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Chintan Patel, Donnicia James, Wenzheng Hu, Robin J Goody, Rahel Zulliger, Gabriella Widmer, Peter D Westenskow, Matthew S Lawrence; Inflammatory cytokine analysis of ocular fluids from a primate model of chronic vascular leakage and neovascularization. Invest. Ophthalmol. Vis. Sci. 2020;61(7):5395.
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The development of wet age-related macular degeneration (AMD), involving vascular leakage and neovascularization (NV), is mediated by various inflammatory and angiogenic cytokines. VEGF, IL-8, FGF, angiopoietins (Ang) and their interplay have been broadly implicated in wet AMD, diabetic retinopathy and retinal vein occlusion. Here we present analysis of pro-inflammatory and pro-angiogenic cytokines perturbed in a nonhuman primate (NHP) model of chronic retinal vascular leakage and NV induced by the gliotoxin DL-2-aminoadipic acid (DLAAA).
African green monkey aqueous and vitreous humor were sampled from control and DLAAA-treated eyes at baseline and weeks 2, 6, 8, 10 and 12 for cytokine analysis. Samples were analyzed using R&D Systems kit (LXSAHM; Minneapolis, USA) or with beads from Luminex Corp (Austin, USA) coated with antibodies in-house. They were diluted 1:5 with assay buffer from the kit or in-house assay buffer. Analysis of beads was performed on a Flexmap 3D system and data analyzed with a LiquiChip Analyzer (Luminex Corp). Eyes were imaged preceding sample collection at each time point.
DLAAA treatment triggered morphological changes in the retina and perturbed a number of cytokines in both aqueous and vitreous humor during early (weeks 2, 6) and late phases (weeks 8, 10, 12) compared to their respective controls. Cytokines significantly elevated during both the early phase and late phase included Ang1, Angptl-4 and gp130 in the aqueous, and Ang1, MCP-1, Angptl-4, gp130, IL-6ra and CRP in the vitreous. Cytokines remaining elevated during early phase but declining during late phase included Ang2, IL-6, MCP-1, S100B, IL-6ra and CRP in the aqueous, and Ang2, IL-6 and S100B in the vitreous. Additionally, aqueous levels of FGF, VEGF and Ang2 were higher at weeks 2, 6 and 8, and the vitreous levels of VEGF and Ang2 were elevated early and later at weeks 8 and 10. These findings highlight a role of interplay of these cytokines in ocular fluids in advancing and stabilizing the DLAAA pathology.
Perturbations in VEGF and Ang2 levels within ocular fluids in response to DLAAA mimic clinical findings in patients with chronic retinal vascular disease. These cytokines response align with pathological changes and together illustrate the utility of the NHP DLAAA model for evaluating novel agents for treatment of chronic retinal vascular diseases.
This is a 2020 ARVO Annual Meeting abstract.
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