Anterior uveitis is a form of intraocular inflammation afflicting millions of individuals each year. NITRIC OXIDE (NO) and TRANSFORMING GROWTH FACTOR-BETA (TGF-beta) have been implicated as key modulators of uveitis. We have shown that NO levels increase during lipopolysaccharide (LPS) - induced uveitis in rabbits and that inhibition of nitric oxide synthase (NOS), the enzyme responsible for synthesizing NO, blocks the uveitic response to LPS. TGF-beta, a cytokine with immunopotentiating and immunosuppressive properties is present in normal intraocular fluids. We have shown that TGF-beta suppresses cellular infiltration during LPS- induced uveitis and that TGF-beta2 levels in intraocular fluids decrease during the acute phase of this response. Based upon these results we suggest that NO and TGF-beta are TWO MAJOR MODULATORS of uveitis and that the severity of intraocular inflammation is a consequence of a balance between the inflammatory effects of NO and the antiinflammatory effects of TGF-beta. In this proposal, we will examine the mechanisms controlling the interaction between NO and TGF-beta in modulation of the inflammatory response to LPS. The following HYPOTHESIS will be addressed: NITRIC OXIDE (NO) AND TRANSFORMING GROWTh FACTOR-BETA (TGF-beta) ARE TWO KEY MEDIATORS OF ThE INTRAOCULAR INFLAMMATORY RESPONSE. NO INITIATES THE RESPONSE BY REACTING WITH SUPEROXIDE TO FORM PEROXYNITRITE, A TISSUE DAMAGING CHEMOATTRACTANT. TGF-beta INHIBITS PEROXYNITRITE - INDUCED CELLULAR INFILTRATION BY DECREASING NO PRODUCTION. To address this hypothesis, we will further characterize the in vivo inhibitory effect of TGF-beta2 and NOS inhibitors on LPS-induced uveitis in rabbits. We will determine if peroxynitrite is generated in LPS- and NO-induced ocular inflammation, and whether or not TGF-beta2-induced suppression of cellular infiltration involves altered iNOS transcription and/or translation of iNOS. Characterization of the roles of TGF-beta and NO in the ocular inflammatory response will provide information critical to understanding the pathogenesis of intraocular inflammation and designing new and effective therapeutic modalities for its treatment.
