Anti-inflammatory effect of angiotensin type 1 receptor antagonist on endotoxin-induced uveitis in rats.
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 microg 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 losartan 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.
Miyazaki
Akiko
A
Department of Ophthalmology and Visual Sciences, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Kitaichi
Nobuyoshi
N
Ohgami
Kazuhiro
K
Iwata
Daiju
D
Jin
Xue-Hai
XH
Iwabuchi
Kazuya
K
Morohashi
Taiki
T
Ohno
Shigeaki
S
Onoé
Kazunori
K
D000208:Acute Disease; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018932:Chemokine CCL2 / Q000378:metabolism; D002924:Ciliary Body / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D008070:Lipopolysaccharides; D019808:Losartan / Q000627:therapeutic use*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D011917:Rats, Inbred Lew; D012084:Renin-Angiotensin System / Q000502:physiology; D012173:Retinitis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012486:Salmonella typhimurium; D013601:T-Lymphocytes / Q000276:immunology; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014605:Uveitis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D047228:Angiotensin II Type 1 Receptor Blockers; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D008070:Lipopolysaccharides; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D019808:Losartan