The biochemical rationale for normobaric hyperoxia treatment of retinal disorders
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PURPOSE: Ischemic retinopathies such as diabetic retinopathy (DR), retinal vein occlusions (RVO), and age-related macular degeneration (AMD) are ocular diseases caused by abnormal changes in the microvasculature that results in ischemia. This is often followed by a secondary phase characterized by pathological neovascularization and leakage of fluid, which contributes to a loss of visual acuity in affected patients. Anti-VEGF therapy, the current standard of treatment for ischemic retinopathies, is invasive, costly, and lacks a known treatment period. Supplemental oxygen provides the therapeutic potential of not only oxygenating hypoxic retinal cells, but also reducing the neovascularization and edema associated with many ischemic retinopathies through the downregulation of proangiogenic and pro-inflammatory cytokines.The objective of this study is to understand the biochemical underpinnings of treating ischemic retinopathies with hyperoxia. The elucidation of the effect hyperoxia on the molecular level may help guide the development of future studies regarding this novel treatment. METHODS: 68 undiluted vitreous samples were obtained during pars plana vitrectomy (PPV) and the concentration analysis of 34 proteins was analyzed using the Bio-Plex Pro Human Cancer Biomarker Assay. Vitreous samples were divided into three groups: (1) eyes of patients who underwent PPV for epiretinal membrane peeling (ERMP) and/or macular hole (MH) with no history of diabetes mellitus (non-DM group); (2) eyes of patients who underwent PPV for ERMP and/or MH with a history of diabetes or nonproliferative diabetic retinopathy (DM group); (3) eyes of patients who underwent PPV for proliferative diabetic retinopathy (PDR group). Mann-Whitney U tests were performed to compare the biomarker concentrations between the three groups. RESULTS: Numerous growth factors and inflammatory cytokines were significantly upregulated between the non-DM and PDR groups - Angiopoietin-2, EGF, Endoglin, G-CSF, HB-EGF, HGF, PDGF, PIGF, sHER2/neu, TIE-2, VEGF-A, VEGF-D, IL-18, IL-6, IL-8, PECAM-1, sCD40L, SCF, sFASL, sIL-6Ra, TNF-⍺, Leptin, PAI-1, and uPA. A literature search of these proteins revealed many to be directly activated by HIF-1 transcription factor, which is the "master switch" for genes transcribed during a hypoxic event. CONCLUSION: The abundance of proangiogenic and pro-inflammatory factors in PDR that are also upregulated by HIF-1 demonstrate the potential for using hypoxia to treat PDR (and other ischemic retinopathies) through the reduction of HIF-1. This study also shows the wide variability in the expression levels of these proteins which helps provide a better understanding of their degree of involvement in the pathogenesis of ischemic retinopathies.
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