ANGIOGENIC AND INFLAMMATORY MARKERS IN THE INTRAOCULAR FLUID OF EYES WITH DIABETIC MACULAR EDEMA AND INFLUENCE OF THERAPY WITH BEVACIZUMAB

Purpose: The purpose of this study was to determine the concentrations of angiogenic and inflammatory markers in human eyes with diffuse diabetic macular edema before and during therapy with intravitreal bevacizumab and their association with disease activity. Methods: In a prospective clinical trial, 10 eyes of 10 consecutive patients with vision loss because of diabetic macular edema were compared with 10 eyes of 10 age-matched controls. Bevacizumab was administered at baseline; retreatments were given monthly according to disease activity. During a follow-up of 6 months, aqueous humor samples were taken each time intravitreal therapy was administered. A multiplex assay was used for measurement of 12 different growth factors and cytokines. Results: Aqueous humor of eyes with diabetic macular edema demonstrated a significantly increased expression of monocyte chemoattractant protein-1 and interleukin-8 and higher, but not significant, levels of interleukin-6 and vascular endothelial growth factor. Intravitreal therapy with bevacizumab resulted in a significant decrease of vascular endothelial growth factor below physiologic levels. This change was not associated with clinical disease activity as measured by visual acuity and central retinal thickness. Conclusion: Eyes with diabetic macular edema showed a different profile of monocyte chemoattractant protein-1 and interleukin-8 as compared with controls. The intraocular vascular endothelial growth factor expression decreased significantly after the first intravitreal injection of bevacizumab; this reduction was prolonged by consecutive monthly retreatment.

[1]  L. Aiello,et al.  Hypoxic regulation of vascular endothelial growth factor in retinal cells. , 1995, Archives of ophthalmology.

[2]  H. Yamashita,et al.  Aqueous humour levels of cytokines are correlated to vitreous levels and severity of macular oedema in branch retinal vein occlusion , 2008, Eye.

[3]  U. Schmidt-Erfurth,et al.  Neovascular age-related macular degeneration: intraocular cytokines and growth factors and the influence of therapy with ranibizumab. , 2009, Ophthalmology.

[4]  GH Tesch ROLE OF MACROPHAGES IN COMPLICATIONS OF TYPE 2 DIABETES , 2007, Clinical and experimental pharmacology & physiology.

[5]  G. Lutty,et al.  Localization of vascular endothelial growth factor in human retina and choroid. , 1996, Archives of ophthalmology.

[6]  S. Pendergast Vitrectomy for diabetic macular edema associated with a taut premacular posterior hyaloid. , 1998, Current opinion in ophthalmology.

[7]  R. Simó,et al.  Interleukin‐8, monocyte chemoattractant protein‐1 and IL‐10 in the vitreous fluid of patients with proliferative diabetic retinopathy , 2005, Diabetic medicine : a journal of the British Diabetic Association.

[8]  Fundus photographic risk factors for progression of diabetic retinopathy. ETDRS report number 12. Early Treatment Diabetic Retinopathy Study Research Group. , 1991, Ophthalmology.

[9]  N. Bressler,et al.  A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. , 2007, Ophthalmology.

[10]  I. Cree,et al.  Vitreous and aqueous concentrations of proangiogenic, antiangiogenic factors and other cytokines in diabetic retinopathy patients with macular edema: Implications for structural differences in macular profiles. , 2006, Experimental eye research.

[11]  T. Mimura,et al.  Association of vitreous inflammatory factors with diabetic macular edema. , 2009, Ophthalmology.

[12]  H. Yamashita,et al.  Aqueous humor levels of cytokines are related to vitreous levels and progression of diabetic retinopathy in diabetic patients , 2004, Graefe's Archive for Clinical and Experimental Ophthalmology.

[13]  R. Jain,et al.  During angiogenesis, vascular endothelial growth factor regulate natural killer cell adhesion to tumor endothelium , 1996, Nature Medicine.

[14]  L. Groop,et al.  Progression to proliferative retinopathy and macular oedema requiring treatment. Assessment of the alternative classification of the Wisconsin Study. , 1999, Acta ophthalmologica Scandinavica.

[15]  J. Gilbert,et al.  Independent effects of complement factor H Y402H polymorphism and cigarette smoking on risk of age-related macular degeneration. , 2007, Ophthalmology.

[16]  G. Vrensen,et al.  Vascular endothelial growth factors and angiogenesis in eye disease , 2003, Progress in Retinal and Eye Research.

[17]  N. Eter,et al.  Intraocular pharmacokinetics of bevacizumab after a single intravitreal injection in humans. , 2008, American journal of ophthalmology.

[18]  T. Sano,et al.  [Diabetic retinopathy]. , 2001, Nihon rinsho. Japanese journal of clinical medicine.

[19]  Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. , 1985, Archives of ophthalmology.

[20]  M. Maia,et al.  Primary intravitreal bevacizumab (Avastin) for diabetic macular edema: results from the Pan-American Collaborative Retina Study Group at 6-month follow-up. , 2007, Ophthalmology.

[21]  D. Graves,et al.  Diabetic complications and dysregulated innate immunity. , 2008, Frontiers in bioscience : a journal and virtual library.

[22]  U. Schmidt-Erfurth,et al.  Intraocular concentrations of growth factors and cytokines in retinal vein occlusion and the effect of therapy with bevacizumab. , 2009, Investigative ophthalmology & visual science.

[23]  H. Yamashita,et al.  Relation of diabetic macular edema to cytokines and posterior vitreous detachment. , 2003, American journal of ophthalmology.

[24]  H. Yamashita,et al.  Increased levels of vascular endothelial growth factor and interleukin-6 in the aqueous humor of diabetics with macular edema. , 2002, American journal of ophthalmology.

[25]  G. King,et al.  Molecular understanding of hyperglycemia's adverse effects for diabetic complications. , 2002, JAMA.

[26]  Osamu Sawada,et al.  Vascular endothelial growth factor in aqueous humor before and after intravitreal injection of bevacizumab in eyes with diabetic retinopathy. , 2007, Archives of ophthalmology.

[27]  C. Gerhardinger,et al.  Early complement activation and decreased levels of glycosylphosphatidylinositol-anchored complement inhibitors in human and experimental diabetic retinopathy. , 2002, Diabetes.

[28]  M. Grant,et al.  The role of growth factors in the pathogenesis of diabetic retinopathy , 2004, Expert opinion on investigational drugs.

[29]  Ulrich Schraermeyer,et al.  A central role for inflammation in the pathogenesis of diabetic retinopathy , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[30]  Kyung Hee Hong,et al.  Monocyte chemoattractant protein-1-induced angiogenesis is mediated by vascular endothelial growth factor-A. , 2005, Blood.

[31]  R. Klein,et al.  The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XV. The long-term incidence of macular edema. , 1995, Ophthalmology.

[32]  P. Korošec,et al.  Vitreous levels of interleukin-8 in patients with proliferative diabetic retinopathy. , 2007, American journal of ophthalmology.

[33]  P. Campochiaro,et al.  Upregulation of vascular endothelial growth factor in ischemic and non-ischemic human and experimental retinal disease. , 1997, Histology and histopathology.

[34]  Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number 2. Early Treatment Diabetic Retinopathy Study Research Group. , 1987, Ophthalmology.

[35]  R. Jain,et al.  During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium. , 1996, Nature medicine.

[36]  H. Yamashita,et al.  Vitreous levels of vascular endothelial growth factor and intercellular adhesion molecule 1 are related to diabetic macular edema. , 2005, Ophthalmology.

[37]  S. Priglinger,et al.  INTRAVITREAL BEVACIZUMAB (AVASTIN) THERAPY FOR PERSISTENT DIFFUSE DIABETIC MACULAR EDEMA , 2006, Retina.

[38]  Yosuf El-Shabrawi,et al.  Multiplex bead analysis of vitreous and serum concentrations of inflammatory and proangiogenic factors in diabetic patients , 2008, Molecular vision.

[39]  M. Bartoli,et al.  Vascular endothelial growth factor and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives , 2003, Diabetes/metabolism research and reviews.

[40]  F. Bandello,et al.  Diabetic retinopathy , 2002, Diabetologia.

[41]  D. Chi,et al.  The role of human mast cell-derived cytokines in eosinophil biology. , 2004, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[42]  G. Lutty,et al.  Vascular endothelial growth factor and vascular permeability changes in human diabetic retinopathy. , 1997, Investigative ophthalmology & visual science.

[43]  J. Jonas,et al.  Vascular Endothelial Growth Factor and Basic Fibroblast Growth Factor in Exudative Age-Related Macular Degeneration and Diffuse Diabetic Macular Edema , 2007, Ophthalmic Research.

[44]  G. Yancopoulos,et al.  VEGF-initiated blood-retinal barrier breakdown in early diabetes. , 2001, Investigative ophthalmology & visual science.

[45]  G. Breier,et al.  The Vascular Endothelial Growth Factor Receptor Flt-1 Mediates Biological Activities , 1996, The Journal of Biological Chemistry.