| Sulfur mustard induces apoptosis in lung epithelial cells via a caspase amplification loop. | |
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MedLine Citation:
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PMID: 20226831 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Sulfur mustard (SM [bis-(2-chloroethyl) sulfide]) is a chemical warfare agent that causes skin blisters presumably due to DNA alkylation and cross-links. We recently showed that SM also induces apoptotic death in cultured normal human bronchial/tracheal epithelial (NHBE) cells and small airway epithelial cells (SAEC) in vitro. In this process, caspases-8 and -3, but not caspase-9, were strongly activated; this suggests a death receptor pathway for apoptosis. We now show that rat lungs were induced to undergo apoptosis in vivo following exposure of rats to SM by inhalation. Further study of the mechanism of apoptosis due to SM was performed with cultured NHBE cells and SAEC using tetrapeptide inhibitors of caspases-3, and -8. Inhibition of caspase-8 drastically reduced the activation of caspase-3 and almost eliminated that of caspase-9. Moreover, caspase-3 inhibition markedly reduced the activation of caspase-8 and also almost completely inhibited activation of caspase-9. These results suggest a death receptor pathway of apoptosis that utilizes a feedback amplification mechanism involving an activated death receptor complex that leads to the activation of caspase-9 via a caspase-3 pathway. These results may be important for the design of inhibitors of these pathways for therapeutic intervention to attenuate SM injury in respiratory tract lesions. |
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Authors:
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Radharaman Ray; Cynthia M Simbulan-Rosenthal; Brian M Keyser; Betty Benton; Dana Anderson; Wesley Holmes; Valerie A Trabosh; Ahmad Daher; Dean S Rosenthal |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. Date: 2010-03-11 |
Journal Detail:
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Title: Toxicology Volume: 271 ISSN: 1879-3185 ISO Abbreviation: Toxicology Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-05-10 Completed Date: 2010-05-20 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0361055 Medline TA: Toxicology Country: Ireland |
Other Details:
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Languages: eng Pagination: 94-9 Citation Subset: IM |
Affiliation:
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Cellular and Molecular Biology Branch, US Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, USA. radharaman.ray@us.army.mil <radharaman.ray@us.army.mil> |
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / drug effects* Caspase 3 / metabolism Caspase 8 / metabolism Caspase 9 / metabolism Caspases / antagonists & inhibitors, metabolism* Cells, Cultured Chemical Warfare Agents / pharmacology* Epithelial Cells / metabolism* Humans Lung / metabolism Male Mustard Gas / pharmacology* Rats |
| Grant Support | |
ID/Acronym/Agency:
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1R01 CA100443-01A1/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Chemical Warfare Agents; 505-60-2/Mustard Gas; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 8; EC 3.4.22.-/Caspase 9; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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