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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011364-05
Application #
2903143
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Liberman, Ellen S
Project Start
1996-05-01
Project End
2002-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
5
Fiscal Year
2000
Total Cost
$255,589
Indirect Cost
Name
North Carolina State University Raleigh
Department
Anatomy/Cell Biology
Type
Schools of Veterinary Medicine
DUNS #
City
Raleigh
State
NC
Country
United States
Zip Code
27695
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