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Originally published In Press as doi:10.1167/iovs.08-3171 on June 10, 2009
 (Investigative Ophthalmology and Visual Science. 2009;50:5487-5494.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.08-3171
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Dual Role of Intravitreous Infliximab in Experimental Choroidal Neovascularization: Effect on the Expression of Sulfated Glycosaminoglycans

Caio V. Regatieri,1,2,3 Juliana L. Dreyfuss,1,3 Gustavo B. Melo,2 Daniel Lavinsky,2 Michel E. Farah,2 and Helena B. Nader1

From the Departments of 1Biochemistry, Molecular Biology Division, and 2Ophthalmology, Universidade Federal de São Paulo, UNIFESP, São Paulo, SP, Brazil.

Corresponding author: Helena B. Nader, Department of Biochemistry, Molecular Biology Division, Universidade Federal de São Paulo, UNIFESP, São Paulo, SP, Brazil; hbnader.bioq{at}epm.br.

Purpose. To determine effects of intravitreous anti-TNF-{alpha} (infliximab) in a laser-induced choroidal neovascularization (CNV) model by fluorescein angiogram (FA), immunofluorescence, ELISA, and glycosaminoglycan analyses.

Methods. CNV induction was performed using argon laser. Rats were divided into eight groups (no-laser no-infliximab; laser; laser with 10, 20, 40, 80, or 320 µg infliximab; and isotype-matched IgG). After 3 weeks, CNV area was measured by FA and von Willebrand factor (vWF) immunofluorescence. VEGF, TGF-β, and syndecan-4 were evaluated by ELISA and immunofluorescence. Glycosaminoglycan expression was determined in retina and choroid of animals metabolically labeled with [35S]-sulfate. Cytotoxicity was investigated using ARPE-19 and endothelial cells.

Results. FA showed significant reduction in the low-dose infliximab groups (10–40 µg), confirmed by vWF immunofluorescence that showed 49% decrease in the CNV. VEGF and TGF-β decreased expression detected by ELISA and immunofluorescence paralleled these results. Similar data were observed for syndecan-4. The expression of these molecules in the neovascularization area using 320 µg was similar to the no-infliximab laser group or laser with isotype-matched IgG. Heparan sulfate expression in retina and choroid paralleled the observed effects on angiogenesis. Increased expression of chondroitin sulfate in retina and dermatan sulfate in choroid reflects the effects of injury and fibrosis using high doses of anti-TNF-{alpha}. Infliximab showed no cytotoxic effect in ARPE-19 cells, whereas high doses led to 20% decrease in endothelial cell viability.

Conclusions. Intravitreal infliximab shows dual effect on the development of laser-induced CNV. It reduces angiogenesis and glycosaminoglycan expression at low doses, whereas opposite effects are observed at high doses.






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