Ultrastructural and Histochemical Features of the Ground Substance in Cyclosporin A‐Induced Gingival Overgrowth

Abstract

The overgrowth-affected gingiva of patients treated with cyclosporin A after kidney transplant was examined with ultrastructural and histochemical methods to evaluate the involvement of connective tissue. Gingival overgrowth has the same clinical signs as local edema. The ultrastructural study showed that the dimensional increase was largely due to increased production of amorphous ground substance by fibroblasts, possibly resulting from an increased release of histamine by mast cells. The histochemical data revealed that the affected tissues contained higher levels of glycosaminoglycans and that cyclosporin A induced comparably high levels of glycosaminoglycans in in vitro cultures of fibroblasts obtained from normal gingiva. The combination of ultrastructural and histochemical data, therefore, strongly suggests that the response of the connective tissue in gingival overgrowth cannot be ignored and may be the main cause of the observed pathological condition.

Growth factors and proliferation of cultured rat gingival cells in response to cyclosporin A

“…However, the 23–25% increases seem to be small in comparison with the report that the administration of cyclosporin A to rats enlarged the cross‐sectional area of the gingival tissue by more than 150% (25). In addition, an abnormal synthesis of collagen and other extracellular matrix components (3, 4, 26), and a decline of collagen turnover via changes in the matrix metalloproteinases and tissue inhibitors of metalloproteinase (9, 27, 28) reportedly occur in association with cyclosporin A‐induced gingival outgrowth. Thus, the mechanism by which cyclosporin A induces the gingival outgrowth is probably comprised of several factors, and includes the enhancement of gingival cell proliferation.…”

Influence of Mast Cells in Drug-Induced Gingival Overgrowth

“…Despite the great number of studies on mast cell populations, at the present time studies regarding the stimulation of local RAS by mast cells in human gingiva are very few. Mariani et al, 1996, examined the overgrowth that affected gingiva of patients treated with cyclosporine after kidney transplant to evaluate the involvement of connective tissue [6]. The ultrastructural study showed that the dimensional increase was largely due to increased production of amorphous ground substance by fibroblasts, possibly resulting from an increased release of mast cells mediators.…”

“…A recently published study demonstrated that mast cell tryptase and chymase were expressed significantly higher in DIGO tissues compared to healthy gingiva and may contribute to alterations in basement membranes [8]. In one clinical study on CsA induced gingival overgrowth found the dimensional increase of amorphous ground substances by fibroblasts and this was possibly resulting from an increased release of mast cell mediators [6]. In contrast to this, Asahara et al, 2000, demonstrated that mast cells are not necessary in the development of cyclosporin A-induced gingival hyperplasia, and that the increased number of mast cell observed in the enlarged gingiva may be a secondary effect of gingival hyperplasia [72].…”

“…Mast cells have been associated with fibrosis in other organs besides gingival tissues, including kidney, heart, lung, and liver.Models of gingival fibrosis in mast cell-deficient mice have not been extensively studied. The available in vitro data [6, 8, 37] showed the functional role of mast cells in fibrogenesis and suggested the net outcome of mast cell involvement as a profibrotic stimulator.…”

“…It may partially or completely cover the tooth surfaces, including the occlusal surfaces, as well as extending the other way, into the sulcus. The epithelial surface is usually smooth and fibrotic, but can be nodular in CsA-induced gingival enlargement [6]. If there is underlying periodontal disease then the tissues may be inflamed, red, or purplish in colour, and highly vascularised, with a tendency to bleed profusely [7].…”