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Anti-inflammatory effect of angiotensin type 1 receptor antagonist on endotoxin-induced uveitis in rats.

Miyazaki A, Kitaichi N, Ohgami K, Iwata D, Jin XH, Iwabuchi K, Morohashi T, Ohno S, Onoé K

Department of Ophthalmology and Visual Sciences, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

BACKGROUND: Angiotensin II type 1 (AT1) receptor-antagonists are widely used for treatment of hypertension. Recent studies have demonstrated a protective effect of renin angiotensin system (RAS) antagonism against immune-mediated inflammatory diseases such as myocarditis, chronic allograft rejection, antiglomerular basement membrane nephritis, colitis, and arthritis. However, only a few reports have demonstrated the effect of RAS in ocular inflammatory conditions. The purpose of this study was to investigate the anti-inflammatory effect of a selective AT1 receptor antagonist, losartan, on endotoxin-induced uveitis (EIU) and compare the effect on experimental autoimmune uveoretinitis (EAU). METHODS: To induce EIU, 7-week-old Lewis rats were injected subcutaneously with 200 mug lipopolysaccharide (LPS). Losartan was administered intravenously at the same time. The aqueous humor was collected from eyes 24 h after LPS injection. The number of infiltrating cells, protein concentration, and levels of tumor necrosis factor (TNF)-alpha and monocyte chemoattractant protein-1 (MCP-1) in the aqueous humor were determined. The collected eyes were immunohistochemically stained with monoclonal antibody for activated nuclear factor (NF)-kappaB. To induce EAU, C57BL/6 mice (6-8 weeks old) were immunized with human interphotoreceptor retinoid binding protein (hIRBP)-derived peptide emulsified in complete Freund's adjuvant (CFA) and concomitantly injected with purified Bordetella pertussis toxin (PTX). Clinical severity of EAU and T cell proliferative response were analyzed. RESULTS: Losartan significantly suppressed the development of EIU. Numbers of aqueous cells of control EIU rats, those from EIU rats treated with 1 or 10 mg/kg of losratan were 75.3 +/- 45.6 x 10(5), 27.9 +/- 8.1 x 10(5), or 41.3 +/- 30.9 x 10(5) cells/ml respectively (p < 0.01 vs control). Aqueous protein, TNF-alpha, and MCP-1 levels were also significantly decreased in a manner dependent on the amount of losartan administered (p < 0.01). Treatment of EIU rats with losartan suppressed activation of NF-kappaB at the iris ciliary body. Thus, the suppressive effect of losartan on ocular inflammation in EIU appeared to result from down-regulation of NF-kappaB activation and reduction of inflammatory cytokine production. On the other hand, in the EAU model, neither the clinical score nor the antigen-specific T cell proliferative response was significantly influenced by the treatment with losartan. CONCLUSIONS: The present findings indicate that RAS may be involved in the acute inflammation of the eye, but not in T cell-dependent ocular autoimmunity. Antagonism of the RAS may be a potential prophylactic strategy for treatment of the human acute ocular inflammation.

Published 8 April 2008 in Graefes Arch Clin Exp Ophthalmol, 246(5): 747-57.
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