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.
    Journal of Ophthalmology 01/2015; 2015(11):1-9. DOI:10.1155/2015/583040 · 1.43 Impact Factor
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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.
    Mediators of Inflammation 10/2013; 2013(2):857380. DOI:10.1155/2013/857380 · 3.24 Impact Factor
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    • "A recent study showed that a cocktail of neutralizing reagents targeted to multiple growth factors and cytokines was able to reduce PVR development. Antibodies against PDGF, EGF, FGF-2, IFN-γ, IL-8, TGF-α, VEGF, TGF-β, HGF, and IGF-1 to IGF-12 were effective in preventing RD in a rabbit model [129]. "
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    ABSTRACT: Eye injury is a significant disabling worldwide health problem. Proliferative Vitreoretinopathy (PVR) is a common complication that develops in up to 40-60% of patients with an open-globe injury. Our knowledge about the pathogenesis of PVR has improved in the last decades. It seems that the introduction of immune cells into the vitreous, like in penetrating ocular trauma, triggers the production of growth factors and cytokines that come in contact with intra-retinal cells, like Müller cells and RPE cells. Growth factors and cytokines drive the cellular responses leading to PVR's development. Knowledge of the pathobiological and pathophysiological mechanisms involved in posttraumatic PVR is increasing the possibilities of management, and it is hoped that in the future our treatment strategies will evolve, in particular adopting a multidrug approach, and become even more effective in vision recovery. This paper reviews the current literature and clinical trial data on the pathogenesis of PVR and its correlation with ocular trauma and describes the biochemical/molecular events that will be fundamental for the development of novel treatment strategies. This literature review included PubMed articles published from 1979 through 2013. Only studies written in English were included.
    Mediators of Inflammation 09/2013; 2013(2):269787. DOI:10.1155/2013/269787 · 3.24 Impact Factor
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