CYCLOSPORINE-A DELAYS WOUND-HEALING AND APOPTOSIS AND SUPPRESSES ACTIVIN BETA-A EXPRESSION IN RATS

Cyclosporine A is a powerful immunosuppressive agent which is widely u sed for the prevention of allograft rejection and for the treatment of autoimmune diseases. Clinical and experimental data show that it may also act on connective tissue. We investigated the influence of cyclos porine A on granulation tissue formation and wound healing. Using an i n vitro approach, we followed the time course of rat dermal fibroblast s during wound repair. Granulation fibroblasts were compared to dermal fibroblasts flow cytometrically and by mRNA analysis with respect to the expression of procollagen alpha 1(I), integrin beta 1, interleukin -6, transforming growth factor beta 1, keratinocyte growth factor and activin beta A. The most pronounced effect in cyclosporine-treated rat s was the strong down-regulation of activin beta expression. In cryose ctions of granulation tissue from the same rats, the distribution and expression intensity of intercellular adhesion molecule and its recept ors were investigated by immunohistology. Clearly, a time course was d etectable. Tissue from CsA-treated animals showed a delay of three day s compared to untreated animals. Apoptosis was also delayed in CsA-tre ated rats by around three days. Furthermore, we investigated the effec t of CsA on the expression of collagen alpha 1(I), fibronectin and mat rix metalloprotease 1 genes in dermal fibroblasts from untreated donor s. No changes in the mRNA steady state levels of these genes were reve aled after direct addition of different doses of CsA to fibroblast cul tures. Our data suggest that CsA may interfere with the complicated ne t of interactions between connective tissue and the immune system by d own-regulation of the inflammatory phase by modulation of cytokines an d a subsequent delay of tissue repair.