epidermal-growth-factor and Gingival-Hyperplasia

Proposed mechanisms of the side effect of drug-induced gingival hyperplasia are reviewed. Hypotheses with regard to inflammation from bacterial plaque, increased sulfated glycosaminoglycans, immunoglobulins, gingival fibroblast phenotype population differences, epithelial growth factor, pharmacokinetics and tissuebinding, collagenase activation, disruption of fibroblast cellular sodium/calcium flux, folic acid and a combination hypothesis are evaluated.

Topics: Dental Plaque; Diltiazem; Epidermal Growth Factor; Fibroblasts; Folic Acid; Gingival Hyperplasia; Glycosaminoglycans; Humans; Immunoglobulin Isotypes; Microbial Collagenase; Nifedipine; Phenytoin

Calcium-channel blockers such as nifedipine could be associated with gingival overgrowth. The aim of this study was to examine the role of nitric oxide (NO) on nifedipine-induced gingival hyperplasia along with submandibular secretory function in rats. Animals in divided groups received nifedipine (250 mg/kg diet) alone and in combination with L-arginine (2.25% w/v) or N(omega)-nitro-L-arginine methyl ester (L-NAME) (0.7% w/v) in drinking water for 20 days. Controls received only tap water. Pure submandibular saliva was collected intraorally by micropolyethylene cannula and the mandibular gingiva was examined by means of dissecting microscope for signs of redness, thickness, inflammation and exuda. Twenty-day nifedipine treatment induced gingival hyperplasia accompanied with reduced salivary flow rate and concentrations of total protein, epidermal growth factor (EGF) and calcium in comparison with controls. Co-treatment of animals with nifedipine and L-arginine protected from gingival hyperplasia and retained flow rate, and concentrations of total protein, EGF and calcium in normal levels. Co-treatment of animals with nifedipine and L-NAME potentiated nifedipine-induced gingival hyperplasia and reductions in flow rate and concentrations of total protein, EGF, and calcium. It is concluded that nifedipine-induced gingival hyperplasia is associated with salivary dysfunction. Activation of cGMP-dependent positive signal-transduction mechanisms in salivary glands might be the mechanism for protective effects of NO against nifedipine-induced gingival hyperplasia.

Topics: Animals; Arginine; Calcium; Calcium Channel Blockers; Epidermal Growth Factor; Gingival Hyperplasia; Male; NG-Nitroarginine Methyl Ester; Nifedipine; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Wistar; Saliva; Salivary Proteins and Peptides; Submandibular Gland

Human gingival fibroblasts derived from tissue explants of two patients with dilantin-induced gingival hyperplasia (DGH) and one patient with idiopathic gingival fibromatosis (GF) were studied with respect to the effect of epidermal growth factor (EGF) on the proliferative characteristics of these cells. Immunohistochemical staining showed that there were more EGF receptor-positive cells among DGH fibroblasts than among either normal gingival fibroblasts (NG) or GF cells. Furthermore, EGF binding studies showed that, in spite of there being no disparity in binding affinity among all these cells, DGH fibroblasts possessed approximately two-fold more EGF receptors than either NG or GF cells. In addition, the growth-promoting effect of exogenously added EGF was concentration-dependent in DGH fibroblasts but was not in either NG or GF cells. All of the above findings clearly demonstrate that DGH and GF fibroblasts exhibit distinct disparity in proliferative responsiveness to EGF and suggest that different mechanisms may be involved in the pathogenesis of these two forms of gingival hyperplasia. These observations also suggest a possible therapeutic approach for blocking EGF-induced cell proliferation in DGH.

Topics: Anticonvulsants; Cell Division; Cells, Cultured; Epidermal Growth Factor; ErbB Receptors; Fibroblasts; Fibromatosis, Gingival; Gingival Hyperplasia; Humans; Immunohistochemistry; Phenytoin

Human gingival fibroblasts derived from 2 patients before and 9 months after the start of phenytoin (PHT) therapy were studied with respect to the effect of epidermal growth factor (EGF) on the incorporation of 3H-thymidine into DNA, binding of EGF to its cell-surface receptor, internalization of EGF-receptor-ligand complexes and, finally, with respect to EGF receptor mRNA levels. In fibroblasts derived from the patient who developed gingival overgrowth during the PHT medication (responder) as well as in the fibroblasts derived from the patient where gingival overgrowth did not develop (non-responder), the affinity of the EGF receptor for EGF was not significantly changed. In the non-responder patient the internalization of EGF receptor ligand was decreased, whereas it was increased in the fibroblasts derived from the responder patient after PHT therapy. The steady-state level of EGF-r mRNA increased significantly (p less than 0.001) in the cultured fibroblasts derived from the non-responder but decreased (p less than 0.05) in the responder patient following PHT therapy. Ligand affinity cross-linking studies revealed one major component of EGF receptor with a molecular weight of 170 KDa in fibroblasts from the non-responder as well as from the responder. The study indicates that PHT medication results in a down-regulation of EGF receptor metabolism in fibroblasts derived from a responder patient, whereas in the non-responder patient EGF receptor metabolism is up-regulated.

Topics: Cell Division; Cells, Cultured; Child; DNA; Epidermal Growth Factor; ErbB Receptors; Fibroblasts; Gingival Hyperplasia; Humans; Phenytoin; RNA, Messenger; Time Factors

Effect of 5,5 diphenylhydantoin (phenytoin; PHT) alone or in combination with epidermal growth factor (EGF) on the intracellular accumulation of the radioisotope 45Ca2+ (4 min labelling period) was determined in gingival fibroblasts. EGF as well as PHT increased the intracellular accumulation of the radioisotope in normal gingival fibroblasts by approximately 2 and 1.6-fold, respectively. In contrast, in fibroblasts derived from the phenytoin-induced gingival overgrowth, neither EGF nor PHT stimulated intracellular accumulation of 45Ca2+. When normal gingival fibroblasts were treated in vitro with EGF in combination with PHT, the EGF-induced increase in intracellular accumulation of the radioisotope 45Ca2+ was abolished. The rate of efflux of the radioisotope 45Ca2+ in prelabelled normal gingival fibroblasts was decreased by PHT treatment in vitro to a level already present in fibroblasts derived from PHT-induced gingival overgrowth. This study indicates that PHT influences the cellular calcium metabolism in fibroblasts which may contribute to the pathogenesis of gingival overgrowth.

Topics: Adolescent; Calcium; Calcium Radioisotopes; Cells, Cultured; Child; Epidermal Growth Factor; Fibroblasts; Gingiva; Gingival Hyperplasia; Humans; Phenytoin; Time Factors

Topics: Cell Division; DNA; Epidermal Growth Factor; Fibroblasts; Gingiva; Gingival Hyperplasia; Humans; Nifedipine