PMID- 18087711
OWN - NLM
STAT- MEDLINE
DCOM- 20080715
LR  - 20220317
IS  - 0721-832X (Print)
IS  - 0721-832X (Linking)
VI  - 246
IP  - 5
DP  - 2008 May
TI  - Anti-inflammatory effect of angiotensin type 1 receptor antagonist on 
      endotoxin-induced uveitis in rats.
PG  - 747-57
AB  - 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.
FAU - Miyazaki, Akiko
AU  - Miyazaki A
AD  - Department of Ophthalmology and Visual Sciences, Hokkaido University Graduate 
      School of Medicine, Sapporo, Japan.
FAU - Kitaichi, Nobuyoshi
AU  - Kitaichi N
FAU - Ohgami, Kazuhiro
AU  - Ohgami K
FAU - Iwata, Daiju
AU  - Iwata D
FAU - Jin, Xue-Hai
AU  - Jin XH
FAU - Iwabuchi, Kazuya
AU  - Iwabuchi K
FAU - Morohashi, Taiki
AU  - Morohashi T
FAU - Ohno, Shigeaki
AU  - Ohno S
FAU - Onoe, Kazunori
AU  - Onoe K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20071218
PL  - Germany
TA  - Graefes Arch Clin Exp Ophthalmol
JT  - Graefe's archive for clinical and experimental ophthalmology = Albrecht von 
      Graefes Archiv fur klinische und experimentelle Ophthalmologie
JID - 8205248
RN  - 0 (Angiotensin II Type 1 Receptor Blockers)
RN  - 0 (Ccl2 protein, rat)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Transcription Factor RelA)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - JMS50MPO89 (Losartan)
SB  - IM
MH  - Acute Disease
MH  - Angiotensin II Type 1 Receptor Blockers/*therapeutic use
MH  - Animals
MH  - Aqueous Humor/metabolism
MH  - Autoimmune Diseases/*drug therapy/metabolism/pathology
MH  - Chemokine CCL2/metabolism
MH  - Ciliary Body/metabolism/pathology
MH  - Disease Models, Animal
MH  - Female
MH  - Lipopolysaccharides
MH  - Losartan/*therapeutic use
MH  - Lymphocyte Activation
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Rats
MH  - Rats, Inbred Lew
MH  - Renin-Angiotensin System/physiology
MH  - Retinitis/*drug therapy/metabolism/pathology
MH  - Salmonella typhimurium
MH  - T-Lymphocytes/immunology
MH  - Transcription Factor RelA/metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
MH  - Uveitis/*drug therapy/metabolism/pathology
EDAT- 2007/12/19 09:00
MHDA- 2008/07/17 09:00
CRDT- 2007/12/19 09:00
PHST- 2007/08/02 00:00 [received]
PHST- 2007/11/08 00:00 [accepted]
PHST- 2007/10/22 00:00 [revised]
PHST- 2007/12/19 09:00 [pubmed]
PHST- 2008/07/17 09:00 [medline]
PHST- 2007/12/19 09:00 [entrez]
AID - 10.1007/s00417-007-0730-2 [doi]
PST - ppublish
SO  - Graefes Arch Clin Exp Ophthalmol. 2008 May;246(5):747-57. doi: 
      10.1007/s00417-007-0730-2. Epub 2007 Dec 18.