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Title: Cytokine-induced nitric oxide mediates tissue damage in experimental autoimmune uveitis
Author: Hoey, Sharon
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 1999
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The large amounts of nitric oxide (NO) produced by the inducible nitric oxide synthase (iNOS) has been described as a double-edged sword eliciting pro- or anti inflammatory effects in different immune situations. The aim of this study was to investigate the role of NO in ocular inflammation. Rat RPE cells were shown to produce NO in vitro in response to inflammatory stimuli but in vivo the RPE expressed little or no iNOS enzyme in the normal Lewis rat eye. However, expression of the iNOS enzyme was closely associated with disease activity in experimental autoimmune uveoretinitis (EAU), a model of ocular inflammation, induced in the Lewis rat following a single footpad injection of retinal antigens. iNOS was predominantly expressed by EDl+ macrophages, infiltrating the rod outer segments and lytic lesions across the retina, during the acute inflammatory stages of EAU. Immunoreactivity to iNOS corresponded with increased urinary NO metabolite (NOJ levels, peak clinical disease, maximum choroidoretinal infiltration, upregulated iNOS mRNA expression and the induction and upregulation of IFN-gamma mRNA expression. Moreover, treating immunised animals with modulators of the L- arginine:NO pathway altered both NO excretion and the pathogenesis of EAU. Increasing the levels of L-arginine increased urinary NO levels, accelerated the inflammatory response and increased disease severity whereas treatment with the NOS inhibitor, N -nitro-L-arginine methyl ester (L-NAME), reduced NO excretion, delayed the onset and reduced the clinical signs of EAU.iNOS mRNA was detected at all stages of disease and expression was upregulated during peak disease activity. L-arginine treatment enhanced cytokine mRNA expression, particularly of IFN-gamma, which was detected earlier than in control animals, corresponding with the more rapid onset of disease and increased disease severity observed in this group. L-NAME had little or no effect on iNOS or inflammatory cytokine mRNA expression. This study suggests that NO mediates tissue damage in EAU and highlights the importance of the macrophage as an effector cell in what is considered a CD4+ T cell-dependent disease. iNOS was also detected in the normal human retina. As the role of iNOS in the pathogenesis of ocular disease in man is revealed then the therapeutic potential of NOS inhibitors, particularly with the development of iNOS specific inhibitors, in the treatment of inflammatory and autoimmune-mediated disease can be assessed.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available