Macular Degeneration: Hisatomi T

Noda K, She H, Nakazawa T, Hisatomi T, Nakao S, Almulki L, Zandi S, Miyahara S, Ito Y, Thomas KL, Garland RC, Miller JW, Gragoudas ES, Mashima Y, Hafezi-Moghadam A. · Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA. · FASEB J. · Pubmed #18436961 links to  free full text

Abstract: 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) -alpha, 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.

Noda K, Miyahara S, Nakazawa T, Almulki L, Nakao S, Hisatomi T, She H, Thomas KL, Garland RC, Miller JW, Gragoudas ES, Kawai Y, Mashima Y, Hafezi-Moghadam A. · Department of Ophthalmology, Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston, Massachusetts, USA. · FASEB J. · Pubmed #18032635 links to  free full text

Abstract: Inflammatory leukocyte accumulation is a common feature of major ocular diseases, such as uveitis, diabetic retinopathy, and age-related macular degeneration. Vascular adhesion protein-1 (VAP-1), a cell surface and soluble molecule that possesses semicarbazide-sensitive amine oxidase (SSAO) activity, is involved in leukocyte recruitment. However, the expression of VAP-1 in the eye and its contribution to ocular inflammation are unknown. Here, we investigated the role of VAP-1 in an established model of ocular inflammation, the endotoxin-induced uveitis (EIU), using a novel and specific inhibitor. Our inhibitor has a half-maximal inhibitory concentration (IC(50)) of 0.007 microM against human and 0.008 microM against rat SSAO, while its IC(50) against the functionally related monoamine oxidase (MAO) -A and MAO-B is >10 microM. In the retina, VAP-1 was exclusively expressed in the vasculature, and its expression level was elevated during EIU. VAP-1 inhibition in EIU animals significantly suppressed leukocyte recruitment to the anterior chamber, vitreous, and retina, as well as retinal endothelial P-selectin expression. Our data suggest an important role for VAP-1 in the recruitment of leukocytes to the immune-privileged ocular tissues during acute inflammation. VAP-1 inhibition may become a novel strategy in the treatment of ocular inflammatory diseases.

Matsumoto H, Yamanaka I, Hisatomi T, Enaida H, Ueno A, Hata Y, Sakamoto T, Ogino N, Ishibashi T. · Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Retina. · Pubmed #17290199 No free full text.

Abstract: OBJECTIVE: To determine whether triamcinolone acetonide (TA) can facilitate residual posterior vitreous hyaloid removal in pars plana vitrectomy (PPV), we examined the ultrastructure of inner limiting membrane (ILM) removed in TA-assisted PPV for diabetic macular edema (DME). PATIENTS AND METHODS: In this retrospective series of 38 eyes of 37 patients who underwent PPV and ILM removal for diffuse DME with posterior hyaloid attachment, 24 eyes underwent standard PPV without TA (control group), and 14 eyes underwent TA-assisted PPV (TA group). Excised ILMs during PPV were examined by transmission electron microscopy (control group, n = 20; TA group, n = 10) or scanning electron microscopy (control group, n = 4; TA group, n = 4). RESULTS: Transmission electron microscopy clearly demonstrated that the ratio of the posterior vitreous hyaloid remaining on ILM was significantly lower (P = 0.0187) in the TA group than in the control group and also that TA-assisted PPV successfully removed posterior hyaloid in five of seven eyes with TA granules remaining on the retinal surface even after surgical separation of the posterior vitreous. Scanning electron microscopy enabled spatial analysis of the residual posterior hyaloid on ILM, which appeared in a patchy fashion in the control group. CONCLUSIONS: TA-assisted PPV clearly demonstrated the residual posterior hyaloid on ILM and allowed more efficient removal of the posterior hyaloid than standard PPV.

Yoshida T, Ohno-Matsui K, Ichinose S, Sato T, Iwata N, Saido TC, Hisatomi T, Mochizuki M, Morita I. · Department of Ophthalmology and Visual Science and Instrumental Analysis Research Center, Tokyo Medical and Dental University, Tokyo, Japan. · J Clin Invest. · Pubmed #16167083 links to  free full text

Abstract: Drusen are extracellular deposits that lie beneath the retinal pigment epithelium (RPE) and are the earliest signs of age-related macular degeneration (AMD). Recent proteome analysis demonstrated that amyloid beta (Abeta) deposition was specific to drusen from eyes with AMD. To work toward a molecular understanding of the development of AMD from drusen, we investigated the effect of Abeta on cultured human RPE cells as well as ocular findings in neprilysin gene-disrupted mice, which leads to an increased deposition Abeta. The results showed that Abeta treatment induced a marked increase in VEGF as well as a marked decrease in pigment epithelium-derived factor (PEDF). Conditioned media from Abeta-exposed RPE cells caused a dramatic increase in tubular formation by human umbilical vein endothelial cells. Light microscopy of senescent neprilysin gene-disrupted mice showed an increased number of degenerated RPE cells with vacuoles. Electron microscopy revealed basal laminar and linear deposits beneath the RPE layer, but we did not observe choroidal neovascularization (CNV). The present study demonstrates that Abeta accumulation affects the balance between VEGF and PEDF in the RPE, and an accumulation of Abeta reproduces features characteristic of human AMD, such as RPE atrophy and basal deposit formation. Some other factors, such as breakdown of integrity of Bruch membrane, might be necessary to induce CNV of AMD.

Tsutsumi C, Sonoda KH, Egashira K, Qiao H, Hisatomi T, Nakao S, Ishibashi M, Charo IF, Sakamoto T, Murata T, Ishibashi T. · Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · J Leukoc Biol. · Pubmed #12832439 links to  free full text

Abstract: Choroidal neovascularization (CNV) is directly related to visual loss in some eye diseases, such as age-related macular degeneration. Although several human histological studies have suggested the participation of macrophages in CNV formation, the precise mechanisms are still not fully understood. In this study, we elucidated the role of ocular-infiltrating macrophages in experimental CNV using CCR2 knockout (KO) mice, wild-type mice, and C57BL/6 (B6) mice. CCR2 is the receptor of monocyte chemoattractant protein-1, and the number of infiltrating macrophage and the area of CNV were significantly reduced in CCR2 KO mice. Enriched ocular-infiltrating macrophages from B6 mice actually showed angiogenic ability in a dorsal air sac assay. Moreover, their expression of class II, CD40, B7-1 and B7-2 molecules, and the mRNA for potential angiogenic factors, such as vascular endothelial growth factor, basic fibroblast growth factor, and tumor necrosis factor alpha, was also observed. Collectively, we conclude that ocular-infiltrating macrophages play an important role in CNV generation.