Myofibroblasts in phenytoin-induced hyperplastic connective tissue in the rat and in human gingival overgrowth

Phenytoin is a commonly used anticonvulsant drug for the prevention of seizures. A common side effect of phenytoin (PHT) therapy is connective tissue hyperplasia, particularly in the oral cavity manifesting as gingival overgrowth. Our previous studies concerning the molecular mechanisms of drug-induced gingival overgrowth have demonstrated that PHT alters the normal tissue turnover/wound healing signal by causing changes in macrophage phenotype, resulting in the upregulation of essential polypeptide growth factors such as platelet-derived growth factor (PDGF). The cellular consequences of this elevation in growth factor have not been investigated. The present light and electron microscopic study of rat hyperplastic connective tissue and human gingival overgrowth induced by PHT treatment revealed the presence of numerous myofibroblasts. Cells identified as myofibroblasts were evident in all PHT-treated tissue samples and were characterized by an elongated fusiform cell shape, abundant cytoplasmic rough endoplasmic reticulum/polyribosomes, and accumulations of sub-plasmalemmal microfilaments containing spindle densities. These cells were never observed in control tissues. Myofibroblasts are associated with the later stages of tissue turnover, specifically with the transition from the granulation to the remodeling phases of the wound healing process. The presence of myofibroblasts in hyperplastic connective and gingival tissues induced by PHT treatment suggests that PHT exacerbates the normal tissue turnover/wound healing signals responsible for the appearance of myofibroblasts.