IN-VITRO DERMAL INTOXICATION BY BIS(CHLOROETHYL)SULFIDE - EFFECT ON SECONDARY EPIDERMIZATION

Skin intoxication by bis(beta-chloroethyl)sulfide (BCES; sulfur mustar d) induces cutaneous lesions similar to thermal burns, characterized b y slowness of skin healing. We have developed an in vitro model of ski n equivalent to investigate mechanisms involved in this delay. Direct intoxication of dermal equivalent produced dose-and time-dependent cyt otoxicity. A decrease of macroscopic retraction of collagen gels was o bserved, parallel to the toxic concentration with, ar. histological le vel, absence of collagen fiber reorganization. Fibroblast synthesis of fibronectin was also inhibited by intoxication, as demonstrated at an immunobiochemical and immunohistochemical level. These dermal alterat ions were correlated with secondary modifications of epithelial matura tion of nonintoxicated normal human keratinocytes. Cellular adhesion w as perturbed, as visualized by a delay in expression and reorganizatio n of basement membrane components, laminen, collagen IV, and fibronect in. 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 fundamen tal role of dermal-epidermal interactions in a normal skin reconstruct ion. Clinical slowness of wound healing observed after cutaneous intox ication by BCES may thus be explained by direct alkylation of some str uctures and further disturbances of their biosynthesis.