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From the Laboratory for Surgical Research,*
Children’s
Hospital, Harvard Medical School, Boston, Massachusetts; the Department
of Ophthalmology,
Massachusetts Eye and Ear
Infirmary, Harvard Medical School, Boston, Massachusetts; the
Department of Ophthalmology,
RWTH Aachen,
Aachen, Germany; and the Joslin Diabetes
Center,§
Harvard Medical School,
Boston, Massachusetts
Endothelial cell death is a hallmark of diabetic retinopathy. Its occurrence is required for the formation of acellular (devitalized) capillaries, lesions that produce irreversible retinal ischemia through their inability to support blood flow. The mechanisms underlying diabetic retinal endothelial cell injury and death remain largely unknown. The current study demonstrates that adherent leukocytes are temporally and spatially associated with retinal endothelial cell injury and death within 1 week of streptozotocin-induced experimental diabetes in rats. Moreover, the antibody-based neutralization of intercellular adhesion molecule-1 and CD18 is shown to prevent both leukocyte adhesion and retinal endothelial cell injury and death. These data highlight the central and causal role of adherent leukocytes in the pathogenesis of diabetic retinopathy. They also underscore the potential utility of anti-intercellular adhesion molecule1- and anti-CD18-based therapies in the treatment of diabetic retinopathy, a newly recognized inflammatory disease.
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S. Y. Kim, M. A. Johnson, D. S. McLeod, T. Alexander, B. C. Hansen, and G. A. Lutty Neutrophils Are Associated With Capillary Closure in Spontaneously Diabetic Monkey Retinas Diabetes, May 1, 2005; 54(5): 1534 - 1542. [Abstract] [Full Text] [PDF]
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J. K. Krady, A. Basu, C. M. Allen, Y. Xu, K. F. LaNoue, T. W. Gardner, and S. W. Levison Minocycline Reduces Proinflammatory Cytokine Expression, Microglial Activation, and Caspase-3 Activation in a Rodent Model of Diabetic Retinopathy Diabetes, May 1, 2005; 54(5): 1559 - 1565. [Abstract] [Full Text] [PDF]
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R. A. Kowluru and S. Odenbach Effect of Long-Term Administration of {alpha}-Lipoic Acid on Retinal Capillary Cell Death and the Development of Retinopathy in Diabetic Rats Diabetes, December 1, 2004; 53(12): 3233 - 3238. [Abstract] [Full Text] [PDF]
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R. A. Kowluru and S. Odenbach Role of Interleukin-1{beta} in the Development of Retinopathy in Rats: Effect of Antioxidants Invest. Ophthalmol. Vis. Sci., November 1, 2004; 45(11): 4161 - 4166. [Abstract] [Full Text] [PDF]
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B. Miljanovic, R. J. Glynn, D. M. Nathan, J. E. Manson, and D. A. Schaumberg A Prospective Study of Serum Lipids and Risk of Diabetic Macular Edema in Type 1 Diabetes Diabetes, November 1, 2004; 53(11): 2883 - 2892. [Abstract] [Full Text] [PDF]
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C. Zhang, J. Yang, and L. K. Jennings Leukocyte-Derived Myeloperoxidase Amplifies High-Glucose--Induced Endothelial Dysfunction Through Interaction With High-Glucose--Stimulated, Vascular Non--Leukocyte-Derived Reactive Oxygen Species Diabetes, November 1, 2004; 53(11): 2950 - 2959. [Abstract] [Full Text] [PDF]
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L. Zheng, C. Szabo, and T. S. Kern Poly(ADP-Ribose) Polymerase Is Involved in the Development of Diabetic Retinopathy via Regulation of Nuclear Factor-{kappa}B Diabetes, November 1, 2004; 53(11): 2960 - 2967. [Abstract] [Full Text] [PDF]
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B. M. Ben-Mahmud, G. E. Mann, A. Datti, A. Orlacchio, E. M. Kohner, and R. Chibber Tumor Necrosis Factor-{alpha} in Diabetic Plasma Increases the Activity of Core 2 GlcNAc-T and Adherence of Human Leukocytes to Retinal Endothelial Cells: Significance of Core 2 GlcNAc-T in Diabetic Retinopathy Diabetes, November 1, 2004; 53(11): 2968 - 2976. [Abstract] [Full Text] [PDF]
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J R MacKinnon, R M Knott, and J V Forrester Altered L-selectin expression in lymphocytes and increased adhesion to endothelium in patients with diabetic retinopathy Br J Ophthalmol, September 1, 2004; 88(9): 1137 - 1141. [Abstract] [Full Text] [PDF]
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V. Poulaki, A. M. Joussen, N. Mitsiades, C. S. Mitsiades, E. F. Iliaki, and A. P. Adamis Insulin-Like Growth Factor-I Plays a Pathogenetic Role in Diabetic Retinopathy Am. J. Pathol., August 1, 2004; 165(2): 457 - 469. [Abstract] [Full Text] [PDF]
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D. C. Yeh, D. V. Bula, J. W. Miller, E. S. Gragoudas, and J. G. Arroyo Expression of Leukocyte Adhesion Molecules in Human Subfoveal Choroidal Neovascular Membranes Treated with and without Photodynamic Therapy Invest. Ophthalmol. Vis. Sci., July 1, 2004; 45(7): 2368 - 2373. [Abstract] [Full Text] [PDF]
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 J. C. Mamputu and G. Renier Advanced glycation end-products increase monocyte adhesion to retinal endothelial cells through vascular endothelial growth factor-induced ICAM-1 expression: inhibitory effect of antioxidants J. Leukoc. Biol., June 1, 2004; 75(6): 1062 - 1069. [Abstract] [Full Text] [PDF]
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A. Canton, E. M. Martinez-Caceres, C. Hernandez, C. Espejo, J. Garcia-Arumi, and R. Simo CD4-CD8 and CD28 Expression in T Cells Infiltrating the Vitreous Fluid in Patients With Proliferative Diabetic Retinopathy: A Flow Cytometric Analysis Arch Ophthalmol, May 1, 2004; 122(5): 743 - 749. [Abstract] [Full Text] [PDF]
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S. Miyahara, J. Kiryu, K. Yamashiro, K. Miyamoto, F. Hirose, H. Tamura, H. Katsuta, K. Nishijima, A. Tsujikawa, and Y. Honda Simvastatin Inhibits Leukocyte Accumulation and Vascular Permeability in the Retinas of Rats with Streptozotocin-Induced Diabetes Am. J. Pathol., May 1, 2004; 164(5): 1697 - 1706. [Abstract] [Full Text] [PDF]
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V. Poulaki, N. Mitsiades, F. E. Kruse, S. Radetzky, E. Iliaki, B. Kirchhof, and A. M. Joussen Activin A in the Regulation of Corneal Neovascularization and Vascular Endothelial Growth Factor Expression Am. J. Pathol., April 1, 2004; 164(4): 1293 - 1302. [Abstract] [Full Text] [PDF]
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M R Stanford The pathogenesis of diabetic retinopathy Br J Ophthalmol, April 1, 2004; 88(4): 444 - 445. [Full Text] [PDF]
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J M Hughes, A Brink, A N Witmer, M Hanraads-de Riemer, I Klaassen, and R O Schlingemann Vascular leucocyte adhesion molecules unaltered in the human retina in diabetes Br J Ophthalmol, April 1, 2004; 88(4): 566 - 572. [Abstract] [Full Text] [PDF]
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W. Chen, D. B. Jump, M. B. Grant, W. J. Esselman, and J. V. Busik Dyslipidemia, but Not Hyperglycemia, Induces Inflammatory Adhesion Molecules in Human Retinal Vascular Endothelial Cells Invest. Ophthalmol. Vis. Sci., November 1, 2003; 44(11): 5016 - 5022. [Abstract] [Full Text] [PDF]
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T. C. B. Moore, J. E. Moore, Y. Kaji, N. Frizzell, T. Usui, V. Poulaki, I. L. Campbell, A. W. Stitt, T. A. Gardiner, D. B. Archer, et al. The Role of Advanced Glycation End Products in Retinal Microvascular Leukostasis Invest. Ophthalmol. Vis. Sci., October 1, 2003; 44(10): 4457 - 4464. [Abstract] [Full Text] [PDF]
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 S. Ishida, T. Usui, K. Yamashiro, Y. Kaji, S. Amano, Y. Ogura, T. Hida, Y. Oguchi, J. Ambati, J. W. Miller, et al. VEGF164-mediated Inflammation Is Required for Pathological, but Not Physiological, Ischemia-induced Retinal Neovascularization J. Exp. Med., August 4, 2003; 198(3): 483 - 489. [Abstract] [Full Text] [PDF]
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K. Yamashiro, A. Tsujikawa, S. Ishida, T. Usui, Y. Kaji, Y. Honda, Y. Ogura, and A. P. Adamis Platelets Accumulate in the Diabetic Retinal Vasculature Following Endothelial Death and Suppress Blood-Retinal Barrier Breakdown Am. J. Pathol., July 1, 2003; 163(1): 253 - 259. [Abstract] [Full Text] [PDF]
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R. Chibber, B. M. Ben-Mahmud, G. E. Mann, J. J. Zhang, and E. M. Kohner Protein Kinase C {beta}2-Dependent Phosphorylation of Core 2 GlcNAc-T Promotes Leukocyte-Endothelial Cell Adhesion: A Mechanism Underlying Capillary Occlusion in Diabetic Retinopathy Diabetes, June 1, 2003; 52(6): 1519 - 1527. [Abstract] [Full Text] [PDF]
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S. Ishida, T. Usui, K. Yamashiro, Y. Kaji, E. Ahmed, K. G. Carrasquillo, S. Amano, T. Hida, Y. Oguchi, and A. P. Adamis VEGF164 Is Proinflammatory in the Diabetic Retina Invest. Ophthalmol. Vis. Sci., May 1, 2003; 44(5): 2155 - 2162. [Abstract] [Full Text] [PDF]
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K. Koizumi, V. Poulaki, S. Doehmen, G. Welsandt, S. Radetzky, A. Lappas, N. Kociok, B. Kirchhof, and A. M. Joussen Contribution of TNF-{alpha} to Leukocyte Adhesion, Vascular Leakage, and Apoptotic Cell Death in Endotoxin-Induced Uveitis In Vivo Invest. Ophthalmol. Vis. Sci., May 1, 2003; 44(5): 2184 - 2191. [Abstract] [Full Text] [PDF]
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A. M. Joussen, V. Poulaki, A. Tsujikawa, W. Qin, T. Qaum, Q. Xu, Y. Moromizato, S.-E. Bursell, S. J. Wiegand, J. Rudge, et al. Suppression of Diabetic Retinopathy with Angiopoietin-1 Am. J. Pathol., May 1, 2002; 160(5): 1683 - 1693. [Abstract] [Full Text] [PDF]
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M. Gotte, A. M. Joussen, C. Klein, P. Andre, D. D. Wagner, M. T. Hinkes, B. Kirchhof, A. P. Adamis, and M. Bernfield Role of Syndecan-1 in Leukocyte-Endothelial Interactions in the Ocular Vasculature Invest. Ophthalmol. Vis. Sci., April 1, 2002; 43(4): 1135 - 1141. [Abstract] [Full Text] [PDF]
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A P Adamis Is diabetic retinopathy an inflammatory disease? Br J Ophthalmol, April 1, 2002; 86(4): 363 - 365. [Full Text] [PDF]
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A. M. Joussen, V. Poulaki, W. Qin, B. Kirchhof, N. Mitsiades, S. J. Wiegand, J. Rudge, G. D. Yancopoulos, and A. P. Adamis Retinal Vascular Endothelial Growth Factor Induces Intercellular Adhesion Molecule-1 and Endothelial Nitric Oxide Synthase Expression and Initiates Early Diabetic Retinal Leukocyte Adhesion in Vivo Am. J. Pathol., February 1, 2002; 160(2): 501 - 509. [Abstract] [Full Text] [PDF]
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A. M. Joussen, S. Huang, V. Poulaki, K. Camphausen, W.-D. Beecken, B. Kirchhof, and A. P. Adamis In Vivo Retinal Gene Expression in Early Diabetes Invest. Ophthalmol. Vis. Sci., November 1, 2001; 42(12): 3047 - 3057. [Abstract] [Full Text] [PDF]
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A. M. Joussen, W.-D. Beecken, Y. Moromizato, A. Schwartz, B. Kirchhof, and V. Poulaki Inhibition of Inflammatory Corneal Angiogenesis by TNP-470 Invest. Ophthalmol. Vis. Sci., October 1, 2001; 42(11): 2510 - 2516. [Abstract] [Full Text] [PDF]
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T. Qaum, Q. Xu, A. M. Joussen, M. W. Clemens, W. Qin, K. Miyamoto, H. Hassessian, S. J. Wiegand, J. Rudge, G. D. Yancopoulos, et al. VEGF-initiated Blood-Retinal Barrier Breakdown in Early Diabetes Invest. Ophthalmol. Vis. Sci., September 1, 2001; 42(10): 2408 - 2413. [Abstract] [Full Text] [PDF]
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