Nagakazu Matsumura

Chronic Photo-oxidative Stress And Subsequent Mcp-1 Activation As Causative Factors For Age-related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in developed countries. Although pathogenic factors, such as oxidative stress, inflammation and genetics are thought to contribute to the development of AMD, little is known about the relationships and priorities between these factors. Here, we show that chronic photo-oxidative stress is an environmental factor involved in AMD pathogenesis. We first demonstrated that exposure to light induced phospholipid oxidation in the mouse retina, which was more prominent in aged animals. The induced oxidized phospholipids led to an increase in the expression of monocyte chemoattractant protein-1, which then resulted in macrophage accumulation, an inflammatory process. Antioxidant treatment prevented light-induced phospholipid oxidation and the subsequent increase of monocyte chemoattractant protein-1 (also known as C-C motif chemokine 2; CCL2), which are the beginnings of the light-induced changes. Subretinal application of oxidized phospholipids induced choroidal neovascularization, a characteristic feature of wet-type AMD, which was inhibited by blocking monocyte chemoattractant protein-1. These findings strongly suggest that a sequential cascade from photic stress to inflammatory processes through phospholipid oxidation has an important role in AMD pathogenesis. Finally, we succeeded in mimicking human AMD in mice with low-level, long-term photic stress, in which characteristic pathological changes, including choroidal neovascularization formation, were observed. Therefore, we propose a consecutive pathogenic pathway involving photic stress, oxidation of phospholipids and chronic inflammation, leading to angiogenesis. These findings add to the current understanding of AMD pathology and suggest protection from oxidative stress or suppression of the subsequent inflammation as new potential therapeutic targets for AMD.

Suppression and regression of choroidal neovascularization in mice by a novel CCR2 antagonist, INCB3344.

Purpose To investigate the effect of an intravitreally administered CCR2 antagonist, INCB3344, on a mouse model of choroidal neovascularization (CNV). Methods CNV was induced by laser photocoagulation on Day 0 in wild type mice. INCB3344 or vehicle was administered intravitreally immediately after laser application. On Day 14, CNV areas were measured on retinal pigment epithelium (RPE)-choroid flat mounts and histopathologic examination was performed on 7 µm-thick sections. Macrophage infiltration was evaluated by immunohistochemistry on RPE-choroid flat mounts and quantified by flow cytometry on Day 3. Expression of vascular endothelial growth factor (VEGF) protein in RPE-choroid tissue was examined by immunohistochemistry and ELISA, VEGF mRNA in sorted macrophages in RPE-choroid tissue was examine by real-time PCR and expression of phosphorylated extracellular signal-regulated kinase (p-ERK 1/2) in RPE-choroid tissue was measured by Western blot analysis on Day 3. We also evaluated the efficacy of intravitreal INCB3344 to spontaneous CNV detected in Cu, Zn-superoxide dismutase (SOD1) deficient mice. Changes in CNV size were assessed between pre- and 1week post-INCB3344 or vehicle administration in fundus photography and fluorescence angiography (FA). Results The mean CNV area in INCB3344-treated mice decreased by 42.4% compared with the vehicle-treated control mice (p<0.001). INCB3344 treatment significantly inhibited macrophage infiltration into the laser-irradiated area (p<0.001), and suppressed the expression of VEGF protein (p = 0.012), VEGF mRNA in infiltrating macrophages (p<0.001) and the phosphorylation of ERK1/2 (p<0.001). The area of spontaneous CNV in Sod1 −/− mice regressed by 70.35% in INCB3344-treated animals while no change was detected in vehicle-treated control mice (p<0.001). Conclusions INCB3344 both inhibits newly forming CNV and regresses established CNV. Controlling inflammation by suppressing macrophage infiltration and angiogenic ability via the CCR-2/MCP-1 signal may be a useful therapeutic strategy for treating CNV associated with age-related macular degeneration.

Relationship between grades of macular perfusion and foveal thickness in branch retinal vein occlusion

Background To study the relationship between retinal perfusion around the macula and the foveal thickness in branch retinal vein occlusion (BRVO). Methods Seventy-four eyes of 74 consecutive patients with BRVO were enrolled. We developed a new grading system to evaluate the status of retinal perfusion around the macula in three grades: full perfusion area (FPA), partial perfusion area (PPA), and nonperfusion area (NPA), using fluorescein angiography. The correlation was assessed between these grades and the central foveal thickness (CFT) measured by optical coherence tomography. We also determined the area with the closest correlation between the perfusion status and the foveal thickness by comparing the correlation coefficient in areas of 1-, 2-, and 3-disc diameter (DD) horizontal hemicircles centered at the fovea. The correlation was determined between the extent of each perfusion grade and CFT. Results We found a significant negative correlation between the CFT and the FPA (r = 0.31, P = 0.006) and a significant positive correlation between the CFT and the PPA (r = 0.45, P < 0.001) in the three areas. The most significant correlations were found in the 2-DD area. Interestingly, the NPA has not correlated with the foveal thickness in any areas. Conclusion The areas of partial but not complete capillary loss seem to be responsible for the macular edema associated with BRVO. Treatments targeting leakage from the dilated capillaries in the PPA should be investigated.

Low-Dose Lipopolysaccharide Pretreatment Suppresses Choroidal Neovascularization via IL-10 Induction

Recent studies have suggested that some kinds of microbial infection may have a crucial role in the development of many diseases such as autoimmune diseases and certain types of cancer. It has been reported that some chronic infections, such as Chlamydia pneumoniae, and immunological dysfunctions are associated with age-related macular degeneration (AMD), a leading cause of blindness. To evaluate the association between systemic low-level inflammation induced by infection and AMD pathogenesis, we investigated whether intraperitoneal injection of lipopolysaccharide (LPS) can modulate the development of laser-induced choroidal neovascularization (CNV), a key feature of AMD. Contrary to our expectations, the sizes of CNV in mice with LPS pretreatment were approximately 65% smaller than those of the control mice. After LPS pretreatment, serum IL-10 concentration and IL-10 gene expression in peritoneal macrophages and in the posterior part of the eye increased. Peritoneal injection of anti-IL10 antibody reduced CNV suppression by LPS pretreatment. Moreover, adoptive transfer of the resident peritoneal macrophages from LPS-treated mice into control littermates resulted in an approximately 26% reduction in the size of CNV compared with PBS-treated mice. We concluded that CNV formation was suppressed by low-dose LPS pretreatment via IL-10 production by macrophages.

Commercially available rigid gas-permeable contact lens for protecting the cornea from drying during vitrectomy with a wide viewing system

Purpose We evaluated the usefulness of commercially available materials for protecting the cornea from drying during vitrectomy with a wide-angle viewing system. Methods Three vitreoretinal surgeons evaluated fundus visibility during vitrectomy on the images of five study materials used on the cornea: balanced saline solution, a viscoelastic agent, a vitrectomy contact lens, a rigid gas permeable (RGP) contact lens, and a soft contact lens. Fundus visibility was graded using the following scale: grade 1, unclear; grade 2, slightly unclear; grade 3, clear; and grade 4, very clear. Results Respective scores for each material used during core vitrectomy and membrane removal were: balanced saline solution, 3.3/3.3; viscoelastic agent, 3.8/3.3; vitrectomy contact lens, 3.3/4.0; RGP contact lens, 4.0/3.9; soft contact lens, 1.1/not applicable. Conclusion The RGP contact lens provided visibility similar to or clearer than that obtained with other methods. Because of its ease of use and lower cost, use of the RGP contact lens is ideal during vitrectomy performed with a wide-angle viewing system.

Simultaneous intravitreal injection of triamcinolone acetonide and tissue plasminogen activator for central retinal vein occlusion: a pilot study

Purpose To evaluate the efficacy and safety of simultaneous intravitreal injection of triamcinolone acetonide (TA) and tissue plasminogen activator (tPA) for macular oedema associated with central retinal vein occlusion (CRVO). Methods Twenty eyes of 20 patients with CRVO were enrolled. A mixture of TA (4 mg) and tPA (25 μg) was injected into the vitreous of 20 eyes with CRVO. Best corrected visual acuity (BCVA) and macular thickness before and 1, 3, 6 and 12 months after the procedure were measured. Results The BCVA improved three lines or more in 65%, 55%, 55% and 53% of eyes and the mean macular thickness decreased from 1072 μm to 455, 450, 480 and 409 μm (p<0.001) at 1, 3, 6 and 12 months, respectively. Fifteen (75%) of the 20 eyes required at least one additional injection to prevent a recurrence of macular oedema. The intraocular pressure increased in four eyes. Conclusion Overall, intravitreal injection of the TA/tPA mixture improved the BCVA by three lines or more in at least 50% of eyes and decreased the mean macular thickness at four time points without serious side effects. A randomised clinical trial is necessary to evaluate the efficacy of this treatment.

Matched control study of visual outcomes after arteriovenous sheathotomy for branch retinal vein occlusion

Background The purpose of this study was to evaluate visual outcomes of arteriovenous sheathotomy for macular edema due to branch retinal vein occlusion (BRVO). Methods The medical records of 45 eyes from 45 patients who had undergone vitrectomy surgery with arteriovenous sheathotomy for BRVO were studied. Forty-five eyes of 45 patients with a BRVO but without intervention were studied as the control group. The best-corrected visual acuity and central macular thickness were compared between the two groups at baseline and at 1, 3, 6, and 12 months postoperatively. Results Improvement of best-corrected visual acuity was 0.42 logarithm of the minimum angle of resolution (logMAR) units in the sheathotomy group and 0.22 logMAR units in the control group (P=0.007). The mean postoperative central macular thickness was significantly thinner in the sheathotomy group at 1 month (P=0.01), but not at 3, 6, and 12 months (P=0.75, P=0.81, and P=0.46, respectively). Improvement of best-corrected visual acuity at 12 months was significantly correlated with baseline best-corrected visual acuity, age, duration of symptoms, and sheathotomy (P<0.05). Conclusion Arteriovenous sheathotomy for BRVO improves best-corrected visual acuity significantly more than the natural course of the BRVO disease process.

Rigid gas-permeable contact lens–assisted cataract surgery in patients with severe keratoconus

&NA; We describe rigid gas‐permeable (RGP) contact lens–assisted cataract surgery in patients with severe keratoconus. During cataract surgery in cases with severe keratoconus, the intraocular images are distorted and visual perspective is lost because of irregular corneal astigmatism. Poor visibility can lead to complications, including posterior capsule rupture and corneal endothelial cell damage. To overcome these problems, an RGP contact lens was placed on the cornea in 2 cases. The image distortion decreased markedly, and the visual perspective improved. Intraocular manipulations such as irrigation/aspiration were performed safely. Improvement in transillumination led to good visualization of the anterior and posterior capsules. No intraoperative or postoperative complications developed in either case. This technique provided excellent visualization during cataract surgery in patients with severe keratoconus. Financial Disclosure No author has a financial or proprietary interest in any material or method mentioned.

Direct photocoagulation to leakage points to treat chronic macular edema associated with branch retinal vein occlusion: a pilot study.

Summary statement Direct photocoagulation reduces the central foveal thickness (CFT) in cases with chronic branch retinal vein occlusion (BRVO) of longer than 12 months duration. Photo-coagulation might be effective for chronic macular edema due to branch retinal vein occlusion. Background The aim was to investigate the effect of direct photocoagulation for treating chronic macular edema associated with BRVO. Methods This study was a noncomparative, pilot interventional case series. We examined the CFT and best-corrected visual acuity over 6 months in patients with BRVO treated with direct photocoagulation. Results Sixteen eyes of 16 patients had been treated with direct photocoagulation (mean follow-up period, 20.5 months). The mean CFT decreased significantly (P<0.001) between the baseline (465 μm) and the final visit (304 μm). The mean (logarithm of the minimum angle of resolution equivalent) best-corrected visual acuity at the baseline was 0.39 and improved significantly (P<0.001) to 0.20 at the final visit. Conclusion Direct photocoagulation to leakage points is beneficial for treating chronic macular edema associated with chronic BRVO of longer than 12 months duration.