title: In vitro dermal intoxication by bis(chloroethyl)sulfide. Effect on secondary epidermization.
abstract: Skin intoxication by bis(beta-chloroethyl)sulfide (BCES; sulfur mustard) induces cutaneous lesions similar to thermal burns, characterized by slowness of skin healing. We have developed an in vitro model of skin equivalent to investigate mechanisms involved in this delay. Direct intoxication of dermal equivalent produced dose- and time-dependent cytotoxicity. A decrease of macroscopic retraction of collagen gels was observed, parallel to the toxic concentration with, at histological level, absence of collagen fiber reorganization. Fibroblast synthesis of fibronectin was also inhibited by intoxication, as demonstrated at an immunobiochemical and immunohistochemical level. These dermal alterations were correlated with secondary modifications of epithelial maturation of nonintoxicated normal human keratinocytes. Cellular adhesion was perturbed, as visualized by a delay in expression and reorganization of basement membrane components, laminen, collagen IV, and fibronectin. Epidermal terminal differentiation was also affected, as shown by the absence of profilaggrin/filaggrin biosynthesis. We demonstrated in vitro, that direct dermal alterations secondarily induce disturbance of epithelial maturation. Taken together, these data show the fundamental role of dermal-epidermal interactions in a normal skin reconstruction. Clinical slowness of wound healing observed after cutaneous intoxication by BCES may thus be explained by direct alkylation of some structures and further disturbances of their biosynthesis.
authors.affiliation: CRSSA, La Tronche, France.
authors.forename: E
authors.initials: E
authors.lastname: Gentilhomme
authors.forename: A
authors.initials: A
authors.lastname: Reano
authors.forename: D
authors.initials: D
authors.lastname: Pradel
authors.forename: J
authors.initials: J
authors.lastname: Bergier
authors.forename: D
authors.initials: D
authors.lastname: Schmitt
authors.forename: Y
authors.initials: Y
authors.lastname: Neveux
mesh_terms: D001485:Basement Membrane / Q000378:metabolism; D015153:Blotting, Western; D002448:Cell Adhesion; D003094:Collagen; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D005353:Fibronectins / Q000378:metabolism; D000091344:Filaggrin Proteins; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007381:Intermediate Filament Proteins / Q000378:metabolism; D009151:Mustard Gas / Q000633:toxicity*; D012038:Regeneration; D012867:Skin / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014945:Wound Healing
chemical_list: C000717249:FLG protein, human; D005353:Fibronectins; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D003094:Collagen; D009151:Mustard Gas