INFLUENCE OF CYCLOSPORINE-A ON GROWTH AND EXTRACELLULAR-MATRIX SYNTHESIS OF HUMAN FIBROBLASTS

Cyclosporine A (CyA) is a powerful nonsteroidal immunosuppressive agent used to prevent graft rejection of organ and bone marrow transplants. A major side effect observed can be attributed to the fibroblast and its functions: proliferation of fibroblasts and formation of fibrotic tissue in the gingiva (fibrous hyperplasia) and in the kidney are induced. The mechanism of both is still obscure. In order to elucidate whether these side effects are due to the drug acting on human fibroblasts itself or whether they are indirect ones mediated by factors released by lymphocytes, cultures of human gingiva fibroblasts were exposed to CyA under defined in vitro conditions. Incubation with CyA for 72 hours resulted in a dose-dependent stimulation of DNA synthesis, whereas glycosaminoglycan (GAG) synthesis was slightly suppressed. Long-term incubation (6 weeks) with 1-mu-g/ml CyA resulted again in stimulation of growth parameters: compared to the drug-free control, cell number increased to 168%, incorporation of H-3-thymidine into DNA to 143%, and overall protein content to 159%. Collagen and GAG synthesis were elevated to approximately 120%. When corrected for cell number or cell protein content, this represents a decline in matrix synthesis, comparable to short-term incubations. These results indicate that a direct effect of CyA on proliferation of human gingival fibroblasts is responsible for some of the observed hyperplasia.