Effects of sulfur mustard on the basal cell adhesion complex.
Among the most intriguing questions about sulfur mustard (di(2-chloroethyl) sulfide) is why basal cells are the primary targets of its vesicating lesions. To investigate this problem, replicate cultures of human epidermal keratinocytes (HEK) were grown from normal skin and exposed to 400 microM sulfur mustard (HD) for 5 min. Using fluorescein isothiocyanate (FITC)-conjugated antibodies, confocal laser microscopy and image analyses, we found that in early passages, sham-treated HEK maintained in a 0.15 mM Ca2+ medium continued to express keratins K5 and K14 as well as alpha6beta4-integrin. Both K5 and K14 are intermediate filaments characteristic of basal cells and linked with attachment mechanisms effecting epidermolysis bullosa simplex, a family of blistering skin diseases. Acute exposure to HD caused a statistically significant (P < 0.01) 30.74% decrease in K14 fluorescence within 1 h of exposure. Within 2 h of exposure, K14 fluorescence decreased to near-zero values. The loss in expression of K14 was progressive and occurred well before the expected appearance of in vivo blisters, which have a dose-dependent, clinical latent phase of 8-24 h. Acute exposure to HD also caused a statistically significant (P < 0.002) decrease in expression of beta4, an integrin which has been associated with junctional epidermolysis bullosa (JEB). Disruption of K14 and alpha6beta4-integrin may be early events in the HD injury pathway; however, they had no immediate or obvious effect on cell to substrate attachment.
Werrlein
R J
RJ
US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA.
Madren-Whalley
J S
JS
D000906:Antibodies; D001768:Blister / Q000139:chemically induced / Q000503:physiopathology; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D018929:Cell Culture Techniques; D003879:Dermatologic Agents / Q000633:toxicity*; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D006801:Humans; D016023:Integrins / Q000096:biosynthesis*; D015603:Keratinocytes / Q000187:drug effects* / Q000473:pathology; D007633:Keratins / Q000096:biosynthesis*; D008188:Lutheran Blood-Group System; D009151:Mustard Gas / Q000633:toxicity*; D009363:Neoplasm Proteins / Q000378:metabolism*
D000906:Antibodies; C090228:BCAM protein, human; D015815:Cell Adhesion Molecules; D003879:Dermatologic Agents; D005456:Fluorescent Dyes; D016023:Integrins; D008188:Lutheran Blood-Group System; D009363:Neoplasm Proteins; D007633:Keratins; D016650:Fluorescein-5-isothiocyanate; D009151:Mustard Gas