A Mouse Model of Proliferative Vitreoretinopathy Induced by Dispase (original) (raw)
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Ophthalmic Research, 2003
During proliferative vitreoretinopathy (PVR) Müller glial cells show an up-regulation of their responsiveness to extracellular adenosine 5)-triphosphate (ATP). In the present study, we investigated if such a glial cell response is also a feature for other retinopathies besides PVR. To this aim, the proteolytic enzyme, dispase (0.1 U), was injected into the vitreous of rabbit eyes. After 3 weeks, a distinct retinopathy had developed which showed no signs of PVR. The retinopathy was characterized by strong alterations of the retinal vasculature in the medullary rays, by photoreceptor degeneration, retinal atrophy, and activation of microglial cells. Müller cells became reactive, as indicated by up-regulation of glial fibrillary acidic protein immunoreactivity and by hypertrophy involving subretinal fibrosis. Müller cell reactivity was also evidenced electrophysiologically by a downregulation of their inwardly rectifying potassium currents and by an up-regulation of their responsiveness to extracellular ATP. Significantly more Müller cells from dispase-treated eyes showed ATP-evoked calcium (83%) and current responses (69%) when compared with cells from control eyes (13 and 9%, respectively). The results indicate that increased responsiveness to extracellular ATP may be a more general feature of Müller cell gliosis, and is also observed in retinopathies besides PVR.
Investigative ophthalmology & visual science, 2002
To test whether in an animal model of proliferative vitreoretinopathy (PVR) the Müller glial cells displayed an upregulation of purinergic P2 receptor-mediated responses. PVR was induced by intravitreal injection of the proteolytic enzyme, dispase, in the eyes of adult rabbits. The developing PVR was examined ophthalmoscopically. After 3 weeks, small retinal pieces were wholemounted and used for calcium imaging, freshly dissociated Müller cells were subjected to calcium imaging, and patch-clamp recordings were made. The presence of P2 receptor-mediated Ca(2+) responses was determined both directly--that is, fluorometrically--and indirectly, by electrophysiological recording of Ca(2+)-activated K(+) currents. According to earlier observations in another model of retinal detachment and PVR, the reactive Müller cells displayed hypertrophy, downregulation of inwardly rectifying K(+) currents, and depolarization of the resting membrane potential, all dependent on the severity of the PVR....
PURPOSE: To provide immunohistochemical characterization of sub retinal bands removed during retinal surgery in eyes with proliferative vitreoretinopathy (PVR). METHODS: This study included all eyes with the clinical diagnosis of PVR that underwent pars plana vitrectomy surgery during which the sub retinal tissue causing retinal detachment was obtained. The sub retinal bands were removed "en bloc" through retinotomy using sub retinal intraocular forceps. The excised tissue was sent for histopathologic analysis. Immunohistochemistry (IHC) was performed to confirm the cellular nature and components of these subretinal membranes. The IHC stains included, glial fibrillary acidic protein (GFAP), Pancytokeratin, CD3, CD20, CD68 and CD34. RESULTS: Sub retinal membranes (SRMs) from 7 eyes were included in the analysis. All cases had successful surgical outcome with reattachment six months after surgery. The microscopic examination of the excised tissue nicely demonstrated the constituents of the SRM as follows: retinal pigmented epithelial (RPE) cells that stained positively with cytokeratin (7/7), avascular plaques of RPE cells showing metaplasia in the form of spindle cells (7/7). Fragments of gliotic GFAP-positive neural retina was adherent to the fibrous plaque (6 /7). Bruch's membrane was identified in one specimen. CD 68 positive macrophages were seen in (5/7) being silicon oil- laden macrophages in 2/5. Rare CD3 positive cells were also noted in 1 specimen. CONCLUSIONS: Sub retinal bands in PVR are mainly composed of reactive avascular plaques of RPE metaplasia and macrophage infiltration. The overlying gliotic retina or Bruch's membrane are likely to be adherent to such plaques and might be inadvertently excised during removal of such membranes. Removal of SRMs is essential for successful reattachment of the retina.
Canadian journal of ophthalmology. Journal canadien d'ophtalmologie, 2002
The most widely used models of proliferative vitreoretinopathy (PVR) rely on injection of cells into the vitreous of animals. Using retinal pigment epithelial (RPE) cells from human PVR membranes may produce a more accurate model of human PVR. We performed a study to determine whether human RPE cells derived from a single epiretinal membrane (ERM) are capable of inducing the same disease in the rabbit eye, and whether the induced ERMs had cellular components similar to those of human PVR membranes. Cells were harvested from a human ERM obtained at surgery for PVR. RPE cells were cultured from the membrane and injected into the right eye of 24 New Zealand albino rabbits. The left eyes served as controls. The eyes were examined by indirect ophthalmoscopy over 4 weeks. The enucleated eyes were then examined by means of microscopy and histochemical analysis. By day 7, PVR had developed in all but 1 of the 24 experimental eyes, with 8 progressing to localized tractional retinal detachmen...
Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical consequences
Progress in Retinal and Eye Research, 2016
During the last four decades, proliferative vitreoretinopathy (PVR) has defied the efforts of many researchers to prevent its occurrence or development. Thus, PVR is still the major complication following retinal detachment (RD) surgery and a bottleneck for advances in cell therapy that require intraocular surgery. In this review we tried to combine basic and clinical knowledge, as an example of translational research, providing new and practical information for clinicians. PVR was defined as the proliferation of cells after RD. This idea was used for classifying PVR and also for designing experimental models used for testing many drugs, none of which were successful in humans. We summarize current information regarding the pathogenic events that follow any RD because this information may be the key for understanding and treating the earliest stages of PVR. A major focus is made on the intraretinal changes derived mainly from retinal glial cell reactivity. These responses can lead to intraretinal PVR, an entity that has not been clearly recognized. Inflammation is one of the major components of PVR, and we describe new genetic biomarkers that have the potential to predict its development. New treatment approaches are analyzed, especially those directed towards neuroprotection, which can also be useful for preventing visual loss after any RD. We also summarize the results of different surgical techniques and clinical information that is oriented toward the identification of high risk patients. Finally, we provide some recommendations for future classification of PVR and for designing comparable protocols for testing new drugs or techniques.
Macrophage modulation of retinal pigment epithelial cell migration and proliferation
Graefe's Archive for Clinical and Experimental Ophthalmology, 1989
Macrophages are fully differentiated cells that do not synthesize an extracellular matrix and do not contract; they do, however, produce substances that modify the behavior and functions of other cells, particularly those involved in the inflammatory and immune responses. Since macrophages are a ubiquitous component of periretinal membranes, we sought to determine whether they modulate proliferation and/or migration of retinal pigment epithelial (RPE) cells, functions that may be essential for the development of proliferative vitreoretinopathy (PVR). Using an in vitro assay, we found that macrophage supernatant contains factors that stimulate proliferation and migration of cultured human RPE cells. Since interleukin-1 (IL-1) is a product of activated macrophages that modulates a number of cellular functions, we also examined its effect on RPE proliferation and migration. We found that IL-I increased migration but did not affect proliferation, and thus could not duplicate the effect of macrophage supernatant. Injection of activated macrophages into the vitreous of rabbits which had a retinal hole stimulated RPE cell proliferation in the area of the retinal hole, where the RPE cells were exposed. These findings suggest the ability of macrophages to modulate functions of RPE cells that are thought to be critical for the development of PVR. Macrophages may thus be an important part of the vitreous environment that favors the development of PVR.
American journal of ophthalmology, 1989
Injection of activated macrophages into the posterior vitreous of the rabbit induced vigorous fibrovascular proliferation over the optic disk and medullary rays, as demonstrated by 3H-thymidine autoradiography. One week after injection, endothelial cells and pericytes of the capillaries near the inner surface of the optic disk and rays were labeled; fibroblast-like cells, which were also labeled, migrated and formed vitreous strands. By the second week after injection, the fibrovascular tissue proliferated most actively, and traction medullary ray detachment and peripapillary retinal fold formation were observed. The cellular proliferation was accompanied by inflammatory cell infiltration. Glial cells within the optic disk, as well as retinal pigment epithelial cells beneath the detached retina, were labeled by 3H-thymidine. These results demonstrate that the fibrovascular proliferation originates from the vessel complex of the optic disk and medullary rays in this experimental mode...
Background There is some in vitro evidence that the adult ciliary body might harbor an inactive population of stem/retinal progenitor cells (RPC), or that ciliary epithelial (CE) cells might have the capacity to transdifferentiate, which may result in a balance between neural and epithelial properties. We have reported alterations in the ciliary body (CB) and adjacent vitreous in vivo by endoscopic evaluation of human eyes with a history of retinal detachment (RD) and anterior proliferative vitreoretinopathy (PVR). Methods The present study examined with light microscopy three paraffin-embedded phthisic human eyes with RD and anterior PVR. One normal eye, exenterated for an orbital tumor, served as the control. All specimens were stained with hematoxilin and eosin safran (HES), and serial sections were immunostained with antibodies against EGFR, Ki67, CD133, NSE, rhodopsin, and GFAP.