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Chunhua Jiao, Christine Spee, Shikun He, Robert Mullins, Dean Eliott, David R Hinton, Elliott H Sohn; Angiofibrotic Response to Bevacizumab on Fibrovascular Membranes in Proliferative Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5821.
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We have previously reported the effect of bevacizumab on vitreous levels of connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF) in eyes operated on for traction retinal detachment (TRD) due to proliferative diabetic retinopathy (PDR). To better characterize the angiofibrotic response, we assessed the morphologic and biochemical alterations of extracted fibrovascular membranes in these eyes after VEGF inhibition.
In a randomized, controlled, prospective trial (www.clinicaltrials.gov NCT01270542) of 20 eyes (n=10 controls, n=10 given preoperative bevacizumab 3-7 days prior to diabetic traction detachment surgery), epiretinal membranes were excised at the time of vitrectomy. The membranes were snap frozen and sectioned at 9 µm. Sections were immunofluorescent stained with anti-CTGF or anti-VEGF antibody followed by antibody specific for endothelial cells (CD31), myofibroblasts (smooth muscle actin [SMA]), or cytokeratin. Quantitative and co-localization analysis of antibody content was obtained through immunofluorescence confocal microscopy. Masson trichrome staining, cell counting of H&E sections, and TUNEL staining was also performed on membranes. Multiple sections for each membrane were averaged for each eye. Data were analyzed using a paired student t-test to compare two groups.
The bevacizumab group had a greater than 25% reduction in co-localization in the CD31-CTGF and cytokeratin-CTGF studies compared to controls. There was no change in VEGF colocalization between the treated and controls. High baseline levels of fibrosis were observed in both groups. Cell apoptosis increased 51.34% (p=0.05) in bevacizumab-treated fibrovascular membranes (20.02%) compared to controls (9.75%).
Intravitreal bevacizumab 1.25 mg administered within one week of surgery significantly suppresses vitreous VEGF levels, but does not significantly alter VEGF or CTGF expression in fibrotic diabetic traction membranes. Bevacizumab may result in apoptosis within fibrovascular membranes. High baseline levels of fibrosis in both groups may explain the relative resistance of switching from angiogenesis to fibrosis in this study.
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