Inhibition of Endotoxin-Induced Uveitis by a Metal Chelator

Abstract

Purpose:: Uveitis, an inflammation inside the eye, can develop due to autoimmune disorders, infection, or exposure to toxins. Severe and permanent visual loss can result from uveitis. In addition, uveitis can lead to other ocular complications which may produce vision loss such as glaucoma, cataracts or retinal damage. Current therapies of uveitis include steroids and immunosuppressive agents. Because inflammation is invariably associated with oxidative stress which may be intertwined with transition metal ions, we have investigated the effect of the metal chelator, EDTA, on endotoxin-induced uveitis (EIU).

Methods:: EIU, an animal model of acute uveitis , was induced in Lewis rats by injecting lipopolysaccharide. Controls were injected with the carrier, saline. Immediately after the injection and then after every four hours, one set of rats in the control and EIU groups was topically treated with EDTA + methylsulfonyl methane (MSM). MSM acts as a permeability enhancer. Using radiolabeled EDTA, we have demonstrated that EDTA enters inside the various parts of the eye when topically applied in conjunction with MSM. At 6 and 24 hrs time points, rats were sacrificed and the number of infiltrating cells, protein, TNF-α and PGE2 were determined in the aqueous humor. The redox sensitive transcription factor, NF-ΚB, the inflammatory markers and oxidative stress markers were analyzed in the sections of the eye after immunohistochemical staining.

Results:: At 24 hrs, aqueous humor of the rats with EIU, showed the presence of infiltrating cells, protein, TNF-α and PGE2 while that of the controls had none. The levels of these markers were significantly lower in the EIU rats which were treated with EDTA + MSM eye drop when compared with those in the untreated EIU rats. Immunohistochemistry also demonstrated that increase in the inflammatory markers and oxidative markers in the EIU rats were significantly suppressed by EDTA + MSM. NF-ΚB activation was more pronounced at 6 hr. time point, consistent to it being upstream of the inflammatory response.

Conclusions:: Topical application of EDTA + MSM decreased the extent of ocular inflammation in the animal model of acute uveitis. It therefore appears that induction of EIU involves transition metal ions and that chelation therapy using the above components have a potential against uveitis.

Keywords: uveitis-clinical/animal model • autoimmune disease • antioxidants