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Sulfur mustard‐induced apoptosis in human airway epithelial cells appears to be via the death receptor (Fas) pathway
Author(s) -
Ray Radharaman,
Benton Betty,
Keyser Brian,
Carpin Chris,
Rosenthal Dean
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a258-d
Subject(s) - apoptosis , caspase , caspase 8 , caspase 3 , microbiology and biotechnology , chemistry , biology , cancer research , programmed cell death , biochemistry
SM (bis‐(2‐chloroethyl) sulfide), commonly called mustard gas causes debilitating skin blisters and eye and respiratory tract injuries due to epithelial damage, particularly basal cell apoptosis. We studied apoptosis pathways in SM (0–300 μM)‐exposed cultured human bronchial/tracheal epithelial cells (HBEC, upper airway model) and small airway epithelial cells (SAEC, deep lung model). Apoptosis was measured and characterized by activation of caspases and their inhibition by caspase type‐specific peptide inhibitors. Assays of caspases were based on fluorogenic caspase substrate hydrolysis. Concentration‐response showed that for SM‐induced apoptosis, HBEC are more sensitive than SAEC. SM activated caspase‐8 and caspase‐3 in both cell types, while caspase‐9 was only activated in HBEC. The caspase‐3 inhibitor Ac‐DEVD‐CHO inhibited caspase‐3, as well as caspase‐8 and caspase‐9 to a lesser extent. Similarly, the caspase‐8 inhibitor Ac‐IETD‐CHO effectively inhibited caspase‐8; however, caspase‐3 and caspase‐9 were also inhibited. From these results, we propose that in airway epithelial cells, SM causes apoptosis predominantly via the Fas pathway and the different caspases observed are due to cross‐talk/amplification loops between these enzymes. Therefore, intervention of the Fas pathway may be a prospective approach to develop respiratory therapeutics against SM inhalation injury.