Yuji Oshima

Kyushu University, Hukuoka, Fukuoka, Japan

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Publications (39)148.52 Total impact

  • Acta ophthalmologica 04/2015; DOI:10.1111/aos.12734 · 2.51 Impact Factor
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    ABSTRACT: To determine whether vitreal concentrations of MCP-1, IL-6 and IL-8 are altered after vitrectomy in patients with proliferative diabetic retinopathy (PDR) and to investigate whether the altered levels of these cytokines are associated with postoperative macular oedema. Vitreous samples were collected from 36 eyes of 33 patients with PDR before pars plana vitrectomy without intraocular lens (IOL) implantation, and also from the same 36 eyes during IOL implantation surgery approximately 7 months after the initial vitrectomy. Levels of MCP-1, IL-6, IL-8 and vascular endothelial growth factor were measured by flow cytometry using cytometric bead array (CBA) technology. The mean vitreous levels of MCP-1, IL-6 and IL-8 in the samples collected before vitrectomy were significantly higher in patients with PDR than in control patients (p<0.0001). The levels of MCP-1 and IL-6 in the samples collected at the time of IOL implantation were significantly higher than those collected before vitrectomy (p<0.05). In contrast, the level of IL-8 was significantly lower after vitrectomy (p<0.05). The levels of IL-6 and IL-8, but not MCP-1, in the vitreous from eyes with PDR were inversely correlated with the interval between the initial vitrectomy and the time of implantation surgery. Among the vitrectomised patients, the mean vitreous level of MCP-1 in eyes with diabetic macular oedema (DME) was significantly higher than in those without DME (p=0.028). The elevated levels of MCP-1 and IL-6 may indicate prolonged inflammation even after successful vitrectomy, which can cause postoperative DME. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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    ABSTRACT: PURPOSE. To determine the profile of genes expressed in fibrovascular membranes (FVMs). METHODS. Six FVMs were surgically removed from patients with proliferative diabetic retinopathy (PDR) during pars plana vitrectomy. Total RNA was isolated from the six FVMs and also from three normal human retinas. DNA microarray analysis was performed to compare the genes expressed in the FVMs to those in normal human retinas and also between three active and three inactive FVMs. Ingenuity Pathway Analysis (IPA) was used to determine the key biological networks related to the genes that were significantly altered. RESULTS. Eighty-seven genes were expressed at significantly higher levels in FVMs than in normal retinas. Functional classification of these genes showed that the most clustered genes were those related to extracellular matrix formation. The top biological network generated by the IPA was cellular assembly and organization involving nodes of genes related to extracellular matrix formation. These networks included the collagen family and matricellular proteins, THBS2, POSTN, and TNC. Ninety-one genes were significantly up-regulated in active FVMs, and the most clustered functional category was angiogenesis. In contrast, 89 genes were significantly up-regulated in inactive FVMs, and the most clustered functional category was metabolism. IPA revealed that the top biological network related to the genes that were significantly altered in this comparison was cell-to-cell signaling and interactions involving the PDGF and TGFβ families. CONCLUSIONS. Our data indicate that extracellular matrix-related molecules such as POSTN, PDGF, TGFβ and angiogenic factors play important roles in promoting the development FVMs associated with PDR. Copyright © 2015 by Association for Research in Vision and Ophthalmology.
    Investigative Ophthalmology &amp Visual Science 01/2015; 56(2). DOI:10.1167/iovs.14-15589 · 3.66 Impact Factor
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    ABSTRACT: The pathogenesis of macular hole formation is widely accepted as a tractional force at the vitreo-retinal interface in fovea. We report a case of macular hole after intravitreous aflibercept injection for age-related macular degeneration (AMD) associated with contraction of the retinal pigment epithelium (RPE) at the edge of a fibrovascular pigment epithelial detachment (PED). A 94-year old man with neovascular AMD affecting his left eye accompanied by a fibrovascular PED was examined for severe vision loss. Although RPE tear in his left eye was identified before the first aflibercept intravitreous injection performed in order to treat neovascular AMD, he received three aflibercept injections as induction treatment. After induction treatment, a full thickness macular hole was identified associated with the contracted rolled RPE edge beneath the retina. Macular hole is commonly formed associated with tangential vitreous traction. Current report suggests that rapid contraction of the RPE underneath the retina can be one of the causes of a macular hole, and one of the side effects of anti-VEGF therapy for neovascular AMD.
    BMC Ophthalmology 01/2015; 15(1):30. DOI:10.1186/s12886-015-0021-3 · 1.08 Impact Factor
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    ABSTRACT: Age-related macular degeneration (AMD) is a vision-threatening disease characterized by choroidal fibrovascular membrane (FVM) formation, choroidal neovascularization (CNV) and choroidal fibrosis. No safe and effective therapeutic method has been developed for the choroidal fibrosis, although anti-vascular endothelial growth factor therapy can partially shrink the CNV. We recently reported that periostin (POSTN), which is produced by retinal pigment epithelial cells, has an important role in the formation of preretinal FVMs, but its role in choroidal FVMs has not been determined. In this study, we used Postn knockout mice to investigate the role played by POSTN in choroidal FVM formation. In addition, we used a new class of RNA interference (RNAi) agent (NK0144) that targets POSTN and determined its effect on choroidal FVM development. Genetic ablation of Postn had an inhibitory effect not only on CNV formation but also on choroidal fibrosis in a mouse CNV model. NK0144 also had a greater inhibitory effect on both the CNV and choroidal fibrosis than control RNAi with no apparent adverse effects. These findings suggest a causal relationship between POSTN and choroidal FVM formation, and also a potential therapeutic role of intravitreal NK0144 for AMD.Gene Therapy advance online publication, 11 December 2014; doi:10.1038/gt.2014.112.
    Gene Therapy 12/2014; 22(2). DOI:10.1038/gt.2014.112 · 4.20 Impact Factor
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    ABSTRACT: We recently demonstrated that M2 macrophages were involved in the development of fibrovascular membranes (FVM) associated with proliferative diabetic retinopathy (PDR) possibly through the induction of periostin. The purpose of this study was to determine whether macrophage colony-stimulating factor (M-CSF) and interleukin (IL)-13, inducers of the M2 polarisation of macrophages from monocytes, are elevated in the vitreous of patients with PDR, and whether M2-polarised macrophages induce periostin production.
    The British journal of ophthalmology 10/2014; DOI:10.1136/bjophthalmol-2014-305860 · 2.81 Impact Factor
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    ABSTRACT: To determine whether CD163, a specific marker for M2 macrophages, is involved in the formation of preretinal fibrovascular membranes (FVMs) present in eyes with proliferative diabetic retinopathy (PDR).
    The British journal of ophthalmology 10/2014; DOI:10.1136/bjophthalmol-2014-305321 · 2.81 Impact Factor
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    ABSTRACT: Murine experimental autoimmune uveitis (EAU) is a model for human autoimmune uveitis, whose pathogenesis is caused by both Th1 and Th17 cell responses. Epstein-Barr virus-induced gene 3 (EBI3) is a component of the heterodimeric cytokines: interleukin (IL)-27 and IL-35. Although IL-27 was shown to initiate Th1 cell development, it is also recognized as a negative regulator of fully activated CD4(+) T cells, including Th17 cells. Recently, IL-35 also has also been reported to play immunosuppressive roles in autoimmunity. To investigate the roles of EBI3 in EAU, EBI3(-∕-) mice were immunized with human interphotoreceptor retinoid binding protein peptide 1-20 (IRBP) to induce EAU. We observed that the clinical score in EBI3(-∕-) mice was diminished compared with that in EBI3(+/+) mice up to day 22 after immunization, whereas the score in EBI3(-∕-) mice reached the same levels as that of EBI3(+/+) mice after day 28. Histological analysis revealed a significant reduction of cellular infiltration into the retina in EBI3(-∕-) mice on day 16. Although Th1 cell responses and IRBP-specific IL-10 production were reduced in EBI3(-∕-) mice, the development of Th17 cell responses was unaffected on day 9. On day 21, Th1 cell responses and IRBP-specific IL-10 production was restored to the same levels as that in EBI3(+/+) mice, and Th17 cell responses significantly increased in EBI3(-∕-) mice. Furthermore, Foxp3 expression in CD4(+) T cells was comparable between EBI3(+/+) and EBI3(-∕-) mice on days 9 and 21. Therefore, these results indicate that EBI3 may be important in EAU initiation by Th1 cell responses and may suppress EAU by inhibition of both Th1 and Th17 cell responses in the late/maintenance phase.
    Experimental Eye Research 06/2014; 125. DOI:10.1016/j.exer.2014.06.004 · 3.02 Impact Factor
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    ABSTRACT: Murine experimental autoimmune uveitis (EAU) is a model for human autoimmune uveitis, whose pathogenesis is caused by both Th1 and Th17 cell responses. Epstein–Barr virus-induced gene 3 (EBI3) is a component of the heterodimeric cytokines: interleukin (IL)-27 and IL-35. Although IL-27 was shown to initiate Th1 cell development, it is also recognized as a negative regulator of fully activated CD4+ T cells, including Th17 cells. Recently, IL-35 also has also been reported to play immunosuppressive roles in autoimmunity. To investigate the roles of EBI3 in EAU, EBI3−/− mice were immunized with human interphotoreceptor retinoid binding protein peptide 1–20 (IRBP) to induce EAU. We observed that the clinical score in EBI3−/− mice was diminished compared with that in EBI3+/+ mice up to day 22 after immunization, whereas the score in EBI3−/− mice reached the same levels as that of EBI3+/+ mice after day 28. Histological analysis revealed a significant reduction of cellular infiltration into the retina in EBI3−/− mice on day 16. Although Th1 cell responses and IRBP-specific IL-10 production were reduced in EBI3−/− mice, the development of Th17 cell responses was unaffected on day 9. On day 21, Th1 cell responses and IRBP-specific IL-10 production was restored to the same levels as that in EBI3+/+ mice, and Th17 cell responses significantly increased in EBI3−/− mice. Furthermore, Foxp3 expression in CD4+ T cells was comparable between EBI3+/+ and EBI3−/− mice on days 9 and 21. Therefore, these results indicate that EBI3 may be important in EAU initiation by Th1 cell responses and may suppress EAU by inhibition of both Th1 and Th17 cell responses in the late/maintenance phase.
    Experimental Eye Research 01/2014; 125:107–113. · 3.02 Impact Factor
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    ABSTRACT: Subretinal fibrosis is directly related to severe visual loss, especially if occurs in the macula, and is frequently observed in advanced age-related macular degeneration and other refractory eye disorders such as diabetic retinopathy and uveitis. In this study, we analyzed the immunosuppressive mechanism of subretinal fibrosis using the novel animal model recently demonstrated. Both TLR2 and TLR4 deficient mice showed significant enlargement of subretinal fibrotic area as compared with wild-type mice. A single intraocular administration of heat shock protein 70 (HSP70), which is an endogenous ligand for TLR2 and TLR4, inhibited subretinal fibrosis in wild-type mice but not in TLR2 and TLR4-deficient mice. Additionally, HSP70 induced IL-10 production in eyes from wild-type mice but was impaired in both TLR2- and TLR4-deficient mice, indicating that HSP70-TLR2/TLR4 axis plays an immunomodulatory role in subretinal fibrosis. Thus, these results suggest that HSP70-TLR2/TLR4 axis is a new therapeutic target for subretinal fibrosis due to prognostic CNV.
    PLoS ONE 12/2013; 8(12):e80288. DOI:10.1371/journal.pone.0080288 · 3.53 Impact Factor
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    ABSTRACT: Proliferative vitreoretinopathy (PVR) is a severe, vision-threatening disorder characterized by the fibrous membrane formation that leads to tractional retinal detachment. There has been no effective therapeutic approach other than vitreoretinal surgery. In this study, DNA microarray analysis of the fibrous membranes revealed significant up-regulation of periostin. We also found increased periostin expression in the vitreous and retinal pigment epithelial (RPE) cells from fibrous membranes of PVR patients. In vitro, periostin increased proliferation, adhesion, migration, and collagen production in RPE cells through integrin αV-mediated FAK and AKT phosphorylation. Periostin blockade suppressed migration and adhesion induced by TGFβ2 and PVR vitreous. In vivo, periostin inhibition had the inhibitory effect on progression of experimental PVR in rabbit eyes without affecting the viability of retinal cells. These results identified periostin as a pivotal molecule for fibrous membrane formation as well as a promising therapeutic target for PVR.-Ishikawa, K., Yoshida, S., Nakao, S., Nakama, T., Kita, T., Asato, R., Sassa, Y., Arita, R., Miyazaki, M., Enaida, H., Oshima, Y., Murakami, N., Niiro, H., Ono, J., Matsuda, A., Goto, Y., Akashi, K., Izuhara, K., Kudo, A., Kono, T., Hafezi-Moghadam, A., Ishibashi, T. Periostin promotes the generation of fibrous membranes in proliferative vitreoretinopathy.
    The FASEB Journal 09/2013; 28(1). DOI:10.1096/fj.13-229740 · 5.48 Impact Factor
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    ABSTRACT: Choroidal neovascularization (CNV) is a critical pathogenesis in age-related macular degeneration (AMD), the most common cause of blindness in developed countries. To date, the precise molecular and cellular mechanisms underlying CNV have not been elucidated. Platelet-activating factor (PAF) has been previously implicated in angiogenesis; however, the roles of PAF and its receptor (PAF-R) in CNV have not been addressed. The present study reveals several important findings concerning the relationship of the PAF-R signaling with CNV. PAF-R was detected in a mouse model of laser-induced CNV and was upregulated during CNV development. Experimental CNV was suppressed by administering WEB2086, a novel PAF-R antagonist. WEB2086-dependent suppression of CNV occurred via the inhibition of macrophage infiltration and the expression of proangiogenic (vascular endothelial growth factor) and proinflammatory molecules (monocyte chemotactic protein-1 and IL-6) in the retinal pigment epithelium-choroid complex. Additionally, WEB2086-induced PAF-R blockage suppresses experimentally induced subretinal fibrosis, which resembles the fibrotic subretinal scarring observed in neovascular AMD. As optimal treatment modalities for neovascular AMD would target the multiple mechanisms of AMD-associated vision loss, including neovascularization, inflammation and fibrosis, our results suggest PAF-R as an attractive molecular target in the treatment of AMD.
    PLoS ONE 06/2013; 8(6):e68173. DOI:10.1371/journal.pone.0068173 · 3.53 Impact Factor
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    ABSTRACT: Background Proliferative vitreoretinopathy (PVR) is a destructive complication of retinal detachment and vitreoretinal surgery which can lead to severe vision reduction by tractional retinal detachments. The purpose of this study was to determine the gene expression profile of epiretinal membranes (ERMs) associated with a PVR (PVR-ERM) and to compare it to the expression profile of less-aggressive secondary ERMs. Methodology/Principal Findings A PCR-amplified complementary DNA (cDNA) library was constructed using the RNAs isolated from ERMs obtained during vitrectomy. The sequence from the 5′ end was obtained for randomly selected clones and used to generate expressed sequence tags (ESTs). We obtained 1116 nonredundant clusters representing individual genes expressed in PVR-ERMs, and 799 clusters representing the genes expressed in secondary ERMs. The transcriptome of the PVR-ERMs was subdivided by functional subsets of genes related to metabolism, cell adhesion, cytoskeleton, signaling, and other functions, by FatiGo analysis. The genes highly expressed in PVR-ERMs were compared to those expressed in the secondary ERMs, and these were subdivided by cell adhesion, proliferation, and other functions. Querying 10 cell adhesion-related genes against the STRING database yielded 70 possible physical relationships to other genes/proteins, which included an additional 60 genes that were not detected in the PVR-ERM library. Of these, soluble CD44 and soluble vascular cellular adhesion molecule-1 were significantly increased in the vitreous of patients with PVR. Conclusions/Significance Our results support an earlier hypothesis that a PVR-ERM, even from genomic points of view, is an aberrant form of wound healing response. Genes preferentially expressed in PVR-ERMs may play an important role in the progression of PVR and could be served as therapeutic targets.
    PLoS ONE 04/2013; 8(1):e54191. DOI:10.1371/journal.pone.0054191 · 3.53 Impact Factor
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    ABSTRACT: Choroidal neovascularization (CNV) is a characteristic of age-related macular degeneration. Genome-wide association studies have provided evidence that the immune system is involved in the pathogenesis of age-related macular degeneration; however, the role of inflammatory cytokines in CNV has not been established. In this study, we demonstrated that IL-17 had a strong potential for promoting neovascularization in a vascular endothelial growth factor-independent manner in laser-induced experimental CNV in mice. Infiltrated γδT cells and Thy-1(+) innate lymphoid cells, but not Th17 cells, were the main sources of IL-17 in injured eyes. IL-23 was dispensable for IL-17 induction in the eye. Instead, we found that IL-1β and high-mobility group box 1 strongly promoted IL-17 expression by γδT cells. Suppression of IL-1β and high-mobility group box 1, as well as depletion of γδT cells, reduced IL-17 levels and ameliorated experimental CNV. Our findings suggest the existence of a novel inflammatory cytokine network that promotes neovascularization in the eye.
    The Journal of Immunology 01/2013; 190(4). DOI:10.4049/jimmunol.1202495 · 5.36 Impact Factor
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    ABSTRACT: Purpose. We determined whether the concentrations of VEGF, erythropoietin, and endostatin in the vitreous are altered after vitrectomy in patient with proliferative diabetic retinopathy (PDR). Methods. We measured the levels of VEGF, erythropoietin, and endostatin by sandwich ELISA in vitreous samples collected from 38 eyes of 33 patients with PDR before pars plana vitrectomy (without IOL implantation) and the same 38 eyes during IOL implantation 3.1 to 25.7 (mean 6.7) months after the initial vitrectomy. Results. The mean vitreous levels of VEGF (964.5 pg/mL) and erythropoietin (1359.5 pg/mL) in the samples collected before vitrectomy were significantly higher in patients with PDR than in the control patients (0.68 and 70.7 pg/mL, respectively; P < 0.01). The levels of VEGF (292.5 pg/mL) and erythropoietin (557.9 pg/mL) in the samples from eyes with PDR collected at the time of IOL implantation were significantly lower than those collected before vitrectomy (P < 0.01). In contrast, the changes in the level of endostatin were not significant after vitrectomy. The VEGF and erythropoietin levels in the vitreous fluid from patients with PDR were correlated inversely with the interval between the initial vitrectomy and the time of the IOL implantation. Conclusions. The significant decrease in the intravitreal concentration of VEGF and erythropoietin, and an absence of a significant change in the endostatin indicated a shift in the antiangiogenic balance in the vitreous of patients with PDR after successful vitrectomy.
    Investigative ophthalmology & visual science 09/2012; 53(11):6997-7003. DOI:10.1167/iovs.12-9671 · 3.66 Impact Factor
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    ABSTRACT: Purpose. A timely regression of the hyaloid vascular system (HVS) is required for the normal ocular development. Although macrophages have a critical role in this process, the exact mechanism remains undetermined. Periostin is a matricellular protein involved in tissue and vascular remodeling. The purpose of our study was to determine whether periostin is involved in the HVS regression. Methods. We used wild type (WT) and periostin knockout (KO) mice. Indocyanine green angiography and immunohistochemistry with isolectin B4 were used to evaluate the HVS regression. TUNEL-labeling was used to quantify the number of apoptotic hyaloid vascular endothelial cells. F4/80 and Iba-1 staining was performed to determine the number and location of macrophages in the vitreous. The location of periostin also was investigated by immunohistochemistry. To determine the functional role of periostin, the degree of adhesion of human monocytes to fibronectin was measured by an adhesion assay. Results. The HVS regression and peak in the number of TUNEL-positive apoptotic endothelial cells were delayed in periostin KO mice. The number of F4/80 positive cells in the vitreous was higher in periostin KO mice. Only a small number of Iba-1-positive cells near the hyaloid vessels was co-stained with periostin, and peripheral blood monocytes were not stained with periostin. Adhesion assay showed that periostin increased the degree of attachment of monocytes to fibronectin. Conclusions. These results suggest that periostin, which is secreted by the intraocular macrophages, enhances the HVS regression by intensifying the adhesion of macrophages to hyaloid vessels.
    Investigative ophthalmology & visual science 08/2012; 53(10):6495-503. DOI:10.1167/iovs.12-9684 · 3.66 Impact Factor
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    ABSTRACT: Purpose: Functional vision score (FVS) recommended by the American Medical Association (AMA) is known to correlate with quality of life (QOL). In this study, we applied FVS to patients with visual impairment who had been graded by Japanese visual disability grading system and compared their FVS with the Japanese visual disability grades.Subjects and Methods: Subjects were 42 patients (20 males and 22 females) who had been certified as visually impaired (Grade 1: 8 patients, Grade 2: 19 patients, Grade 3: 6 patients, Grade 4: 3 patients and Grade 5: 6 patients). To obtain FVS, functional acuity score was calculated from visual acuity and functional field score was calculated from the Goldmann visual field results. We compared the subjects' FVS with the disability grade they were classified to.Results: The FVS was equivalent to each Japanese visual disability grade as follows: the FVS of 0%-19.9% was equivalent to Grade 1, 2.9%-60.2% to Grade 2, 6.9%-62.1% to Grade 3, 7.6%-27.5% to Grade 4, and 11.9%-74.4% to Grade 5. A significant correlation was observed between the Japanese visual disability grades and the FVS (r=0.47, p=0.0014; Spearman's rank correlation). We further classified the subjects using the AMA Guides to vision loss. The results showed that 6 patients in Grade 1, 5 in Grade 2, and 1 each in Grades 3, 4 and 5 belonged to the AMA Class 4 ("Near total vision loss" by International Ranges of Vision Loss); 2 patients in Grade 1, 8 patients in Grade 2, 4 patients in Grade 3, 2 patients in Grade 4, and 1 patient in Grade 5 belonged to Class 3b ("Profound vision loss"); 3 patients in Grade 2 and 3 patients in Grade 5 belonged to Class 3a ("Severe vision loss"); 3 patients in Grade 2 and 1 patient in Grade 3 belonged to Class 2 ("Moderate vision loss"); 1 patient in Grade 5 belonged to Class 1 ("Mild vision loss"); and no patient in any grade belonged to Class 0 ("Range of normal vision").Conclusion: A significant correlation was observed between the Japanese visual disability grades and FVS. However, some patients from the same Japanese disability grade could be classified into different AMA classes based on their FVS.
    01/2012; 41:163-169. DOI:10.4263/jorthoptic.041F115
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    ABSTRACT: AMD is the most common disease leading to acquired blindness in developed countries. CNV is the foremost cause of AMD and is thought to be induced by regional inflammation as a result of age-related conformational changes of the chorioretinal interface. Here, we show that IL-27, a member of the IL-6/IL-12 cytokine family, has an angiostatic effect and regulates the development of laser-induced experimental CNV in mice. In this model, IL-27 expression increased in the damaged choroid and peaked at the 24 h-time-point. IL-27 neutralization, induced by inoculating an antagonistic antibody into the vitreous cavity, enhanced VEGF production and the extent of CNV. By contrast, the administration of rIL-27 reduced VEGF production and the extent of CNV. Mice deficient in the EBI3, which lack IL-27, also showed more CNV than C57BL/6 mice, and this was reduced by IL-27 supplementation. We additionally investigated the effect of IL-27 on the function of macrophages, which play a critical role in CNV. IL-27 did not affect macrophage migration but inhibited its VEGF production. IL-27 therefore appears to regulate CNV and is a promising candidate target for treating sight-threatening diseases caused by ocular neovascularization.
    Journal of leukocyte biology 11/2011; 91(2):267-73. DOI:10.1189/jlb.1110603 · 4.99 Impact Factor
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    ABSTRACT: Age-related macular degeneration (AMD), the leading cause of irreversible blindness in the world, is a complex disease caused by multiple environmental and genetic risk factors. To identify genetic factors that modify the risk of exudative AMD in the Japanese population, we conducted a genome-wide association study and a replication study using a total of 1,536 individuals with exudative AMD and 18,894 controls. In addition to CFH (rs800292, P = 4.23 × 10(-15)) and ARMS2 (rs3750847, P = 8.67 × 10(-29)) loci, we identified two new susceptibility loci for exudative AMD: TNFRSF10A-LOC389641 on chromosome 8p21 (rs13278062, combined P = 1.03 × 10(-12), odds ratio = 0.73) and REST-C4orf14-POLR2B-IGFBP7 on chromosome 4q12 (rs1713985, combined P = 2.34 × 10(-8), odds ratio = 1.30). Fine mapping revealed that rs13278062, which is known to alter TNFRSF10A transcriptional activity, had the most significant association in 8p21 region. Our results provide new insights into the pathophysiology of exudative AMD.
    Nature Genetics 09/2011; 43(10):1001-4. DOI:10.1038/ng.938 · 29.65 Impact Factor
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    ABSTRACT: Subretinal fibrosis causes damage to visual acuity, especially if the lesion is in the macula, as is frequently observed in advanced age-related macular degeneration. Exudate leukocytes form abnormal vessels that initiate regional inflammation accompanied with local glial proliferation and matrix production. The purpose of this study was to establish an animal model of focal subretinal fibrosis. Macrophage-rich peritoneal exudate cells (PECs) were injected into the subretinal space of C57BL/6 or MCP-1 knockout (KO) mice. Seven days later, the size of the subretinal fibrotic tissue was evaluated by the adherent area of glial fibrillary acidic protein (GFAP)-positive retinal glial cells on choroidal flat mounts. Myofibroblastic changes and collagen synthesis were detected by α-smooth muscle actin (α-SMA) and Masson trichrome staining of the histologic section, respectively. α-SMA expression was also examined on retinal pigment epithelium (RPE) cells during co-culture with activated macrophages. Subretinal fibrous tissue was observed by funduscopy in PEC-injected mice after 7 days. The tissue consisted of a monotonous, low-cell-density area that expressed α-SMA with collagen synthesis. Both steroid and antioxidant treatment can reduce residual glia. Because PEC-injected MCP-1 KO mice showed less residual glia, not only exogenous macrophages, but also intrinsic macrophages were activated. The macrophages directly induced myofibrotic changes in RPE cells in vitro. Activated macrophages form subretinal fibrosis when they are placed in the subretinal space and induce myofibrotic changes in RPE cells.
    Investigative ophthalmology & visual science 11/2010; 52(9):6089-95. DOI:10.1167/iovs.10-5189 · 3.66 Impact Factor

Publication Stats

684 Citations
148.52 Total Impact Points

Institutions

  • 1996–2015
    • Kyushu University
      • Department of Ophthalmology
      Hukuoka, Fukuoka, Japan
  • 2013
    • St.Mary's Hospital (Fukuoka - Japan)
      Hukuoka, Fukuoka, Japan
    • Keio University
      • Department of Microbiology and Immunology
      Tokyo, Tokyo-to, Japan