Cyclosporin A‐induced gingival overgrowth in the rat: a histological, ultrastructural and histomorphometric evaluation

Abstract

This investigation was undertaken to further study cyclosporin A (CsA)-induced gingival overgrowth. Thirty mg/kg/d of vehicle or CsA solutions were given orally to 6-wk-old male Sprague-Dawley rats. After 4, 9, 14 and 19 wk 2 control and 2 experimental rats were anaesthetized, tissues fixed by intracardiac perfusion of fixative solution and jaws processed for Epon inclusion. Histological and ultrastructural studies conducted in a gingival portion (free gingiva) revealed the presence of hyalinization areas and of multinucleated cells (MCs) containing collagen fibrils (connective tissue), of amorphous areas and disorders of keratinization (epithelia). Histomorphometric evaluation indicated that in the CsA rats the mean cross-sectional area of the free gingiva was 2.52-fold increased compared to the controls. The connective tissue comprised 41.43% of this area (instead of 31.49% in controls). Additional histomorphometric evaluation was performed in 3 groups of free gingival portions: control (C group), CsA-non-respondent (CsA-nR) and CsA-respondent (CsA-R). The cross-sectional gingival areas studied were slightly lower than the mean area of all the control sites previously defined (groups C and CsA-nR) or showed the higher degrees of enlargement (CsA-R). In the CsA-R group the mean cross-sectioned area of the vessel profiles was increased and the number of fibroblast profiles decreased. In the CsA-nR group the number of vessel profiles and that of MCs profiles were increased. In the epithelia of the CsA-R group were increased (a) keratinized epithelia: thickness; thickness of the inner and of the outer compartments; surface area of spinous cell profiles; (b) oral gingival epithelium: number of cell layers (inner compartment); (c) oral sulcular epithelium: surface area of granular cell profiles; (d) junctional epithelium: thickness; number of cell layers. These results indicate that (a) the CsA induced modifications are not limited to enlarged gingiva (b) the overgrowth of the GCT is the result of a vasodilatation and of an increase in the volume of the extracellular matrix and (c) the increase of the epithelial thickness is mainly the result of a cell hypertrophy in the keratinized epithelia and of a cell hyperplasia in the junctional epithelium.

Loss of Basement Membrane Integrity in Human Gingival Overgrowth

“…Our previous studies have provided evidence that fibrotic enlargement of the gingival tissue is regulated by TGF-β1 and CCN2 and an imbalance of inflammatory mediators, accompanied by markers of EMT (Uzel et al, 2001;Kantarci et al, 2006;Sume et al, 2010). Elongated epithelial structures extending deep into the underlying connective tissues are characteristic of gingival overgrowth (Pernu et al, 1989;Seymour et al, 1996;Ayanoglou and Lesty, 1999). This histopathology suggested to us that EMT could be a biological process contributing to gingival overgrowth in which epithelial cells lose cell-to-cell contacts and become motile and migrate into the underlying connective tissue stroma.…”

“…In addition to fibrosis in the lamina propria, drug-induced gingival overgrowth is associated with thickening of epithelium and elongated rete pegs extending deep into the underlying connective tissue (Pernu et al, 1989). This phenomenon is related to expansion of the Stratum spinosum and is associated with increased mitotic activity within the epithelial layer (Ayanoglou and Lesty, 1999;Saito et al, 1999;Sume et al, 2010). It is not known, however, how such epithelial structures form and function in gingival overgrowth tissues.…”

Local Inflammation Exacerbates Cyclosporine A-Induced Gingival Overgrowth in Rats

“…Group IV (ligation and CsA): 10 rats were placed with orthodontic wires on the necks of right mandibular first molars. 1 week later, CsA was given to the rats in this group for 9 weeks with a daily dose of 30 mg/kg by gastric feeding, in olive oil [24].…”

Previous exposure to Cyclosporine A and periodontal breakdown in rats

“…However, enlargement of epithelial thickness, height and width of connective tissue, and increased density of fibroblasts and collagen have also been observed in some studies. [9][10][11] These studies were all designed applying CsA medication at the same time as the induction of periodontal disease. However, there is a lack of studies in which animals were immunosuppressed with cyclosporine first, followed by induction of periodontal disease to examine periodontal changes described in the literature.…”