Mechanisms of Lumen Formation: Morphologic Observations on Experimental Subretinal Neovascularization

Ishibashi, Tatsuro; Miller, Hedva; Orr, Gavin; Sorgente, Nino; Ryan, Stephen J.

doi:10.1007/978-94-009-3337-8_66

Cited by 29 publications

(33 citation statements)

References 10 publications

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“…In the acute phase after injury, macrophages are recruited into the injury site. 28 About 70% of macrophages in laserinduced CNV were reported to be derived from bone marrow, 29 which is comparable with our result with subretinal HpODE, where abundant ED1-positive cells are present at 3 days after the injection (Figure 4). On the other hand, ED2-positive resident macrophages did not seem to contribute to development of HpODE-induced CNV, because no ED2-positive cells were present in the subretinal space.…”

Section: Discussionsupporting

confidence: 81%

A Rat Model for Choroidal Neovascularization Using Subretinal Lipid Hydroperoxide Injection

Baba

Bhutto

Merges

et al. 2010

The American Journal of Pathology

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The purpose of this study was to develop and characterize a rat model of choroidal neovascularization (CNV) as occurs in age-related macular degeneration. The lipid hydroperoxide 13(S)-hydroperoxy-9Z,11E-octadecadienoic acid (HpODE) is found in submacular Bruch's membrane in aged humans and has been reported to generate neovascularization in a rabbit model. Three weeks after a single subretinal injection of 30 g of HpODE, eyes of Sprague-Dawley rats were harvested. Follow-up fluorescein angiography was done on other animals until 5 weeks postinjection. Histological studies, immunohistochemical staining, and flatmount choroids for CNV measurements were performed. In addition, we used murine neuronal, bovine endothelial, and human ARPE19 cells for testing the in vitro effects of HpODE. CNV developed in 85.7% of HpODE-injected eyes. The neovascular areas were significantly greater in HpODE-injected eyes compared with those in control eyes (P ‫؍‬ 0.023). The CNV had maximum dye leakage at 3 weeks, which subsided by the 5th week. Histologically, CNV extended from the choriocapillaris into the subretinal space. ED1-positive macrophages were recruited to the site. In vitro assays demonstrated that only 30 ng/ml HpODE induced cell proliferation and migration of endothelial cells. HpODE-induced CNV was highly reproducible, and its natural course seems to be ideal for evaluating therapeutic modalities. Because HpODE has been isolated from aged humans, the HpODE-induced rat model seems to be a relevant experimental model for CNV in age-related macular degeneration. Age-related macular degeneration (AMD) is the leading cause of central vision loss for populations older than 65 years in developed countries.1 There are two major types of AMD: dry and wet (or exudative). One type of dry AMD is geographic atrophy, which is the atrophy of the retinal pigment epithelium (RPE) in a well defined area centered on the fovea. Wet AMD progresses faster and results in more severe visual loss. In wet AMD, choroidal neovascularization (CNV) is associated with many pathological changes such as subretinal hemorrhage, serous retinal detachment, fibrovascular and serous pigment epithelium detachment, and subretinal scar formation. Both forms of AMD have characteristic extracellular lesions (drusen and basal linear and laminar deposits) that have an impact on RPE and photoreceptor viability and health. 2,3An experimental model is essential to investigate the nature and treatment of CNV. The first experimental CNV model of Ryan and his colleagues was reported in 1979. 4 They attempted to generate CNV using three different methods in monkeys. Their hypothesis was that disruption of Bruch's membrane induces neovascularization from choroid. According to their report, mechanical/enzymatic disruption of Bruch's membrane (BrM) via transscleral and transvitreal injections resulted in a low incidence of CNV (8.9 and 12.5%). Laser-induced disruption of BrM eventually produced CNV at a higher rate (80%), and the authors hypothesized that subretinal scar ...

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Section: Discussionsupporting

confidence: 81%

A Rat Model for Choroidal Neovascularization Using Subretinal Lipid Hydroperoxide Injection

Baba

Bhutto

Merges

et al. 2010

The American Journal of Pathology

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“…Several groups studied morphological changes in AMD analyzing surgically excised CNV by immunohistochemistry and electron microscopy (Grossniklaus et al, 1994;Lafaut et al, 2000;Lopez et al, 1996). In animal models, choroidal neovascularization is induced by laser photocoagulation (Frank et al, 1989;Ishibashi et al, 1987), subretinal instillation of angiogenic growth factors (Cui et al, 2000), or transgenic overexpression of VEGF in the retina (Okamoto et al, 1997). Recently, spontaneous development of CNV in ageing mice was reported for Bst/ mice (Smith et al, 2000).…”

Section: Introductionmentioning

confidence: 98%

Cultivation of Retinal Pigment Epithelial Cells from Human Choroidal Neovascular Membranes in Age Related Macular Degeneration

Schlunck

Martin

Agostini

et al. 2002

Experimental Eye Research

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“…IL-1 staining was found in cells cytologically identical to macro phages within the subretinal space early in the reparative process on day 3 and to a lesser extent on day 8 after laser treatment. This co incides with the period during which SRN de velops in this model [5]. In the orthogonal seri al reconstruction, these cells were most dense about the site of rupture of Bruch's mem brane.…”

Section: Discussionmentioning

confidence: 99%

“…phenomenon [1][2][3][4][5]. Inflammation, including migration of cells into the subretinal space, is an important feature in the early development of SRN.…”

Section: Introductionmentioning

confidence: 99%

Activated Macrophages in Experimental Subretinal Neovascularization (With 1 color plate)

Nishimura

Goodnight²,

Prendergast³

et al. 1990

Ophthalmologica

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Laser-induced subretinal neovascularization (SRN) in monkey retinas was investigated by immunohistochemical techniques to identify the presence and location of activated macrophages. Retinal lesions were examined 3, 8 and 14 days after intensive argon laser treatment, and the distribution of interleukin-1 (IL-1)-containing cells in the lesions was determined by the orthogonal reconstruction of serial sections. Macrophages were present in the subretinal space of day 3 and day 8 lesions. These IL-1-containing cells were distributed about the area of rupture of Bruch’s membrane and were quite common in lesions taken 3 days following laser treatment. While still apparent, the number was decreased at 8 days, and none were found 14 days after laser treatment. The temporal and spatial distribution of IL-1-staining macrophages paralleled the development of SRN, suggesting a relationship between the presence of activated macrophages and the initiation of neovascularization in this model.

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Mechanisms of Lumen Formation: Morphologic Observations on Experimental Subretinal Neovascularization

Cited by 29 publications

References 10 publications

A Rat Model for Choroidal Neovascularization Using Subretinal Lipid Hydroperoxide Injection

A Rat Model for Choroidal Neovascularization Using Subretinal Lipid Hydroperoxide Injection

Cultivation of Retinal Pigment Epithelial Cells from Human Choroidal Neovascular Membranes in Age Related Macular Degeneration

Activated Macrophages in Experimental Subretinal Neovascularization (With 1 color plate)

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