The effect of cyclosporin and lipopolysaccharide on fibroblasts: Implications for cyclosporin-induced gingival overgrowth

Drug-induced gingival overgrowth is an adverse side effect associated principally with 3 different types of drugs; specifically the antiepileptic phenytoin, the calcium channel antagonist nifedipine, and the immunosuppressant cyclosporin. The present study has analyzed the effect of cyclosporin and lipopolysaccharide on fibroblasts from 3 different sources: 1) normal healthy human gingiva (NHGF); 2) overgrown gingiva from 2 patients taking cyclosporin (CHGF); and 3) human fetal lung (WI-38). Fibroblasts isolated from cyclosporin-associated gingival overgrowth were significantly less responsive to cyclosporin in terms of DNA, total protein, and proteoglycan synthesis. This finding supports the in vivo response where few fibroblasts are seen but marked overgrowth of fibrous tissue occurs. Lipopolysaccharide derived from Fusobacterium nucleatum and Escherichia coli was capable of inhibiting DNA synthesis significantly in all 3 fibroblast types. Total protein synthesis by CHGF cells was inhibited differentially by Fusobacterium nucleatum LPS and addition of cyclosporin to this system resulted in reversal of the inhibition. A synergistic effect was noted when the proteoglycan output of NHGF cells was assessed in response to co-incubation with cyclosporin and Escherichia coli LPS. The study shows that bacterial LPS may be an important co-factor in the pathogenesis of cyclosporin-induced gingival overgrowth