Inflammatory Mediators and Angiogenic Factors in Choroidal Neovascularization: Pathogenetic Interactions and Therapeutic Implications (original) (raw)
Related papers
Effect of Inhibition of Colony-Stimulating Factor 1 Receptor on Choroidal Neovascularization in Mice
The American Journal of Pathology, 2019
Neovascular age-related macular degeneration is one of the leading causes of blindness. Microglia and macrophages play a critical role in choroidal neovascularization (CNV) and may, therefore, be potential targets to modulate the disease course. This study evaluated the effect of the colony-stimulating factor-1 receptor inhibitor PLX5622 on experimental laser-induced CNV. A 98% reduction of retinal microglia cells was observed in the retina 1 week after initiation of PLX5622 treatment, preventing accumulation of macrophages within the laser site and leading to a reduction of leukocytes within the choroid after CNV induction. Mice treated with PLX5622 had a significantly faster decrease of the CNV lesion size, as revealed by in vivo imaging and immunohistochemistry from day 3 to day 14 compared with untreated mice. Several inflammatory modulators, such as chemokine (C-C motif) ligand 9, granulocytemacrophage colony-stimulating factor, soluble tumor necrosis factor receptor-I, IL-1a, and matrix metallopeptidase-2, were elevated in the acute phase of the disease when microglia were ablated with PLX5622, whereas other cytokines (eg, interferon-g, IL-4, and IL-10) were reduced. Our results suggest that colony-stimulating factor-1 receptor inhibition may be a novel therapeutic target in patients with neovascular age-related macular degeneration.
Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics, 2018
Mononuclear phagocytes (MNPs) are present in neovascular age-related macular degeneration (nv AMD) which is also called choroidal neovascularization (CNV). The number and phenotype of the MNPs depend upon the local environment in the CNV and effect of nv AMD therapy. We investigated ocular cell infiltration and conditions that modulate angiogenesis in a laser-induced mouse CNV model. We developed assays to quantify MNPs in our established mouse CNV model. One MNP assay quantified the number of subretinal cells peripheral to the CNV lesions. A second assay semiquantitatively assesses the number of MNPs localized to the CNV lesion. We used these assays to measure the effect of toll-like receptor-2 (TLR-2) activation, anti-vascular endothelial growth factor (VEGF) therapy, and chemokine (C-C motif) ligand 2 (Ccl2) genetic deletion on MNP infiltration after laser injury. Laser injury induced blood vessel growth and infiltration of MNPs. Systemic administration of a TLR-2 activating pept...
Indian journal of ophthalmology, 2017
The aim was to study the clinical profile of inflammatory choroidal neovascularization (CNV) and its treatment response to intravitreal bevacizumab or ranibizumab on pro re nata (PRN) basis in Indian eyes. This was a retrospective case series of consecutive patients with inflammatory CNV treated with anti-vascular endothelial growth factor (anti-VEGF) in a tertiary eye care center in Eastern India between 2009 and 2014. The data about clinical features, investigations, treatment, and outcomes were obtained from the medical records. We included patients with active inflammatory CNV but with no evidence of inflammation and were treated with anti-VEGF alone, with a minimum follow-up of 6 months. Main outcome measures were a clinical and etiological profile of inflammatory CNV in Indian eyes and their response to treatment. Thirty eyes of 28 patients were included in the study. The mean follow-up was 17.93 ± 14.28 months (range 6-53 months). In our cohort, seven (23.33%) eyes had inflam...
Journal of Current Ophthalmology, 2021
Purpose: To report the visual outcomes of intravitreal (IVT) anti-vascular endothelial growth factor (anti-VEGF) in inflammatory choroidal neovascularization (iCNV). Methods: A retrospective study of 43 eyes of 38 patients with active choroidal neovascularization (CNV) related to ocular inflammatory disease, treated with IVT injections of anti-VEGF (bevacizumab, ranibizumab, or aflibercept), with or without associated systemic anti-inflammatory therapy, at Fattouma Bourguiba University Hospital, Monastir, Tunisia (24 eyes of 23 patients) and at Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (19 eyes of 15 patients) from January 1, 2013, to December 31, 2018. Results: The mean age was 35.5 ± 16.4 years. The sex ratio male:female was 0.27. Seventeen eyes (39.5%) of 17 patients (44.7%) had only anti-VEGF injections, and 26 eyes (60.5%) of 21 patients (45.3%) had anti-VEGF injections and associated systemic anti-inflammatory therapy. Bevacizumab was injected...
Vascular adhesion protein-1 blockade suppresses choroidal neovascularization
The FASEB Journal, 2008
Vascular adhesion protein-1 (VAP-1) is an endothelial cell adhesion molecule involved in leukocyte recruitment. Leukocytes and, in particular, macrophages play an important role in the development of choroidal neovascularization (CNV), an integral component of age-related macular degeneration (AMD). Previously, we showed a role for VAP-1 in ocular inflammation. Here, we investigate the expression of VAP-1 in the choroid and its role in CNV development. VAP-1 was expressed in the choroid, exclusively in the vessels, and colocalized in the vessels of the CNV lesions. VAP-1 blockade with a novel and specific inhibitor significantly decreased CNV size, fluorescent angiographic leakage, and the accumulation of macrophages in the CNV lesions. Furthermore, VAP-1 blockade significantly reduced the expression of inflammation-associated molecules such as tumor necrosis factor (TNF) -␣, monocyte chemoattractant protein (MCP) -1, and intercellular adhesion molecule (ICAM) -1. This work provides evidence for an important role of VAP-1 in the recruitment of macrophages to CNV lesions, establishing a novel link between VAP-1 and angiogenesis. Inhibition of VAP-1 may become a new therapeutic strategy in the treatment of AMD.
The American Journal of Pathology, 2011
The pro-inflammatory cytokine IL-1 has been shown to promote angiogenesis. It can have a neurotoxic or neuroprotective effect. Here, we have studied the expression of IL-1 in vivo and the effect of the IL-1 receptor antagonist on choroidal neovascularization (CNV) and retinal degeneration (RD). IL-1 expression significantly increased after laser injury (real time PCR) in C57BL/6 mice, in the C57BL/6 Cx3cr1 ؊/؊ model of age-related macular degeneration (enzyme-linked immunoabsorbent assay), and in albino Wistar rats and albino BALB Cx3cr1 ؉/؉ and Cx3cr1 ؊/؊ mice (enzymelinked immunoabsorbent assay) after light injury. IL-1 was localized to Ly6G-positive, Iba1-negative infiltrating neutrophils in laser-induced CNV as determined by IHC. IL-1 receptor antagonist treatment significantly inhibited CNV but did not affect Iba1-positive macrophage recruitment to the injury site. IL-1 significantly increased endothelial cell outgrowth in aortic ring assay independently of vascular endothelial growth factor, suggesting a direct effect of IL-1 on choroidal endothelial cell proliferation. Inhibition of IL-1 in light-and laser-induced RD models did not alter photoreceptor degeneration in Wistar rats, C57BL/6 mice, or RD-prone Cx3cr1 ؊/؊ mice. Our results suggest that IL-1 inhibition might represent a valuable and safe alternative to inhibition of vascular endothelial growth factor in the control of CNV in the context of concomitant photoreceptor degeneration as observed in age-related macular degeneration.
Cardiovascular disease and hypertension are strong risk factors for choroidal neovascularization
Ophthalmology, 2008
To investigate the association of cardiovascular risk factors and inflammatory markers with neovascular age-related macular degeneration (AMD). Cross-sectional case-control study. Of the 410 of the >/=65-year-old community sample invited to attend, 205 participated (50% response rate). Of the 215 clinic attendees who were invited to participate, 212 agreed to take part (98% response rate). A diagnosis of neovascular AMD in at least one eye was made in 193 clinic attendees and 2 of the community sample. Clinic and community participants underwent a detailed ophthalmic examination with fundus imaging, were interviewed for assessment of putative risk factors, and provided a blood sample. Analysis included levels of serum lipids, intercellular adhesion molecule 1 (ICAM), vascular cellular adhesion molecule (VCAM), and C-reactive protein (CRP). All participants were classified by fundus image grading on the basis of the eye with more severe AMD features. Neovascular AMD. There were 19...
American Journal of Cardiology, 2001
Choroidal neovascularization in age-related macular degeneration is a frequent and poorly treatable cause of vision loss in elderly Caucasians. This choroidal neovascularization has been associated with the expression of vascular endothelial growth factor (VEGF). In current animal models choroidal neovascularization is induced by subretinal injection of growth factors or vectors encoding growth factors such as VEGF, or by disruption of the Bruch’s membrane/retinal pigment epithelium complex with laser treatment. We wished to establish a transgenic murine model of age-related macular degeneration, in which the overexpression of VEGF by the retinal pigment epithelium induces choroidal neovascularization. A construct consisting of a tissue-specific murine retinal pigment epithelium promoter (RPE65 promoter) coupled to murine VEGF164 cDNA with a rabbit β-globin-3′ UTR was introduced into the genome of albino mice. Transgene mRNA was expressed in the retinal pigment epithelium at all ages peaking at 4 months. The expression of VEGF protein was increased in both the retinal pigment epithelium and choroid. An increase of intravascular adherent leukocytes and vessel leakage was observed. Histopathology revealed intrachoroidal neovascularization that did not penetrate through an intact Bruch’s membrane. These results support the hypothesis that additional insults to the integrity of Bruch’s membrane are required to induce growth of choroidal vessels into the subretinal space as seen in age-related macular degeneration. This model may be useful to screen for inhibitors of choroidal vessel growth.