. Results using annexin Vpropidium iodidestained cells showed that both apoptosis and necrosis were involved in cell death due to SM FasR siRNA decreased both apoptotic and necrotic cell populations. Bronchoalveolar lavage fluid BALF of rats exposed to SM 1 mgkg, 50 minutes revealed a significant P , 0.05 increase in soluble Fas ligand and active caspase-3 in BALF cells. These findings suggest an intervention of Fas-mediated apoptosis as a postexposure therapeutic strategy with a therapeutic window for SM inhalation injury and possibly other respiratory diseases involving the Fas response.

Subject Categories:

  • Organic Chemistry
  • Chemical, Biological and Radiological Warfare

Distribution Statement:

APPROVED FOR PUBLIC RELEASE