SUPEROXIDE RADICAL PRODUCTION STIMULATES RETROOCULAR FIBROBLAST PROLIFERATION IN GRAVES OPHTHALMOPATHY

Retroocular fibroblast proliferation is believed to be a key component in the pathogenesis of Graves' ophthalmopathy. In the present study, we assessed the ability of superoxide radicals, generated using the xa nthine oxidase/hypoxanthine system to induce cellular proliferation in cultured human retroocular fibroblasts obtained from two patients wit h severe Graves' ophthalmopathy and two control patients undergoing co rrective eye surgery, In tissue obtained from patients with Graves' op hthalmopathy, fibroblast proliferation, as assessed by [H-3]-thymidine incorporation, was induced by superoxide radicals in a dose-dependent manner, Xanthine oxidase or hypoxanthine alone had no proliferative e ffect, and control retroocular fibroblasts showed no proliferation in response to superoxide generation. Preincubation with the antithyroid drug methimazole, at concentrations ranging from 0-25 mu M, prevented superoxide-induced fibroblast proliferation in a dose-response pattern . Preincubation With the xanthine oxidase inhibitor, allopurinol (1.0 mM) or the antioxidant nicotinamide (10 mu M) also inhibited superoxid e-induced fibroblast proliferation, whereas propylthiouracil (10 mu M) had little effect. These studies suggest a pathway through which oxyg en free radicals may contribute to the retroocular fibroblast prolifer ation observed in patients with Graves' ophthalmopathy. (C) 1997 Acade mic Press Limited.