Responsiveness of eyes with polypoidal choroidal vasculopathy with choroidal hyperpermeability to intravitreal ranibizumab.

BACKGROUND: To determine the role played by vascular endothelial growth factor (VEGF) in polypoidal choroidal vasculopathy (PCV) based on an interventional immunology theory. METHODS: Eyes with PCV were divided in a masked fashion into those with choroidal hyperpermeability (HP group) and those with normal choroidal permeability (NP group) based on the indocyanine green angiograms. The inter-rater agreement rate was evaluated using Fleiss' kappa. Patients were treated by intravitreal ranibizumab (IVB). The central choroidal thickness and central foveal thickness (CFT) at the baseline and 7 days after the treatment were measured by optical coherence tomography. RESULTS: Among the 57 consecutive eyes diagnosed with PCV, 42 eyes of 42 patients met the inclusion criteria (21 eyes/HP group vs 21 eyes /NP group). Central choroidal thickness in HP group was significantly thicker than that in the NP group (P < .001, Mann-Whitney U test). The inter-rater agreement was high with a Fleiss' kappa = 0.95, P < .0001. The percentage reduction in the CFT in HP group (14.0%) was significantly less than that in NP group (20.4%; P = .013, Mann-Whitney U test). CONCLUSIONS: Eyes with PCV that are associated with choroidal hyper-permeability may not be strongly associated with VEGF-related pathology, and may not respond favorably to anti-VEGF monotherapy.

Long-term intraocular pressure changes after combined phacoemulsification, intraocular lens implantation, and vitrectomy.

PURPOSE: To observe long-term changes in intraocular pressure (IOP) after a combined phacoemulsification, intraocular lens implantation, and vitrectomy procedure. METHODS: This was a retrospective case series at a single hospital. Of 105 consecutive cases that received combined phacoemulsification, intraocular lens implantation, and vitrectomy for macular hole or epiretinal membrane, 85 eyes (patients) were followed up for 1 year or longer. The IOP of both eyes in the subjects who had surgery in one eye was measured at baseline and at 1, 3, 6, 12, 24, 36, 48, and 60 months postoperatively. The IOP of the treated eye was compared with the fellow eye and with the baseline value at each follow-up visit. RESULTS: Intraocular pressure in the operated eyes at 3 months after surgery was significantly lower than that at baseline and than that in the respectively fellow eyes (P < 0.001, paired-t test with Bonferroni correction). The IOP subsequently returned to the baseline value or was the same as that of the fellow eye within 3 months of the observation time point. Only two treated eyes had elevated IOP exceeding 21 mmHg after 6 months postoperatively. CONCLUSIONS: The change in the IOP after phacovitrectomy may be limited, and care when using this procedure because some eyes show increased IOP compared to the fellow eye after a long period.

B cell-derived vascular endothelial growth factor A promotes lymphangiogenesis and high endothelial venule expansion in lymph nodes.

Vascular endothelial growth factor A (VEGF-A) is a prominent growth factor for both angiogenesis and lymphangiogenesis. Recent studies have shown the importance of VEGF-A in enhancing the growth of lymphatic endothelial cells in lymph nodes (LNs) and the migration of dendritic cells into LNs. VEGF-A is produced in inflamed tissues and/or in draining LNs, where B cells are a possible source of this growth factor. To study the effect of B cell-derived VEGF-A, we created transgenic mice (CD19(Cre)/hVEGF-A(fl)) that express human VEGF-A specifically in B cells. We found that the human VEGF-A produced by B cells not only induced lymphangiogenesis in LNs, but also induced the expansion of LNs and the development of high endothelial venules. Contrary to our expectation, we observed a significant decrease in the Ag-specific Ab production postimmunization with OVA and in the proinflammatory cytokine production postinoculation with LPS in these mice. Our findings suggest immunomodulatory effects of VEGF-A: B cell-derived VEGF-A promotes both lymphangiogenesis and angiogenesis within LNs, but then suppresses certain aspects of the ensuing immune responses.

Intraocular expression and release of high-mobility group box 1 protein in retinal detachment.

High-mobility group box 1 (HMGB1) protein is a multifunctional protein, which is mainly present in the nucleus and is released extracellularly by dying cells and/or activated immune cells. Although extracellular HMGB1 is thought to be a typical danger signal of tissue damage and is implicated in diverse diseases, its relevance to ocular diseases is mostly unknown. To determine whether HMGB1 contributes to the pathogenesis of retinal detachment (RD), which involves photoreceptor degeneration, we investigated the expression and release of HMGB1 both in a retinal cell death induced by excessive oxidative stress in vitro and in a rat model of RD-induced photoreceptor degeneration in vivo. In addition, we assessed the vitreous concentrations of HMGB1 and monocyte chemoattractant protein 1 (MCP-1) in human eyes with RD. We also explored the chemotactic activity of recombinant HMGB1 in a human retinal pigment epithelial (RPE) cell line. The results show that the nuclear HMGB1 in the retinal cell is augmented by death stress and upregulation appears to be required for cell survival, whereas extracellular release of HMGB1 is evident not only in retinal cell death in vitro but also in the rat model of RD in vivo. Furthermore, the vitreous level of HMGB1 is significantly increased and is correlated with that of MCP-1 in human eyes with RD. Recombinant HMGB1 induced RPE cell migration through an extracellular signal-regulated kinase-dependent mechanism in vitro. Our findings suggest that HMGB1 is a crucial nuclear protein and is released as a danger signal of retinal tissue damage. Extracellular HMGB1 might be an important mediator in RD, potentially acting as a chemotactic factor for RPE cell migration that would lead to an ocular pathological wound-healing response.

High-mobility group box 1 protein in endophthalmitis.

BACKGROUND: High-mobility group box 1 protein (HMGB1) is recently described as a late mediator of lethal endotoxemia with proinflammatory cytokine-like properties. The purpose of this study was to determine whether HMGB1 is involved in endophthalmitis. METHODS: In this retrospective case-control study, vitreous levels of HMGB1 were measured by an enzyme-linked immunosorbent assay in ten eyes with endophthalmitis, and in 12 eyes with idiopathic macular holes which served as controls. Formalin-fixed and paraffin-embedded tissue sections of an enucleated eye with endophthalmitis, and a control eye with recurrent conjunctival malignant melanoma, were analyzed by immunohistochemistry with an anti-HMGB1 antibody. RESULTS: The vitreous HMGB1 level of the patients with endophthalmitis was 13.96 +/- 17.17 ng/ml (mean+/-SD), which was significantly higher than that of the controls (0.236 +/- 0.128 ng/ml; P = .0006, Mann-Whitney U test). There were significant correlations between HMGB1 level and disease duration, presenting visual acuity, and final visual acuity. In the eye with endophthalmitis, HMGB1 expression was diffusely observed, particularly in the extranuclear region of the retina and the choroid with infiltrating inflammatory cells. CONCLUSION: HMGB1 can be released in the vitreous of eyes with endophthalmitis depending on inflammation and tissue damage. Our results suggest that HMGB1 may be a late mediator of endophthalmitis, and related to the progression of endophthalmitis.

Stromal-derived factor-1 and inflammatory cytokines in retinal vein occlusion.

PURPOSE: To identify the roles of stromal-derived factor (SDF-1) and inflammatory cytokines in retinal vein occlusion (RVO). METHODS: Samples were collected by vitrectomy and the levels of SDF-1, vascular endothelial growth factor, and inflammatory cytokines (interleukins [IL-1beta, IL-6, IL-8, IL-10, IL-12p70]; tumor necrosis factor-alpha) were measured in 20 eyes with RVO, and 9 eyes with epiretinal membrane served as negative controls. Four eyes with inflammatory diseases were also investigated. RESULTS: SDF-1 levels in active RVO (A-RVO; 4 eyes with iris neovascularization) were significantly higher than those in quiescent RVO (Q-RVO; 16 eyes without iris neovascularization) and the negative controls (p < .01), whereas there were no significant difference between the Q-RVO and the negative controls. There were no significant correlations between the concentrations of SDF-1 and other cytokines. CONCLUSIONS: Elevation of intravitreous SDF-1 levels in A-RVO but not Q-RVO suggested a pivotal role of SDF-1 in angiogenic changes during RVO.