A Novel Strategy to Develop Therapeutic Approaches to Prevent Proliferative Vitreoretinopathy

Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts 02114, USA.
American Journal Of Pathology (Impact Factor: 4.59). 12/2011; 179(6):2931-40. DOI: 10.1016/j.ajpath.2011.08.043
Source: PubMed


Proliferative vitreoretinopathy (PVR) thwarts the repair of rhegmatogenous retinal detachments. Currently, there is no effective prevention for PVR. Platelet-derived growth factor receptor α (PDGFRα) is associated with PVR in humans and strongly promotes experimental PVR driven by multiple vitreal growth factors outside the PDGF family. We sought to identify vitreal factors required for experimental PVR and to establish a potential approach to prevent PVR. Vitreous was obtained from normal rabbits or those in which PVR was either developing or stabilized. Normal vitreous contained substantial levels of growth factors and cytokines, which changed quantitatively and/or qualitatively as PVR progressed and stabilized. Neutralizing a subset of these agents in rabbit vitreous eliminated their ability to induce PVR-relevant signaling and cellular responses. A single intravitreal injection of neutralizing reagents for this subset prevented experimental PVR. To identify growth factors and cytokines likely driving PVR in humans, we subjected vitreous from patients with or without PVR to a similar series of analyses. This analysis accurately identified those agents required for vitreous-induced contraction of cells from a patient PVR membrane. We conclude that combination therapy encompassing a subset of vitreal growth factors and cytokines is a potential approach to prevent PVR.

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    • "The postulated epithelial-to-mesenchymal transition of RPE cells and Müller cell activation and growth onto the retinal surfaces are believed to be pivotal events in PVR [4] [5]. It appears that the exposure of such cells to the vitreous and associated growth factors as a result of RRD significantly contributes to the pathogenesis of PVR, though the basic cause as well as a clinically effective therapeutic approach for this condition remains elusive [5] [6]. Proteomics studies proteins on a large scale in pursuit of a global and integrated view of disease processes at the protein level, which may potentially lead to the identification of novel biomarkers and therapeutic targets useful in clinical practice [7] [8] [9] [10] [11]. "
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    ABSTRACT: Purpose . The pathogenesis of rhegmatogenous retinal detachment (RRD) remains incompletely understood, with no clinically effective treatment for potentially severe complications such as photoreceptor cell death and proliferative vitreoretinopathy. Here we investigate the protein profile of the vitreous following experimental retinal detachment using a comparative proteomic based approach. Materials and Methods . Retinal detachment was created in the right eyes of six New Zealand red pigmented rabbits. Sham surgery was undertaken in five other rabbits that were used as controls. After seven days the eyes were enucleated and the vitreous was removed. The vitreous samples were evaluated with two-dimensional polyacrylamide gel electrophoresis and the differentially expressed proteins were identified with tandem mass spectrometry. Results . Ten protein spots were found to be at least twofold differentially expressed when comparing the vitreous samples of the sham and retinal detachment surgery groups. Protein spots that were upregulated in the vitreous following retinal detachment were identified as albumin fragments, and those downregulated were found to be peroxiredoxin 2, collagen-I α 1 fragment, and α -1-antiproteinase F. Conclusions . Proteomic investigation of the rabbit vitreous has identified a set of proteins that help further our understanding of the pathogenesis of rhegmatogenous retinal detachment and its complications.
    Full-text · Article · Dec 2015 · Journal of Ophthalmology
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    • "Proliferative vitreoretinopathy (PVR) is a complication of a retinal detachment and occurs in approximately 8–10% of patients developing retinal detachment [1] [2] [3]. In retinal detachment, a full-thickness retinal break exposes cells, allowing macrophages, retinal pigment epithelial cells, glial cells, and fibroblasts to migrate into the vitreous, a rich source of growth factors and cytokines correlated to PVR activity [4] [5] [6]. All these cells proliferate in the vitreous, survive, form extracellular matrix proteins, and assemble into membranes. "
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    ABSTRACT: . Proliferative vitreoretinopathy (PVR) is a severe inflammatory complication of retinal detachment. Pathological epiretinal membranes grow on the retina surface leading to contraction, and surgery fails in 5% to 10% of the cases. We evaluated the expression of VEGF-A, Otx1, Otx2, Otx3, and p53 family members from PVR specimens to correlate their role in inducing or preventing the pathology. Methods . Twelve retinal samples were taken from patients affected by PVR during therapeutic retinectomies in vitreoretinal surgery. Gene expression was evaluated using quantitative real-time reverse transcriptase PCR analysis and immunohistochemistry, using four healthy human retinae as control. Result . Controls showed basal expression of all genes. PVR samples showed little or no expression of Otx1 and variable expression of VEGF-A, Otx2, Otx3, p53, and p63 genes. Significant correlation was found among VEGF-A, Otx2, p53, and p63 and between Otx1 and Otx3. Conclusions . Otx homeobox, p53 family, and VEGF-A genes are expressed in PVR human retina. We individuated two possible pathways (VEGF-A, Otx2, p53, p63 and Otx1 and Otx3) involved in PVR progression that could influence in different manners the course of the pathology. Individuating the genetic pathways of PVR represents a novel approach to PVR therapies.
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    • "Hypoxiainducible factor-1alpha (HIF-1毩) is a transcription factor closely related to ischemic tolerance. There is evidence that HIF-1毩 exhibits strong protective effects on hypoxic-ischemic brain damage by promoting anaerobic metabolism of brain cells, vasoformation, oxygen transport of erythrocytes, improving energy metabolism disorder, haemodynamic recovery, and reducing cell apoptosis after cerebral ischemia [1] . The mechanism by which HIF-1毩 protects endogenous neural stem cells (NSCs) from cerebral hemorrhage remains poorly understood. "
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    ABSTRACT: To investigate the effects of adenovirus (Ad)-mediated hypoxia-inducible factor-1alpha (HIF-1α) gene on proliferation and differentiation of endogenous neural stem cells (NSCs) in rats following intracerebral hemorrhage (ICH) and the underlying mechanisms. A total of 120 specific pathogen-free, adult, male Sprague-Dawley rats were included in this study. After establishment of ICH models in rats, PBS, Ad, or Ad-HIF-1α was administered via the ischemic ventricle. On the 1st, 7th, 14th, 21st and 28th d after ICH, rat neurological deficits were scored, doublecortin (DCX) expression in the subventricular zone cells was detected by immunohistochemical staining, and 5-bromo-2'-deoxyuridine (BrdU)-, BrdU/DCX-, and BrdU/glial fibrillary acidic protein-positive cells in the subventricular zone were counted using immumofluorescence method among PBS, Ad, and Ad-HIF-1α groups. On the 7th, 14th, 21st and 28th d after ICH, neurological deficit scores in the Ad-HIF-1α group were significantly lower than in the PBS and Ad groups (P<0.05). In the Ad-HIF-1α group, DCX expression was significantly increased on the 7th d, peaked on the 14th d, and then gradually decreased. In the Ad-HIF-1α group, BrdU-positive cells were significantly increased over time course, and significant difference in BrdU-positive cell counts was observed when compared with the PBS and Ad groups at each time point (P<0.01 or 0.05). On the 7th, 14th, 21st and 28th d after ICH, the number of DCX-, BrdU-, BrdU/DCX-, and BrdU/DCX-positive cells in the Ad-HIF-1α group was significantly greater than in the PBS and Ad groups (P<0.05). HIF-1α gene can promote the proliferation, migration and differentiation of endogenous neural stem cells after ICH, thereby contributing to neurofunctional recovery after ICH.
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