Seminars in Immunopathology

, Volume 30, Issue 2, pp 65–84 | Cite as

Immunological mechanisms in the pathogenesis of diabetic retinopathy

Review

Abstract

There is an accumulating body of evidence that immunological mechanisms play a prominent role in the pathogenesis of diabetic retinopathy (DR), which is characterized by many features typical of inflammation. The upregulation of cytokines and other inflammatory mediators leading to persistent low-grade inflammation and an influx of leukocytes, is believed to contribute actively to DR-associated damage to the retinal vasculature and retinal neovascularization. This review will describe preclinical and clinical studies that document an inflammatory basis for DR and that support the use of nonsteroidal anti-inflammatory drugs, corticosteroids, and anti-vascular endothelial growth factor agents in its treatment. In addition, emerging therapeutic approaches based on ongoing investigations will be discussed, including those involving blockade of angiotensin receptors and other molecular targets such as tumor necrosis factor-α.

Keywords

Diabetic retinopathy Immune system Inflammation Leukostasis Neovascularization 

References

  1. 1.
    Sheetz MJ, King GL (2002) Molecular understanding of hyperglycemia’s adverse effects for diabetic complications. JAMA 288:2579–2588PubMedGoogle Scholar
  2. 2.
    Caldwell RB, Bartoli M, Behzadian MA, El-Remessy AE, Al-Shabrawey M, Platt DH, Caldwell RW (2003) Vascular endothelial growth factor and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives. Diabetes Metab Res Rev 19:442–455PubMedGoogle Scholar
  3. 3.
    Antonetti DA, Barber AJ, Bronson SK, Freeman WM, Gardner TW, Jefferson LS, Kester M, Kimball SR, Krady JK, LaNoue KF, Norbury CC, Quinn PG, Sandirasegarane L, Simpson IA (2006) Diabetic retinopathy: seeing beyond glucose-induced microvascular disease. Diabetes 55:2401–2411PubMedGoogle Scholar
  4. 4.
    Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE et al (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480–1487PubMedGoogle Scholar
  5. 5.
    Adamis AP, Miller JW, Bernal MT, D’Amico DJ, Folkman J, Yeo TK, Yeo KT (1994) Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol 118:445–450PubMedGoogle Scholar
  6. 6.
    Demircan N, Safran BG, Soylu M, Ozcan AA, Sizmaz S (2006) Determination of vitreous interleukin-1 (IL-1) and tumour necrosis factor (TNF) levels in proliferative diabetic retinopathy. Eye (London) 20:1366–1369Google Scholar
  7. 7.
    Funatsu H, Yamashita H, Shimizu E, Kojima R, Hori S (2001) Relationship between vascular endothelial growth factor and interleukin-6 in diabetic retinopathy. Retina 21:469–477PubMedGoogle Scholar
  8. 8.
    Yuuki T, Kanda T, Kimura Y, Kotajima N, Tamura J, Kobayashi I, Kishi S (2001) Inflammatory cytokines in vitreous fluid and serum of patients with diabetic vitreoretinopathy. J Diabetes Complications 15:257–259PubMedGoogle Scholar
  9. 9.
    Canataroglu H, Varinli I, Ozcan AA, Canataroglu A, Doran F, Varinli S (2005) Interleukin (IL)-6, interleukin (IL)-8 levels and cellular composition of the vitreous humor in proliferative diabetic retinopathy, proliferative vitreoretinopathy, and traumatic proliferative vitreoretinopathy. Ocul Immunol Inflamm 13:375–381PubMedGoogle Scholar
  10. 10.
    Brooks HL Jr., Caballero S Jr., Newell CK, Steinmetz RL, Watson D, Segal MS, Harrison JK, Scott EW, Grant MB (2004) Vitreous levels of vascular endothelial growth factor and stromal-derived factor 1 in patients with diabetic retinopathy and cystoid macular edema before and after intraocular injection of triamcinolone. Arch Ophthalmol 122:1801–1807PubMedGoogle Scholar
  11. 11.
    Funatsu H, Yamashita H, Ikeda T, Nakanishi Y, Kitano S, Hori S (2002) Angiotensin II and vascular endothelial growth factor in the vitreous fluid of patients with diabetic macular edema and other retinal disorders. Am J Ophthalmol 133:537–543PubMedGoogle Scholar
  12. 12.
    Patel JI, Hykin PG, Gregor ZJ, Boulton M, Cree IA (2005) Angiopoietin concentrations in diabetic retinopathy. Br J Ophthalmol 89:480–483PubMedGoogle Scholar
  13. 13.
    Watanabe D, Suzuma K, Suzuma I, Ohashi H, Ojima T, Kurimoto M, Murakami T, Kimura T, Takagi H (2005) Vitreous levels of angiopoietin 2 and vascular endothelial growth factor in patients with proliferative diabetic retinopathy. Am J Ophthalmol 139:476–481PubMedGoogle Scholar
  14. 14.
    Watanabe D, Suzuma K, Matsui S, Kurimoto M, Kiryu J, Kita M, Suzuma I, Ohashi H, Ojima T, Murakami T, Kobayashi T, Masuda S, Nagao M, Yoshimura N, Takagi H (2005) Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy. N Engl J Med 353:782–792PubMedGoogle Scholar
  15. 15.
    Hernandez C, Fonollosa A, Garcia-Ramirez M, Higuera M, Catalan R, Miralles A, Garcia-Arumi J, Simo R (2006) Erythropoietin is expressed in the human retina and it is highly elevated in the vitreous fluid of patients with diabetic macular edema. Diabetes Care 29:2028–2033PubMedGoogle Scholar
  16. 16.
    Limb GA, Chignell AH, Green W, LeRoy F, Dumonde DC (1996) Distribution of TNF alpha and its reactive vascular adhesion molecules in fibrovascular membranes of proliferative diabetic retinopathy. Br J Ophthalmol 80:168–173PubMedGoogle Scholar
  17. 17.
    Meleth AD, Agron E, Chan CC, Reed GF, Arora K, Byrnes G, Csaky KG, Ferris FL 3rd, Chew EY (2005) Serum inflammatory markers in diabetic retinopathy. Invest Ophthalmol Vis Sci 46:4295–4301PubMedGoogle Scholar
  18. 18.
    Barber AJ, Lieth E, Khin SA, Antonetti DA, Buchanan AG, Gardner TW (1998) Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. J Clin Invest 102:783–791PubMedGoogle Scholar
  19. 19.
    Mizutani M, Kern TS, Lorenzi M (1996) Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy. J Clin Invest 97:2883–2890PubMedGoogle Scholar
  20. 20.
    Esser P, Heimann K, Wiedemann P (1993) Macrophages in proliferative vitreoretinopathy and proliferative diabetic retinopathy: differentiation of subpopulations. Br J Ophthalmol 77:731–733PubMedGoogle Scholar
  21. 21.
    Rungger-Brandle E, Dosso AA, Leuenberger PM (2000) Glial reactivity, an early feature of diabetic retinopathy. Invest Ophthalmol Vis Sci 41:1971–1980PubMedGoogle Scholar
  22. 22.
    Zeng XX, Ng YK, Ling EA (2000) Neuronal and microglial response in the retina of streptozotocin-induced diabetic rats. Vis Neurosci 17:463–471PubMedGoogle Scholar
  23. 23.
    Krady JK, Basu A, Allen CM, Xu Y, LaNoue KF, Gardner TW, Levison SW (2005) Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy. Diabetes 54:1559–1565PubMedGoogle Scholar
  24. 24.
    Miyamoto K, Khosrof S, Bursell SE, Rohan R, Murata T, Clermont AC, Aiello LP, Ogura Y, Adamis AP (1999) Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition. Proc Natl Acad Sci USA 96:10836–10841PubMedGoogle Scholar
  25. 25.
    Joussen AM, Poulaki V, Le ML, Koizumi K, Esser C, Janicki H, Schraermeyer U, Kociok N, Fauser S, Kirchhof B, Kern TS, Adamis AP (2004) A central role for inflammation in the pathogenesis of diabetic retinopathy. FASEB J 18:1450–1452PubMedGoogle Scholar
  26. 26.
    Zhang J, Gerhardinger C, Lorenzi M (2002) Early complement activation and decreased levels of glycosylphosphatidylinositol-anchored complement inhibitors in human and experimental diabetic retinopathy. Diabetes 51:3499–3504PubMedGoogle Scholar
  27. 27.
    Joussen AM, Poulaki V, Mitsiades N, Cai WY, Suzuma I, Pak J, Ju ST, Rook SL, Esser P, Mitsiades CS, Kirchhof B, Adamis AP, Aiello LP (2003) Suppression of Fas–FasL-induced endothelial cell apoptosis prevents diabetic blood–retinal barrier breakdown in a model of streptozotocin-induced diabetes. FASEB J 17:76–78PubMedGoogle Scholar
  28. 28.
    Gerhardinger C, Costa MB, Coulombe MC, Toth I, Hoehn T, Grosu P (2005) Expression of acute-phase response proteins in retinal Muller cells in diabetes. Invest Ophthalmol Vis Sci 46:349–357PubMedGoogle Scholar
  29. 29.
    Gardner TW, Antonetti DA, Barber AJ, LaNoue KF, Levison SW (2002) Diabetic retinopathy: more than meets the eye. Surv Ophthalmol 47(Suppl 2):S253–S262PubMedGoogle Scholar
  30. 30.
    McLeod DS, Lefer DJ, Merges C, Lutty GA (1995) Enhanced expression of intracellular adhesion molecule-1 and P-selectin in the diabetic human retina and choroid. Am J Pathol 147:642–653PubMedGoogle Scholar
  31. 31.
    Song H, Wang L, Hui Y (2007) Expression of CD18 on the neutrophils of patients with diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 245:24–31PubMedGoogle Scholar
  32. 32.
    Lutty GA, Cao J, McLeod DS (1997) Relationship of polymorphonuclear leukocytes to capillary dropout in the human diabetic choroid. Am J Pathol 151:707–714PubMedGoogle Scholar
  33. 33.
    Schroder S, Palinski W, Schmid-Schonbein GW (1991) Activated monocytes and granulocytes, capillary nonperfusion, and neovascularization in diabetic retinopathy. Am J Pathol 139:81–100PubMedGoogle Scholar
  34. 34.
    Kim SY, Johnson MA, McLeod DS, Alexander T, Hansen BC, Lutty GA (2005) Neutrophils are associated with capillary closure in spontaneously diabetic monkey retinas. Diabetes 54:1534–1542PubMedGoogle Scholar
  35. 35.
    Canton A, Martinez-Caceres EM, Hernandez C, Espejo C, Garcia-Arumi J, Simo R (2004) CD4–CD8 and CD28 expression in T cells infiltrating the vitreous fluid in patients with proliferative diabetic retinopathy: a flow cytometric analysis. Arch Ophthalmol 122:743–749PubMedGoogle Scholar
  36. 36.
    Barouch FC, Miyamoto K, Allport JR, Fujita K, Bursell SE, Aiello LP, Luscinskas FW, Adamis AP (2000) Integrin-mediated neutrophil adhesion and retinal leukostasis in diabetes. Invest Ophthalmol Vis Sci 41:1153–1158PubMedGoogle Scholar
  37. 37.
    Senger DR, Connolly DT, Van de Water L, Feder J, Dvorak HF (1990) Purification and NH2-terminal amino acid sequence of guinea pig tumor-secreted vascular permeability factor. Cancer Res 50:1774–1778PubMedGoogle Scholar
  38. 38.
    Iijima K, Yoshikawa N, Connolly DT, Nakamura H (1993) Human mesangial cells and peripheral blood mononuclear cells produce vascular permeability factor. Kidney Int 44:959–966PubMedGoogle Scholar
  39. 39.
    Freeman MR, Schneck FX, Gagnon ML, Corless C, Soker S, Niknejad K, Peoples GE, Klagsbrun M (1995) Peripheral blood T lymphocytes and lymphocytes infiltrating human cancers express vascular endothelial growth factor: a potential role for T cells in angiogenesis. Cancer Res 55:4140–4145PubMedGoogle Scholar
  40. 40.
    Gaudry M, Bregerie O, Andrieu V, El Benna J, Pocidalo MA, Hakim J (1997) Intracellular pool of vascular endothelial growth factor in human neutrophils. Blood 90:4153–4161PubMedGoogle Scholar
  41. 41.
    Horiuchi T, Weller PF (1997) Expression of vascular endothelial growth factor by human eosinophils: upregulation by granulocyte macrophage colony-stimulating factor and interleukin-5. Am J Respir Cell Mol Biol 17:70–77PubMedGoogle Scholar
  42. 42.
    Del Maschio A, Zanetti A, Corada M, Rival Y, Ruco L, Lampugnani MG, Dejana E (1996) Polymorphonuclear leukocyte adhesion triggers the disorganization of endothelial cell-to-cell adherens junctions. J Cell Biol 135:497–510PubMedGoogle Scholar
  43. 43.
    Bolton SJ, Anthony DC, Perry VH (1998) Loss of the tight junction proteins occludin and zonula occludens-1 from cerebral vascular endothelium during neutrophil-induced blood-brain barrier breakdown in vivo. Neuroscience 86:1245–1257PubMedGoogle Scholar
  44. 44.
    Joussen AM, Murata T, Tsujikawa A, Kirchhof B, Bursell SE, Adamis AP (2001) Leukocyte-mediated endothelial cell injury and death in the diabetic retina. Am J Pathol 158:147–152PubMedGoogle Scholar
  45. 45.
    Boeri D, Maiello M, Lorenzi M (2001) Increased prevalence of microthromboses in retinal capillaries of diabetic individuals. Diabetes 50:1432–1439PubMedGoogle Scholar
  46. 46.
    Ishibashi T, Tanaka K, Taniguchi Y (1981) Platelet aggregation and coagulation in the pathogenesis of diabetic retinopathy in rats. Diabetes 30:601–606PubMedGoogle Scholar
  47. 47.
    Yamashiro K, Tsujikawa A, Ishida S, Usui T, Kaji Y, Honda Y, Ogura Y, Adamis AP (2003) Platelets accumulate in the diabetic retinal vasculature following endothelial death and suppress blood–retinal barrier breakdown. Am J Pathol 163:253–259PubMedGoogle Scholar
  48. 48.
    Sharma NK, Gardiner TA, Archer DB (1985) A morphologic and autoradiographic study of cell death and regeneration in the retinal microvasculature of normal and diabetic rats. Am J Ophthalmol 100:51–60PubMedGoogle Scholar
  49. 49.
    Tepper OM, Galiano RD, Capla JM, Kalka C, Gagne PJ, Jacobowitz GR, Levine JP, Gurtner GC (2002) Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation 106:2781–2786PubMedGoogle Scholar
  50. 50.
    Segal MS, Shah R, Afzal A, Perrault CM, Chang K, Schuler A, Beem E, Shaw LC, Li Calzi S, Harrison JK, Tran-Son-Tay R, Grant MB (2006) Nitric oxide cytoskeletal-induced alterations reverse the endothelial progenitor cell migratory defect associated with diabetes. Diabetes 55:102–109PubMedGoogle Scholar
  51. 51.
    Caballero S, Sengupta N, Afzal A, Chang KH, Li Calzi S, Guberski DL, Kern TS, Grant MB (2007) Ischemic vascular damage can be repaired by healthy, but not diabetic, endothelial progenitor cells. Diabetes 56:960–967PubMedGoogle Scholar
  52. 52.
    Ishida S, Usui T, Yamashiro K, Kaji Y, Amano S, Ogura Y, Hida T, Oguchi Y, Ambati J, Miller JW, Gragoudas ES, Ng YS, D’Amore PA, Shima DT, Adamis AP (2003) VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization. J Exp Med 198:483–489PubMedGoogle Scholar
  53. 53.
    Clauss M, Gerlach M, Gerlach H, Brett J, Wang F, Familletti PC, Pan YC, Olander JV, Connolly DT, Stern D (1990) Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration. J Exp Med 172:1535–1545PubMedGoogle Scholar
  54. 54.
    Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, Marme D (1996) Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 87:3336–3343PubMedGoogle Scholar
  55. 55.
    Usui T, Ishida S, Yamashiro K, Kaji Y, Poulaki V, Moore J, Moore T, Amano S, Horikawa Y, Dartt D, Golding M, Shima DT, Adamis AP (2004) VEGF164(165) as the pathological isoform: differential leukocyte and endothelial responses through VEGFR1 and VEGFR2. Invest Ophthalmol Vis Sci 45:368–374PubMedGoogle Scholar
  56. 56.
    Harmey JH, Dimitriadis E, Kay E, Redmond HP, Bouchier-Hayes D (1998) Regulation of macrophage production of vascular endothelial growth factor (VEGF) by hypoxia and transforming growth factor beta-1. Ann Surg Oncol 5:271–278PubMedGoogle Scholar
  57. 57.
    Grossniklaus HE, Ling JX, Wallace TM, Dithmar S, Lawson DH, Cohen C, Elner VM, Elner SG, Sternberg P Jr. (2002) Macrophage and retinal pigment epithelium expression of angiogenic cytokines in choroidal neovascularization. Mol Vis 8:119–126PubMedGoogle Scholar
  58. 58.
    Tsutsumi C, Sonoda KH, Egashira K, Qiao H, Hisatomi T, Nakao S, Ishibashi M, Charo IF, Sakamoto T, Murata T, Ishibashi T (2003) The critical role of ocular-infiltrating macrophages in the development of choroidal neovascularization. J Leukoc Biol 74:25–32PubMedGoogle Scholar
  59. 59.
    Espinosa-Heidmann DG, Suner IJ, Hernandez EP, Monroy D, Csaky KG, Cousins SW (2003) Macrophage depletion diminishes lesion size and severity in experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 44:3586–3592PubMedGoogle Scholar
  60. 60.
    Sakurai E, Anand A, Ambati BK, van Rooijen N, Ambati J (2003) Macrophage depletion inhibits experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 44:3578–3585PubMedGoogle Scholar
  61. 61.
    Giulian D, Li J, Bartel S, Broker J, Li X, Kirkpatrick JB (1995) Cell surface morphology identifies microglia as a distinct class of mononuclear phagocyte. J Neurosci 15:7712–7726PubMedGoogle Scholar
  62. 62.
    Ishida S, Yamashiro K, Usui T, Kaji Y, Ogura Y, Hida T, Honda Y, Oguchi Y, Adamis AP (2003) Leukocytes mediate retinal vascular remodeling during development and vaso-obliteration in disease. Nat Med 9:781–788PubMedGoogle Scholar
  63. 63.
    Starita C, Patel M, Katz B, Adamis AP (2007) Vascular endothelial growth factor and the potential therapeutic use of pegaptanib (Macugen) in diabetic retinopathy. Dev Ophthalmol 39:122–148PubMedCrossRefGoogle Scholar
  64. 64.
    Lu M, Kuroki M, Amano S, Tolentino M, Keough K, Kim I, Bucala R, Adamis AP (1998) Advanced glycation end products increase retinal vascular endothelial growth factor expression. J Clin Invest 101:1219–1224PubMedGoogle Scholar
  65. 65.
    Gao BB, Clermont A, Rook S, Fonda SJ, Srinivasan VJ, Wojtkowski M, Fujimoto JG, Avery RL, Arrigg PG, Bursell SE, Aiello LP, Feener EP (2007) Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation. Nat Med 13:181–188PubMedGoogle Scholar
  66. 66.
    Kuroki M, Voest EE, Amano S, Beerepoot LV, Takashima S, Tolentino M, Kim RY, Rohan RM, Colby KA, Yeo KT, Adamis AP (1996) Reactive oxygen intermediates increase vascular endothelial growth factor expression in vitro and in vivo. J Clin Invest 98:1667–1675PubMedGoogle Scholar
  67. 67.
    Poulaki V, Joussen AM, Mitsiades N, Mitsiades CS, Iliaki EF, Adamis AP (2004) Insulin-like growth factor-I plays a pathogenetic role in diabetic retinopathy. Am J Pathol 165:457–469PubMedGoogle Scholar
  68. 68.
    Hangai M, He S, Hoffmann S, Lim JI, Ryan SJ, Hinton DR (2006) Sequential induction of angiogenic growth factors by TNF-alpha in choroidal endothelial cells. J Neuroimmunol 171:45–56PubMedGoogle Scholar
  69. 69.
    Aiello LP, Northrup JM, Keyt BA, Takagi H, Iwamoto MA (1995) Hypoxic regulation of vascular endothelial growth factor in retinal cells. Arch Ophthalmol 113:1538–1544PubMedGoogle Scholar
  70. 70.
    Famiglietti EV, Stopa EG, McGookin ED, Song P, LeBlanc V, Streeten BW (2003) Immunocytochemical localization of vascular endothelial growth factor in neurons and glial cells of human retina. Brain Res 969:195–204PubMedGoogle Scholar
  71. 71.
    Ng EW, Adamis AP (2005) Targeting angiogenesis, the underlying disorder in neovascular age-related macular degeneration. Can J Ophthalmol 40:352–368PubMedGoogle Scholar
  72. 72.
    Blaauwgeers HG, Holtkamp GM, Rutten H, Witmer AN, Koolwijk P, Partanen TA, Alitalo K, Kroon ME, Kijlstra A, van Hinsbergh VW, Schlingemann RO (1999) Polarized vascular endothelial growth factor secretion by human retinal pigment epithelium and localization of vascular endothelial growth factor receptors on the inner choriocapillaris. Evidence for a trophic paracrine relation. Am J Pathol 155:421–428PubMedGoogle Scholar
  73. 73.
    Miller JW, Adamis AP, Shima DT, D’Amore PA, Moulton RS, O’Reilly MS, Folkman J, Dvorak HF, Brown LF, Berse B et al (1994) Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. Am J Pathol 145:574–584PubMedGoogle Scholar
  74. 74.
    Tolentino MJ, Miller JW, Gragoudas ES, Jakobiec FA, Flynn E, Chatzistefanou K, Ferrara N, Adamis AP (1996) Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate. Ophthalmology 103:1820–1828PubMedGoogle Scholar
  75. 75.
    Qaum T, Xu Q, Joussen AM, Clemens MW, Qin W, Miyamoto K, Hassessian H, Wiegand SJ, Rudge J, Yancopoulos GD, Adamis AP (2001) VEGF-initiated blood–retinal barrier breakdown in early diabetes. Invest Ophthalmol Vis Sci 42:2408–2413PubMedGoogle Scholar
  76. 76.
    Joussen AM, Poulaki V, Qin W, Kirchhof B, Mitsiades N, Wiegand SJ, Rudge J, Yancopoulos GD, Adamis AP (2002) 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 160:501–509PubMedGoogle Scholar
  77. 77.
    Miyamoto K, Khosrof S, Bursell SE, Moromizato Y, Aiello LP, Ogura Y, Adamis AP (2000) Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-1). Am J Pathol 156:1733–1739PubMedGoogle Scholar
  78. 78.
    Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25:581–611PubMedGoogle Scholar
  79. 79.
    Ishida S, Usui T, Yamashiro K, Kaji Y, Ahmed E, Carrasquillo KG, Amano S, Hida T, Oguchi Y, Adamis AP (2003) VEGF164 is proinflammatory in the diabetic retina. Invest Ophthalmol Vis Sci 44:2155–2162PubMedGoogle Scholar
  80. 80.
    Taylor PC, Williams RO, Feldmann M (2004) Tumour necrosis factor alpha as a therapeutic target for immune-mediated inflammatory diseases. Curr Opin Biotechnol 15:557–563PubMedGoogle Scholar
  81. 81.
    Eizirik DL, Mandrup-Poulsen T (2001) A choice of death—the signal-transduction of immune-mediated beta-cell apoptosis. Diabetologia 44:2115–2133PubMedGoogle Scholar
  82. 82.
    Ruan H, Lodish HF (2003) Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-alpha. Cytokine Growth Factor Rev 14:447–455PubMedGoogle Scholar
  83. 83.
    Navarro JF, Mora-Fernandez C (2006) The role of TNF-alpha in diabetic nephropathy: pathogenic and therapeutic implications. Cytokine Growth Factor Rev 17:441–450PubMedGoogle Scholar
  84. 84.
    Joussen AM, Poulaki V, Mitsiades N, Kirchhof B, Koizumi K, Dohmen S, Adamis AP (2002) Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression. FASEB J 16:438–440PubMedGoogle Scholar
  85. 85.
    Cantor J, Haskins K (2005) Effector function of diabetogenic CD4 Th1 T cell clones: a central role for TNF-alpha. J Immunol 175:7738–7745PubMedGoogle Scholar
  86. 86.
    Kasama T, Miwa Y, Isozaki T, Odai T, Adachi M, Kunkel SL (2005) Neutrophil-derived cytokines: potential therapeutic targets in inflammation. Curr Drug Targets Inflamm Allergy 4:273–279PubMedGoogle Scholar
  87. 87.
    Hawrami K, Hitman GA, Rema M, Snehalatha C, Viswanathan M, Ramachandran A, Mohan V (1996) An association in non-insulin-dependent diabetes mellitus subjects between susceptibility to retinopathy and tumor necrosis factor polymorphism. Hum Immunol 46:49–54PubMedGoogle Scholar
  88. 88.
    Limb GA, Webster L, Soomro H, Janikoun S, Shilling J (1999) Platelet expression of tumour necrosis factor-alpha (TNF-alpha), TNF receptors and intercellular adhesion molecule-1 (ICAM-1) in patients with proliferative diabetic retinopathy. Clin Exp Immunol 118:213–218PubMedGoogle Scholar
  89. 89.
    Ben-Mahmud BM, Mann GE, Datti A, Orlacchio A, Kohner EM, Chibber R (2004) 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 53:2968–2976PubMedGoogle Scholar
  90. 90.
    Giraudo E, Primo L, Audero E, Gerber HP, Koolwijk P, Soker S, Klagsbrun M, Ferrara N, Bussolino F (1998) Tumor necrosis factor-alpha regulates expression of vascular endothelial growth factor receptor-2 and of its co-receptor neuropilin-1 in human vascular endothelial cells. J Biol Chem 273:22128–22135PubMedGoogle Scholar
  91. 91.
    Gerl VB, Bohl J, Pitz S, Stoffelns B, Pfeiffer N, Bhakdi S (2002) Extensive deposits of complement C3d and C5b-9 in the choriocapillaris of eyes of patients with diabetic retinopathy. Invest Ophthalmol Vis Sci 43:1104–1108PubMedGoogle Scholar
  92. 92.
    Garcia-Ramirez M, Canals F, Hernandez C, Colome N, Ferrer C, Carrasco E, Garcia-Arumi J, Simo R (2007) Proteomic analysis of human vitreous fluid by fluorescence-based difference gel electrophoresis (DIGE): a new strategy for identifying potential candidates in the pathogenesis of proliferative diabetic retinopathy. Diabetologia 50:1294–1303PubMedGoogle Scholar
  93. 93.
    Campbell DJ (2003) The renin–angiotensin and the kallikrein–kinin systems. Int J Biochem Cell Biol 35:784–791PubMedGoogle Scholar
  94. 94.
    Schmaier AH (2003) The kallikrein–kinin and the renin–angiotensin systems have a multilayered interaction. Am J Physiol 285:R1–R13Google Scholar
  95. 95.
    Couture R, Harrisson M, Vianna RM, Cloutier F (2001) Kinin receptors in pain and inflammation. Eur J Pharmacol 429:161–176PubMedGoogle Scholar
  96. 96.
    Bracho FA (2005) Hereditary angioedema. Curr Opin Hematol 12:493–498PubMedGoogle Scholar
  97. 97.
    Duchene J, Lecomte F, Ahmed S, Cayla C, Pesquero J, Bader M, Perretti M, Ahluwalia A (2007) A novel inflammatory pathway involved in leukocyte recruitment: role for the kinin B1 receptor and the chemokine CXCL5. J Immunol 179:4849–4856PubMedGoogle Scholar
  98. 98.
    Tan Y, Keum JS, Wang B, McHenry MB, Lipsitz SR, Jaffa AA (2007) Targeted deletion of B2-kinin receptors protects against the development of diabetic nephropathy. Am J Physiol Renal Physiol 293:F1026–F1035PubMedGoogle Scholar
  99. 99.
    Lawson SR, Gabra BH, Nantel F, Battistini B, Sirois P (2005) Effects of a selective bradykinin B1 receptor antagonist on increased plasma extravasation in streptozotocin-induced diabetic rats: distinct vasculopathic profile of major key organs. Eur J Pharmacol 514:69–78PubMedGoogle Scholar
  100. 100.
    Gardner TW, Antonetti DA (2007) A prize catch for diabetic retinopathy. Nat Med 13:131–132PubMedGoogle Scholar
  101. 101.
    American Diabetes Association (2007) Standards of medical care in diabetes—2007. Diabetes Care 30(Suppl 1):S4–S41Google Scholar
  102. 102.
    Chaturvedi N, Sjolie AK, Stephenson JM, Abrahamian H, Keipes M, Castellarin A, Rogulja-Pepeonik Z, Fuller JH (1998) Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB controlled trial of lisinopril in insulin-dependent diabetes mellitus. Lancet 351:28–31PubMedGoogle Scholar
  103. 103.
    Funatsu H, Yamashita H, Nakanishi Y, Hori S (2002) Angiotensin II and vascular endothelial growth factor in the vitreous fluid of patients with proliferative diabetic retinopathy. Br J Ophthalmol 86:311–315PubMedGoogle Scholar
  104. 104.
    Zheng Z, Chen H, Xu X, Li C, Gu Q (2007) Effects of angiotensin-converting enzyme inhibitors and beta-adrenergic blockers on retinal vascular endothelial growth factor expression in rat diabetic retinopathy. Exp Eye Res 84:745–752PubMedGoogle Scholar
  105. 105.
    Wilkinson-Berka JL, Tan G, Jaworski K, Ninkovic S (2007) Valsartan but not atenolol improves vascular pathology in diabetic Ren-2 rat retina. Am J Hypertens 20:423–430PubMedGoogle Scholar
  106. 106.
    Nagai N, Izumi-Nagai K, Oike Y, Koto T, Satofuka S, Ozawa Y, Yamashiro K, Inoue M, Tsubota K, Umezawa K, Ishida S (2007) Suppression of diabetes-induced retinal inflammation by blocking the angiotensin II type 1 receptor or its downstream nuclear factor-kappaB pathway. Invest Ophthalmol Vis Sci 48:4342–4350PubMedGoogle Scholar
  107. 107.
    Powell ED, Field RA (1964) Diabetic retinopathy and rheumatoid arthritis. Lancet 41:17–18Google Scholar
  108. 108.
    ETDRS Group (1991) Effects of aspirin treatment on diabetic retinopathy. ETDRS report number 8. Early Treatment Diabetic Retinopathy Study research group. Ophthalmology 98:757–765Google Scholar
  109. 109.
    DAMAD Study Group (1989) Effect of aspirin alone and aspirin plus dipyridamole in early diabetic retinopathy. A multicenter randomized controlled clinical trial. Diabetes 38:491–498Google Scholar
  110. 110.
    Hattori Y, Hashizume K, Nakajima K, Nishimura Y, Naka M, Miyanaga K (2007) The effect of long-term treatment with sulindac on the progression of diabetic retinopathy. Curr Med Res Opin 23:1913–1917PubMedGoogle Scholar
  111. 111.
    Kern TS, Engerman RL (2001) Pharmacological inhibition of diabetic retinopathy: aminoguanidine and aspirin. Diabetes 50:1636–1642PubMedGoogle Scholar
  112. 112.
    Sun W, Gerhardinger C, Dagher Z, Hoehn T, Lorenzi M (2005) Aspirin at low-intermediate concentrations protects retinal vessels in experimental diabetic retinopathy through non-platelet-mediated effects. Diabetes 54:3418–3426PubMedGoogle Scholar
  113. 113.
    Zheng L, Howell SJ, Hatala DA, Huang K, Kern TS (2007) Salicylate-based anti-inflammatory drugs inhibit the early lesion of diabetic retinopathy. Diabetes 56:337–345PubMedGoogle Scholar
  114. 114.
    Kern TS, Miller CM, Du Y, Zheng L, Mohr S, Ball SL, Kim M, Jamison JA, Bingaman DP (2007) Topical administration of nepafenac inhibits diabetes-induced retinal microvascular disease and underlying abnormalities of retinal metabolism and physiology. Diabetes 56:373–379PubMedGoogle Scholar
  115. 115.
    Amrite AC, Ayalasomayajula SP, Cheruvu NP, Kompella UB (2006) Single periocular injection of celecoxib-PLGA microparticles inhibits diabetes-induced elevations in retinal PGE2, VEGF, and vascular leakage. Invest Ophthalmol Vis Sci 47:1149–1160PubMedGoogle Scholar
  116. 116.
    Jonas JB (2006) Intravitreal triamcinolone acetonide: a change in a paradigm. Ophthalmic Res 38:218–245PubMedGoogle Scholar
  117. 117.
    Penfold PL, Wen L, Madigan MC, King NJ, Provis JM (2002) Modulation of permeability and adhesion molecule expression by human choroidal endothelial cells. Invest Ophthalmol Vis Sci 43:3125–3130PubMedGoogle Scholar
  118. 118.
    Matsuda S, Gomi F, Oshima Y, Tohyama M, Tano Y (2005) Vascular endothelial growth factor reduced and connective tissue growth factor induced by triamcinolone in ARPE19 cells under oxidative stress. Invest Ophthalmol Vis Sci 46:1062–1068PubMedGoogle Scholar
  119. 119.
    Kim YH, Choi MY, Kim YS, Park CH, Lee JH, Chung IY, Yoo JM, Choi WS, Cho GJ, Kang SS (2007) Triamcinolone acetonide protects the rat retina from STZ-induced acute inflammation and early vascular leakage. Life Sci 81:1167–1173PubMedGoogle Scholar
  120. 120.
    Funatsu H, Yamashita H, Sakata K, Noma H, Mimura T, Suzuki M, Eguchi S, Hori S (2005) Vitreous levels of vascular endothelial growth factor and intercellular adhesion molecule 1 are related to diabetic macular edema. Ophthalmology 112:806–816PubMedGoogle Scholar
  121. 121.
    Funatsu H, Yamashita H, Ikeda T, Mimura T, Eguchi S, Hori S (2003) Vitreous levels of interleukin-6 and vascular endothelial growth factor are related to diabetic macular edema. Ophthalmology 110:1690–1696PubMedGoogle Scholar
  122. 122.
    Spranger J, Meyer-Schwickerath R, Klein M, Schatz H, Pfeiffer A (1995) [TNF-alpha level in the vitreous body. Increase in neovascular eye diseases and proliferative diabetic retinopathy]. Med Klin (Munich) 90:134–137Google Scholar
  123. 123.
    Joussen AM, Huang S, Poulaki V, Camphausen K, Beecken WD, Kirchhof B, Adamis AP (2001) In vivo retinal gene expression in early diabetes. Invest Ophthalmol Vis Sci 42:3047–3057PubMedGoogle Scholar
  124. 124.
    Koyama R, Nakanishi T, Ikeda T, Shimizu A (2003) Catalogue of soluble proteins in human vitreous humor by one-dimensional sodium dodecyl sulfate–polyacrylamide gel electrophoresis and electrospray ionization mass spectrometry including seven angiogenesis-regulating factors. J Chromatogr B Analyt Technol Biomed Life Sci 792:5–21PubMedGoogle Scholar
  125. 125.
    Cunningham ET Jr., Adamis AP, Altaweel M, Aiello LP, Bressler NM, D’Amico DJ, Goldbaum M, Guyer DR, Katz B, Patel M, Schwartz SD (2005) A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology 112:1747–1757PubMedGoogle Scholar
  126. 126.
    Adamis AP, Altaweel M, Bressler NM, Cunningham ET Jr., Davis MD, Goldbaum M, Gonzales C, Guyer DR, Barrett K, Patel M (2006) Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals. Ophthalmology 113:23–28PubMedGoogle Scholar
  127. 127.
    Gonzalez V (2006) Selective VEGF inhibition: effectiveness in modifying the progression of proliferative diabetic retinopathy. In: Proceedings of the American Academy of Ophthalmology 2006 Annual Meeting, November 12, Las Vegas, NV, Poster 309Google Scholar
  128. 128.
    Ferrara N, Damico L, Shams N, Lowman H, Kim R (2006) Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina 26:859–870PubMedGoogle Scholar
  129. 129.
    Nguyen QD, Tatlipinar S, Shah SM, Haller JA, Quinlan E, Sung J, Zimmer-Galler I, Do DV, Campochiaro PA (2006) Vascular endothelial growth factor is a critical stimulus for diabetic macular edema. Am J Ophthalmol 142:961–969PubMedGoogle Scholar
  130. 130.
    Chun DW, Heier JS, Topping TM, Duker JS, Bankert JM (2006) A pilot study of multiple intravitreal injections of ranibizumab in patients with center-involving clinically significant diabetic macular edema. Ophthalmology 113:1706–1712PubMedGoogle Scholar
  131. 131.
    Avery RL, Pearlman J, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ, Wendel R, Patel A (2006) Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology 113:1695.e1–1695.e15Google Scholar
  132. 132.
    Arevalo JF, Fromow-Guerra J, Quiroz-Mercado H, Sanchez JG, Wu L, Maia M, Berrocal MH, Solis-Vivanco A, Farah ME (2007) Primary intravitreal bevacizumab (Avastin) for diabetic macular edema: results from the Pan-American Collaborative Retina Study Group at 6-month follow-up. Ophthalmology 114:743–750PubMedGoogle Scholar
  133. 133.
    Mason JO 3rd, Nixon PA, White MF (2006) Intravitreal injection of bevacizumab (Avastin) as adjunctive treatment of proliferative diabetic retinopathy. Am J Ophthalmol 142:685–688PubMedGoogle Scholar
  134. 134.
    Oshima Y, Sakaguchi H, Gomi F, Tano Y (2006) Regression of iris neovascularization after intravitreal injection of bevacizumab in patients with proliferative diabetic retinopathy. Am J Ophthalmol 142:155–158PubMedGoogle Scholar
  135. 135.
    van Wijngaarden P, Coster DJ, Williams KA (2005) Inhibitors of ocular neovascularization: promises and potential problems. JAMA 293:1509–1513PubMedGoogle Scholar
  136. 136.
    Sfikakis PP, Markomichelakis N, Theodossiadis GP, Grigoropoulos V, Katsilambros N, Theodossiadis PG (2005) Regression of sight-threatening macular edema in type 2 diabetes following treatment with the anti-tumor necrosis factor monoclonal antibody infliximab. Diabetes Care 28:445–447PubMedGoogle Scholar
  137. 137.
    Markomichelakis NN, Theodossiadis PG, Sfikakis PP (2005) Regression of neovascular age-related macular degeneration following infliximab therapy. Am J Ophthalmol 139:537–540PubMedGoogle Scholar
  138. 138.
    Suhler EB, Smith JR, Wertheim MS, Lauer AK, Kurz DE, Pickard TD, Rosenbaum JT (2005) A prospective trial of infliximab therapy for refractory uveitis: preliminary safety and efficacy outcomes. Arch Ophthalmol 123:903–912PubMedGoogle Scholar
  139. 139.
    Klotz U, Teml A, Schwab M (2007) Clinical pharmacokinetics and use of infliximab. Clin Pharmacokinet 46:645–660PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  1. 1.Jerini OphthalmicNew YorkUSA
  2. 2.University of Illinois Eye and Ear InfirmaryChicagoUSA

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