Oxidative stress and Graves' ophthalmopathy: in vitro studies and therapeutic implications

Graves' ophthalmopathy (GO) is a disorder of autoimmune origin caused by a complex interplay of endogenous and environmental factors. After recognition of one or more antigens shared by thyroid and orbit, activated T lymphocytes infiltrating the orbit trigger a cascade of events leading to production of cytokines, growth factors and oxygen reactive species. Proliferation of adipocytes and fibroblasts then follows, with an increased synthesis of glycosaminoglycans (GAG), which attract water and cause edema of orbital structures and venous congestion. Proliferation of orbital fibroblasts and adipocytes, both in the retroocular tissue and in the perimysium of extraocular muscles, are among the most important events leading to the increased volume of orbital structures (fibroadipose tissue and extraocular muscles). The contribution of oxygen reactive species to the changes occurring in the orbit is underscored by in vitro studies. Superoxide radical stimulates orbital fibroblasts to proliferate and to produce GAG. Furthermore, hydrogen peroxide induces expression of HLA-DR and heat shock protein-72, involved in antigen recognition and T-lymphocyte recruitment. Cigarette smoking, which is probably the most important environmental factor associated with GO occurrence and maintenance, might also act, among other mechanisms, by enhancing generation of oxygen reactive species and reducing antioxidant production. Substances such as nicotinamide, allopurinol and pentoxifylline reduce superoxide- or hydrogen peroxide-induced proliferation of fibroblasts, GAG production and HLA-DR or HSP-72 expression by GO orbital fibroblasts, possibly through scavenging oxygen free radicals. Two small, non-randomized and/or uncontrolled studies investigated the effects of nicotinamide, allopurinol or pentoxifylline on GO. Favorable results were reported, but data are not fully convincing and the true effectiveness of these agents needs to be verified in randomized, controlled trials enrolling a larger number of patients. It currently seems unlikely that they may find a relevant place in the limited armamentarium available for the management of severe GO.