Article

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: 4.6). 12/2011; 179(6):2931-40. DOI: 10.1016/j.ajpath.2011.08.043
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
128 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Die proliferative Vitreoretinopathie (PVR) ist die wichtigste Komplikation der Netzhautablösung und die Hauptursache für ein Therapieversagen in der vitreoretinalen Chirurgie. Im Rahmen der PVR kommt es zur Neuentstehung fibrozellulärer Membranen, deren Kontraktion zur traktiven Netzhautablösung führen kann. Epithelial mesenchymale Transformation, Adhäsion, Migration und Proliferation von durch die Verletzung der Netzhaut freigesetzten retinalen Pigmentepithelzellen, Gliazellen, Hyalozyten und Immunzellen im Zusammenspiel mit der Freisetzung von Wachstumsfaktoren gelten als initiale Schritte in der Pathogenese der PVR. Eine pharmakologische Beeinflussung dieser frühen zellvermittelten Prozesse ist ein interessanter Ansatz, um die Ergebnisse in der chirurgischen Therapie von Netzhautablösungen in Zukunft zu verbessern oder etwa die Ausbildung einer PVR zu verhindern. In den wenigen vorhandenen klinischen Studien überzeugte keine der bisher getesteten Substanzen durch eine eindeutige Wirksamkeit, sodass sich bislang keine adjuvante pharmakologische Therapie in der klinischen Routine etablieren konnte. Ein zunehmendes Verständnis der zugrunde liegenden Pathogenese der PVR führte in den vergangenen Jahren jedoch zur Entdeckung vieler interessanter experimenteller therapeutischer Ansätze, die einen ersten Grundstein zur Entwicklung einer medikamentösen Therapie der PVR darstellen könnten. Der folgende Beitrag gibt einen Überblick über bisherige klinische Studien zur Testung medikamentöser Therapieansätze und widmet sich insbesondere vielversprechenden experimentellen Ideen.
    Der Ophthalmologe 10/2013; 110(10). DOI:10.1007/s00347-013-2832-z · 0.72 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The platelet-derived growth factor (PDGF) receptors (PDGFRs) are central to a spectrum of human diseases. When PDGFRs are activated by PDGF, reactive oxygen species (ROS) and Src family kinases (SFKs) act downstream of PDGFRs to enhance PDGF-mediated tyrosine phosphorylation of various signaling intermediates. In contrast to these firmly established principles of signal transduction, much less is known regarding the recently appreciated ability of ROS and SFKs to indirectly and chronically activate monomeric PDGF receptor α (PDGFRα) in the setting of a blinding condition called proliferative vitreoretinopathy (PVR). In this context, we made a series of discoveries that substantially expands our appreciation of epigenetic-based mechanisms to chronically activate PDGFRα. Vitreous, which contains growth factors outside the PDGF family but little or no PDGFs, promoted formation of a unique SFK-PDGFRα complex that was dependent on SFK-mediated phosphorylation of PDGFRα and activated the receptor's kinase activity. While vitreous engaged a total of five receptor tyrosine kinases, PDGFRα was the only one that was activated persistently (at least 16 h). Prolonged activation of PDGFRα involved mTOR-mediated inhibition of autophagy and accumulation of mitochondrial ROS. These findings reveal that growth factor-containing biological fluids, such as vitreous, are able to tirelessly activate PDGFRα by engaging a ROS-mediated, self-perpetuating loop.
    Molecular and Cellular Biology 01/2014; 34(1). DOI:10.1128/MCB.00839-13 · 5.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Proliferative vitreoretinopathy (PVR) is a nonneovascular blinding disease and the leading cause for failure in surgical repair of rhegmatogenous retinal detachments. Once formed, PVR is difficult to treat. Hence, there is an acute interest in developing approaches to prevent PVR. Of the many growth factors and cytokines that accumulate in vitreous as PVR develops, neutralizing vascular endothelial growth factor (VEGF) A has recently been found to prevent PVR in at least one animal model. The goal of this study was to test if Food and Drug Administration–approved agents could protect the eye from PVR in multiple animal models and to further investigate the underlying mechanisms. Neutralizing VEGF with aflibercept (VEGF Trap-Eye) safely and effectively protected rabbits from PVR in multiple models of disease. Furthermore, aflibercept reduced the bioactivity of both experimental and clinical PVR vitreous. Finally, although VEGF could promote some PVR-associated cellular responses via VEGF receptors expressed on the retinal pigment epithelial cells that drive this disease, VEGF's major contribution to vitreal bioactivity occurred via platelet-derived growth factor receptor α. Thus, VEGF promotes PVR by a noncanonical ability to engage platelet-derived growth factor receptor α. These findings indicate that VEGF contributes to nonangiogenic diseases and that anti–VEGF-based therapies may be effective on a wider spectrum of diseases than previously appreciated.
    American Journal Of Pathology 09/2014; 184(11). DOI:10.1016/j.ajpath.2014.07.026 · 4.60 Impact Factor

Preview

Download
0 Downloads
Available from