Exploring the Regulation of Inducible Nitric Oxide Synthase and the Effects of Nitric Oxide Production in Endotoxin-induced Uveitis

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Title: Exploring the Regulation of Inducible Nitric Oxide Synthase and the Effects of Nitric Oxide Production in Endotoxin-induced Uveitis
Author: Pittman, Kristianna Marie
Advisors: Kenneth B Adler, Committee Co-Chair
Brian C Gilger, Committee Member
Janice B. Allen, Committee Co-Chair
Barry P Peters, Committee Member
Abstract: In this study, we hypothesized that during anterior uveitis NF-kappaB activity and subsequent iNOS gene expression increase as a result of the decrease in TGFbeta2 activity. Increased iNOS expression leads to increased NO activity and production of peroxynitrite. We further proposed that exogenous administration of TGFbeta2, i.e. increasing TGFbeta2 activity or scavenging peroxynitrite may protect against EIU. Scavenging of peroxynitrite was examined by using the peroxynitrite scavenger, ebselen. All studies were undertaken using either the in vivo model of anterior uveitis, endotoxin-induced uveitis (EIU) or the in vitro system of iris ciliary body cells stimulated with IL-1beta. Results demonstrated that TGFbeta2 decreases iNOS expression during EIU, however, the mechanism is NF-kappaB-independent. Exogenous administration of TGFbeta2 did not protect against EIU. These studies identified peroxynitrite as a component of EIU, through the identification of nitrated MnSOD, a peroxynitrite target. Scavenging of peroxynitrite by the compound ebselen did protect against EIU. Ebselen mediated inhibition of EIU by scavenging peroxynitrite, inhibiting the recruitment of polymorphonuclear (PMN) leukocytes and suppressing NF-kappaB activation. This study demonstrated that TGFbeta2 negatively regulates iNOS expression during EIU and that iNOS, NO, and peroxynitrite are key mediators in the pathogenesis of EIU. Attentuation of uveitis occurs when suppression of these mediators is coupled to PMN suppression and inhibition of NF-kappaB activation.
Date: 2003-09-17
Degree: PhD
Discipline: Comparative Biomedical Sciences
URI: http://www.lib.ncsu.edu/resolver/1840.16/3017


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