Anti-inflammatory therapy for diabetic retinopathy

Immunotherapy

Volumn 3, Issue 5, 2011, Pages 609-628

  Zhang, Wenbo ^a   Liu, Hua ^a   Rojas, Modesto ^a   Caldwell, Robert W ^a   Caldwell, Ruth B ^a,b  

^a MEDICAL COLLEGE OF GEORGIA   (United States)

^b VETERANS AFFAIRS MEDICAL CENTER   (United States)

Author keywords

diabetic retinopathy; inflammation; leukostasis; neovascularization; NF B; nitric oxide; oxidative stress; vessel degeneration; vessel leakage

Indexed keywords

ACETYLSALICYLIC ACID; ADVANCED GLYCATION END PRODUCT; ALPHA TOCOPHEROL; ANTIINFLAMMATORY AGENT; APOCYNIN; ASCORBIC ACID; CANDESARTAN; CAPTOPRIL; CD49 NEUTRALIZING ANTIBODY; CORTICOSTEROID; CYTOKINE; DEXAMETHASONE; ENALAPRIL; ETANERCEPT; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; INFLIXIMAB; LR 90; NITRIC OXIDE SYNTHASE; NONSTEROID ANTIINFLAMMATORY AGENT; OLMESARTAN; SAR 1118; TELMISARTAN; UNCLASSIFIED DRUG;

ADAPTIVE IMMUNITY; ANTIINFLAMMATORY ACTIVITY; CELLULAR IMMUNITY; CHRONIC INFLAMMATION; CYTOKINE RELEASE; DIABETIC RETINOPATHY; DISEASE COURSE; DRUG EFFECT; DYSLIPIDEMIA; HUMAN; HYPERTENSION; INFLAMMATORY CELL; NEOVASCULARIZATION (PATHOLOGY); NERVE CELL; NONHUMAN; OXIDATIVE STRESS; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; VASCULAR DISEASE;

ANIMALS; ANTI-INFLAMMATORY AGENTS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; CLINICAL TRIALS AS TOPIC; DIABETIC RETINOPATHY; HUMANS; INFLAMMATION; RATS; STEROIDS;

EID: 79955912644     PISSN: 1750743X     EISSN: None     Source Type: Journal    
DOI: 10.2217/imt.11.24     Document Type: Review

References (172)

1. Fong DS, Aiello L, Gardner TW et al.: Retinopathy in diabetes. Diabetes Care 27(Suppl. 1), S84-S87 (2004). (Pubitemid 38197476)
2. Aiello LP, Gardner TW, King GL et al.: Diabetic retinopathy. Diabetes Care 21(1), 143-156 (1998). (Pubitemid 28030402)
3. Klein R, Knudtson MD, Lee KE, Gangnon R, Klein BE: The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XXII the twenty-five-year progression of retinopathy in persons with Type 1 diabetes. Ophthalmology 115(11), 1859-1868 (2008).
4. Williams R, Airey M, Baxter H, Forrester J, Kennedy-Martin T, Girach A: Epidemiology of diabetic retinopathy and macular oedema: a systematic review. Eye (Lond.) 18(10), 963-983 (2004). (Pubitemid 39430033)
5. Varma R: From a population to patients: the Wisconsin epidemiologic study of diabetic retinopathy. Ophthalmology 115(11), 1857-1858 (2008).
6. Cheung N, Mitchell P, Wong TY: Diabetic retinopathy. Lancet 376(9735), 124-136 (2010).
7. Yam JC, Kwok AK: Update on the treatment of diabetic retinopathy. Hong Kong Med. J. 13(1), 46-60 (2007). (Pubitemid 46482034)
8. Arevalo JF, Sanchez JG, Lasave AF et al.: Intravitreal bevacizumab (avastin) for diabetic retinopathy at 24-months: the 2008 Juan Verdaguer-Planas lecture®).Curr. Diabetes Rev. 6(5), 313-322 (2010).
9. Kowluru RA, Zhong Q, Kanwar M: Metabolic memory and diabetic retinopathy: role of inflammatory mediators in retinal pericytes. Exp. Eye Res. 90(5), 617-623 (2010).
10. Villeneuve LM, Natarajan R: The role of epigenetics in the pathology of diabetic complications. Am. J. Physiol. Renal Physiol. 299(1), F14-F25 (2010).
11. Nishijima K, Ng YS, Zhong L et al.: Vascular endothelial growth factor-α is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury. Am. J. Pathol. 171(1), 53-67 (2007). (Pubitemid 47339226)
12. Klein R, Klein BE: Diabetic eye disease. Lancet 350(9072), 197-204 (1997). (Pubitemid 27303635)
13. Sheetz MJ, King GL: Molecular understanding of hyperglycemia's adverse effects for diabetic complications. JAMA 288(20), 2579-2588 (2002). (Pubitemid 35386893)
14. Stitt AW, Curtis TM: Advanced glycation and retinal pathology during diabetes. Pharmacol. Rep. 57(Suppl.), 156-168 (2005).
15. Caldwell RB, Bartoli M, Behzadian MA et al.: Vascular endothelial growth factor and diabetic retinopathy: role of oxidative stress. Curr. Drug Targets 6(4), 511-524 (2005). (Pubitemid 40916276)
16. Brownlee M: The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54(6), 1615-1625 (2005). (Pubitemid 40770750)
17. Rahman I: Oxidative stress, transcription factors and chromatin remodelling in lung inflammation. Biochem. Pharmacol. 64(5-6), 935-942 (2002). (Pubitemid 35232267)
18. Aveleira CA, Lin CM, Abcouwer SF, Ambrosio AF, Antonetti DA: TNF-α signals through PKCz/NF-kB to alter the tight junction complex and increase retinal endothelial cell permeability. Diabetes 59(11), 2872-2882 (2010).
19. Barreiro O, Martin P, Gonzalez-Amaro R, Sanchez-Madrid F: Molecular cues guiding inflammatory responses. Cardiovasc. Res. 86(2), 174-182 (2010).
20. Joussen AM, Poulaki V, Mitsiades N et al.: Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-α suppression. FASEB J. 16(3), 438-440 (2002).
21. Demircan N, Safran BG, Soylu M, Ozcan AA, Sizmaz S: Determination of vitreous interleukin-1 (IL-1) and tumour necrosis factor (TNF) levels in proliferative diabetic retinopathy. Eye (Lond.) 20(12), 1366-1369 (2006). (Pubitemid 44921137)
22. Limb GA, Chignell AH, Green W, LeRoy F, Dumonde DC: Distribution of TNF a and its reactive vascular adhesion molecules in fibrovascular membranes of proliferative diabetic retinopathy. Br. J. Ophthalmol. 80(2), 168-173 (1996). (Pubitemid 26058553)
23. Hawrami K, Hitman GA, Rema M et al.: An association in non-insulin-dependent diabetes mellitus subjects between susceptibility to retinopathy and tumor necrosis factor polymorphism. Hum. Immunol. 46(1), 49-54 (1996). (Pubitemid 26131461)
24. Vincent JA, Mohr S: Inhibition of caspase-1/ interleukin-1b signaling prevents degeneration of retinal capillaries in diabetes and galactosemia. Diabetes 56(1), 224-230 (2007).
25. Kowluru RA, Odenbach S: Role of interleukin-1b in the development of retinopathy in rats: effect of antioxidants. Invest. Ophthalmol. Vis. Sci. 45(11), 4161-4166 (2004). (Pubitemid 39411175)
26. Mocan MC, Kadayifcilar S, Eldem B: Elevated intravitreal interleukin-6 levels in patients with proliferative diabetic retinopathy. Can. J. Ophthalmol. 41(6), 747-752 (2006). (Pubitemid 46113030)
27. Funatsu H, Yamashita H, Ikeda T, Mimura T, Eguchi S, Hori S: Vitreous levels of interleukin-6 and vascular endothelial growth factor are related to diabetic macular edema. Ophthalmology 110(9), 1690-1696 (2003). (Pubitemid 37025424)
28. Murugeswari P, Shukla D, Rajendran A, Kim R, Namperumalsamy P, Muthukkaruppan V: Proinflammatory cytokines and angiogenic and anti-angiogenic factors in vitreous of patients with proliferative diabetic retinopathy and Eales' disease. Retina 28(6), 817-824 (2008).
29. Maier R, Weger M, Haller-Schober EM et al.: Multiplex bead analysis of vitreous and serum concentrations of inflammatory and proangiogenic factors in diabetic patients. Mol. Vis. 14, 637-643 (2008). (Pubitemid 351486723)
30. Meleth AD, Agron E, Chan CC et al.: Serum inflammatory markers in diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 46(11), 4295-4301 (2005). (Pubitemid 44264635)
31. Adamiec-Mroczek J, Oficjalska-Mlynczak J: Assessment of selected adhesion molecule and proinflammatory cytokine levels in the vitreous body of patients with Type 2 diabetes - role of the inflammatory-immune process in the pathogenesis of proliferative diabetic retinopathy. Graefes Arch. Clin. Exp. Ophthalmol. 246(12), 1665-1670 (2008).
32. Petrovic MG, Osredkar J, Saraga-Babic M, Petrovic D: K469E polymorphism of the intracellular adhesion molecule 1 gene is associated with proliferative diabetic retinopathy in Caucasians with Type 2 diabetes. Clin. Experiment. Ophthalmol. 36(5), 468-472 (2008).
33. McLeod DS, Lefer DJ, Merges C, Lutty GA: Enhanced expression of intracellular adhesion molecule-1 and P-selectin in the diabetic human retina and choroid. Am. J. Pathol. 147(3), 642-653 (1995).
34. Al-Shabrawey M, Bartoli M, El-Remessy AB et al.: Role of NADPH oxidase and Stat3 in statin-mediated protection against diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 49(7), 3231-3238 (2008).
35. Chaplin DD: Overview of the immune response. J. Allergy Clin. Immunol. 125(2 Suppl. 2), S3-S23 (2010).
36. Kim SY, Johnson MA, McLeod DS, Alexander T, Hansen BC, Lutty GA: Neutrophils are associated with capillary closure in spontaneously diabetic monkey retinas. Diabetes 54(5), 1534-1542 (2005). (Pubitemid 40586687)
37. Schroder S, Palinski W, Schmid-Schonbein GW: Activated monocytes and granulocytes, capillary nonperfusion, and neovascularization in diabetic retinopathy. Am. J. Pathol. 139(1), 81-100 (1991).
38. Miyamoto K, Khosrof S, Bursell SE et al.: Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition. Proc. Natl Acad. Sci. USA 96(19), 10836-10841 (1999). (Pubitemid 29442230)
39. Joussen AM, Poulaki V, Le ML et al.: A central role for inflammation in the pathogenesis of diabetic retinopathy. FASEB J. 18(12), 1450-1452 (2004). (Pubitemid 39561611)
40. Barouch FC, Miyamoto K, Allport JR et al.: Integrin-mediated neutrophil adhesion and retinal leukostasis in diabetes. Invest. Ophthalmol. Vis. Sci. 41(5), 1153-1158 (2000). (Pubitemid 30187554)
41. Chen L, Yang P, Kijlstra A: Distribution, markers, and functions of retinal microglia. Ocul. Immunol. Inflamm. 10(1), 27-39 (2002). (Pubitemid 36042844)
42. Yang LP, Sun HL, Wu LM et al.: Baicalein reduces inflammatory process in a rodent model of diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 50(5), 2319-2327 (2009).
43. Ibrahim AS, El-shishtawy MM, Zhang W, Caldwell RB, Liou GI: α2A adenosine receptor (α2AAR) as a therapeutic target in diabetic retinopathy. Am. J. Pathol. (2011) (In Press).
44. Ibrahim AS, El-Remessy AB, Matragoon S et al.: Retinal microglial activation and inflammation induced by amadori-glycated albumin in a rat model of diabetes. Diabetes 60(4), 1122-1133 (2011).
45. Davidson JA, Ciulla TA, McGill JB, Kles KA, Anderson PW: How the diabetic eye loses vision. Endocrine 32(1), 107-116 (2007). (Pubitemid 350242540)
46. Yuan SY: Protein kinase signaling in the modulation of microvascular permeability. Vascul. Pharmacol. 39(4-5), 213-223 (2002). (Pubitemid 37490747)
47. Matter K, Balda MS: Signalling to and from tight junctions. Nat. Rev. Mol. Cell Biol. 4(3), 225-236 (2003). (Pubitemid 36288044)
48. Stamatovic SM, Dimitrijevic OB, Keep RF, Andjelkovic AV: Protein kinase Cα-RhoA cross-talk in CCL2-induced alterations in brain endothelial permeability. J. Biol. Chem. 281(13), 8379-8388 (2006). (Pubitemid 43847939)
49. Gavard J, Hou X, Qu Y et al.: A role for a CXCR2/phosphatidylinositol 3-kinase g signaling axis in acute and chronic vascular permeability. Mol. Cell Biol. 29(9), 2469-2480 (2009).
50. Miyamoto K, Khosrof S, Bursell SE et al.: Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-1).Am. J. Pathol. 156(5), 1733-1739 (2000). (Pubitemid 30646710)
51. Del Maschio A, Zanetti A, Corada M et al.: Polymorphonuclear leukocyte adhesion triggers the disorganization of endothelial cell-to-cell adherens junctions. J. Cell Biol. 135(2), 497-510 (1996). (Pubitemid 26359342)
52. Kowluru RA, Odenbach S: Role of interleukin-1b in the pathogenesis of diabetic retinopathy. Br. J. Ophthalmol. 88(10), 1343-1347 (2004). (Pubitemid 39312984)
53. Joussen AM, Poulaki V, Mitsiades N et al.: Suppression of Fas-FasL-induced endothelial cell apoptosis prevents diabetic blood-retinal barrier breakdown in a model of streptozotocin-induced diabetes. FASEB J. 17(1), 76-78 (2003).
54. Costa C, Incio J, Soares R: Angiogenesis and chronic inflammation: cause or consequence? Angiogenesis 10(3), 149-166 (2007). (Pubitemid 47305203)
55. Ishikawa K, Yoshida S, Kadota K et al.: Gene expression profile of hyperoxic and hypoxic retinas in a mouse model of oxygen-induced retinopathy. Invest. Ophthalmol. Vis. Sci. 51(8), 4307-4319 (2010).
56. Sato T, Kusaka S, Hashida N, Saishin Y, Fujikado T, Tano Y: Comprehensive gene-expression profile in murine oxygen-induced retinopathy. Br. J. Ophthalmol. 93(1), 96-103 (2009).
57. Connor KM, SanGiovanni JP, Lofqvist C et al.: Increased dietary intake of omega-3- polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nat. Med. 13(7), 868-873 (2007). (Pubitemid 47038185)
58. Gardiner TA, Gibson DS, de Gooyer TE, de la Cruz VF, McDonald DM, Stitt AW: Inhibition of tumor necrosis factor-α improves physiological angiogenesis and reduces pathological neovascularization in ischemic retinopathy. Am. J. Pathol. 166(2), 637-644 (2005). (Pubitemid 40189058)
59. Ishida S, Usui T, Yamashiro K et al.: VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization. J. Exp. Med. 198(3), 483-489 (2003). (Pubitemid 36976059)
60. Davies MH, Stempel AJ, Powers MR: MCP-1 deficiency delays regression of pathologic retinal neovascularization in a model of ischemic retinopathy. Invest. Ophthalmol. Vis. Sci. 49(9), 4195-4202 (2008).
61. Tezel G, Wax MB: Increased production of tumor necrosis factor-α by glial cells exposed to simulated ischemia or elevated hydrostatic pressure induces apoptosis in cocultured retinal ganglion cells. J. Neurosci. 20(23), 8693-8700 (2000).
62. Allan SM, Tyrrell PJ, Rothwell NJ: Interleukin-1 and neuronal injury. Nat. Rev. Immunol. 5(8), 629-640 (2005). (Pubitemid 41113194)
63. Lam TT, Tso MO: Nitric oxide synthase (NOS) inhibitors ameliorate retinal damage induced by ischemia in rats. Res. Commun. Mol. Pathol. Pharmacol. 92(3), 329-340 (1996). (Pubitemid 26243052)
64. Fuchs C, Forster V, Balse E, Sahel JA, Picaud S, Tessier LH: Retinal-cell-conditioned medium prevents TNF-α -induced apoptosis of purified ganglion cells. Invest. Ophthalmol. Vis. Sci. 46(8), 2983-2991 (2005). (Pubitemid 43086723)
65. + homeostasis. Brain Res. 1233, 63-78 (2008).
66. Neufeld AH, Kawai S, Das S et al.: Loss of retinal ganglion cells following retinal ischemia: the role of inducible nitric oxide synthase. Exp. Eye Res. 75(5), 521-528 (2002). (Pubitemid 35435607)
67. Nakazawa T, Takahashi H, Nishijima K et al.: Pitavastatin prevents NMDA-induced retinal ganglion cell death by suppressing leukocyte recruitment. J. Neurochem. 100(4), 1018-1031 (2007). (Pubitemid 46213926)
68. Barber AJ, Lieth E, Khin SA, Antonetti DA, Buchanan AG, Gardner TW: Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. J. Clin. Invest. 102(4), 783-791 (1998). (Pubitemid 28399611)
69. Zheng L, Howell SJ, Hatala DA, Huang K, Kern TS: Salicylate-based anti-inflammatory drugs inhibit the early lesion of diabetic retinopathy. Diabetes 56(2), 337-345 (2007).
70. Jezek P, Hlavata L: Mitochondria in homeostasis of reactive oxygen species in cell, tissues, and organism. Int. J. Biochem. Cell. Biol. 37(12), 2478-2503 (2005). (Pubitemid 41400319)
71. Giacco F, Brownlee M: Oxidative stress and diabetic complications. Circ. Res. 107(9), 1058-1070 (2010).
72. Nishikawa T, Edelstein D, Du XL et al.: Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404(6779), 787-790 (2000). (Pubitemid 30212409)
73. Merzouk S, Hichami A, Madani S et al.: Antioxidant status and levels of different vitamins determined by high performance liquid chromatography in diabetic subjects with multiple complications. Gen. Physiol. Biophys. 22(1), 15-27 (2003). (Pubitemid 36748377)
74. Bhatia S, Shukla R, Venkata Madhu S, Kaur Gambhir J, Madhava Prabhu K: Antioxidant status, lipid peroxidation and nitric oxide end products in patients of Type 2 diabetes mellitus with nephropathy. Clin. Biochem. 36(7), 557-562 (2003). (Pubitemid 37244019)
75. Thornalley PJ: Glycation in diabetic neuropathy: characteristics, consequences, causes, and therapeutic options. Int. Rev. Neurobiol. 50, 37-57 (2002).
76. Vlassara H, Palace MR: Diabetes and advanced glycation endproducts. J. Intern. Med. 251(2), 87-101 (2002). (Pubitemid 34146691)
77. Curtis TM, Scholfield CN: The role of lipids and protein kinase Cs in the pathogenesis of diabetic retinopathy. Diabetes Metab. Res. Rev. 20(1), 28-43 (2004). (Pubitemid 38196246)
78. Inoguchi T, Sonta T, Tsubouchi H et al.: Protein kinase C-dependent increase in reactive oxygen species (ROS) production in vascular tissues of diabetes: role of vascular NAD(P)H oxidase. J. Am. Soc. Nephrol. 14(8 Suppl. 3), S227-S232 (2003). (Pubitemid 36903930)
79. Geraldes P, King GL: Activation of protein kinase C isoforms and its impact on diabetic complications. Circ. Res. 106(8), 1319-1331 (2010).
80. 2, vascular endothelial growth factor and receptors in the retina of the BBZ/Wor diabetic rat. Free Radic. Biol. Med. 28(1), 91-101 (2000). (Pubitemid 30045577)
81. Inoguchi T, Tsubouchi H, Etoh T et al.: A possible target of antioxidative therapy for diabetic vascular complications-vascular NAD(P)H oxidase. Curr. Med. Chem. 10(17), 1759-1764 (2003). (Pubitemid 37038598)
82. Sonta T, Inoguchi T, Tsubouchi H et al.: Evidence for contribution of vascular NAD(P)H oxidase to increased oxidative stress in animal models of diabetes and obesity. Free Radic. Biol. Med. 37(1), 115-123 (2004). (Pubitemid 38746655)
83. Griendling KK, Sorescu D, Ushio-Fukai M: NAD(P)H oxidase: role in cardiovascular biology and disease. Circ. Res. 86(5), 494-501 (2000). (Pubitemid 30165039)
84. Cave AC, Brewer AC, Narayanapanicker A et al.: NADPH oxidases in cardiovascular health and disease. Antioxid. Redox Signal 8(5-6), 691-728 (2006). (Pubitemid 44043102)
85. Heyworth PG, Curnutte JT, Nauseef WM et al.: Neutrophil nicotinamide adenine dinucleotide phosphate oxidase assembly. Translocation of p47-phox and p67-phox requires interaction between p47-phox and cytochrome b558. J. Clin. Invest. 87(1), 352-356 (1991).
86. Hoyal CR, Gutierrez A, Young BM et al.: Modulation of p47PHOX activity by site-specific phosphorylation: Akt-dependent activation of the NADPH oxidase. Proc. Natl Acad. Sci. USA 100(9), 5130-5135 (2003). (Pubitemid 36542670)
87. Dang PM, Fontayne A, Hakim J, El Benna J, Perianin A: Protein kinase C z phosphorylates a subset of selective sites of the NADPH oxidase component p47phox and participates in formyl peptide-mediated neutrophil respiratory burst. J. Immunol. 166(2), 1206-1213 (2001). (Pubitemid 32060281)
88. Korchak HM, Kilpatrick LE: Roles for b II-protein kinase C and RACK1 in positive and negative signaling for superoxide anion generation in differentiated HL60 cells. J. Biol. Chem. 276(12), 8910-8917 (2001).
89. El Benna J, Han J, Park JW, Schmid E, Ulevitch RJ, Babior BM: Activation of p38 in stimulated human neutrophils: phosphorylation of the oxidase component p47phox by p38 and ERK but not by JNK. Arch. Biochem. Biophys. 334(2), 395-400 (1996). (Pubitemid 26347324)
90. Koga H, Terasawa H, Nunoi H, Takeshige K, Inagaki F, Sumimoto H: Tetratricopeptide repeat (TPR) motifs of p67(phox) participate in interaction with the small GTPase Rac and activation of the phagocyte NADPH oxidase. J. Biol. Chem. 274(35), 25051-25060 (1999).
91. Doughan AK, Harrison DG, Dikalov SI: Molecular mechanisms of angiotensin II-mediated mitochondrial dysfunction: linking mitochondrial oxidative damage and vascular endothelial dysfunction. Circ. Res. 102(4), 488-496 (2008). (Pubitemid 351651106)
92. Dikalova AE, Bikineyeva AT, Budzyn K et al.: Therapeutic targeting of mitochondrial superoxide in hypertension. Circ. Res. 107(1), 106-116 (2010).
93. Turpaev KT: Reactive oxygen species and regulation of gene expression. Biochemistry (Mosc.) 67(3), 281-292 (2002).
94. Sanz AB, Sanchez-Nino MD, Ramos AM et al.: NF-kB in renal inflammation. J. Am. Soc. Nephrol. 21(8), 1254-1262 (2010).
95. Hoffmann A, Baltimore D: Circuitry of nuclear factor kB signaling. Immunol. Rev. 210, 171-186 (2006).
96. Hayden MS, Ghosh S: Shared principles in NF-kB signaling. Cell 132(3), 344-362 (2008).
97. Pantano C, Reynaert NL, van der Vliet A, Janssen-Heininger YM: Redox-sensitive kinases of the nuclear factor-kB signaling pathway. Antioxid. Redox Signal 8(9-10), 1791-1806 (2006). (Pubitemid 44726352)
98. Nagai N, Izumi-Nagai K, Oike Y et al.: Suppression of diabetes-induced retinal inflammation by blocking the angiotensin II type 1 receptor or its downstream nuclear factor-kB pathway. Invest. Ophthalmol. Vis. Sci. 48(9), 4342-4350 (2007). (Pubitemid 351261068)
99. Romeo G, Liu WH, Asnaghi V, Kern TS, Lorenzi M: Activation of nuclear factor-kB induced by diabetes and high glucose regulates a proapoptotic program in retinal pericytes. Diabetes 51(7), 2241-2248 (2002). (Pubitemid 34729031)
100. Harada C, Okumura A, Namekata K et al.: Role of monocyte chemotactic protein-1 and nuclear factor kB in the pathogenesis of proliferative diabetic retinopathy. Diabetes Res. Clin. Pract. 74(3), 249-256 (2006). (Pubitemid 44572564)
101. Zheng L, Szabo C, Kern TS: Poly(ADP-ribose) polymerase is involved in the development of diabetic retinopathy via regulation of nuclear factor-kB. Diabetes 53(11), 2960-2967 (2004). (Pubitemid 39425922)
102. Kowluru RA, Koppolu P, Chakrabarti S, Chen S: Diabetes-induced activation of nuclear transcriptional factor in the retina, and its inhibition by antioxidants. Free Radic. Res. 37(11), 1169-1180 (2003). (Pubitemid 37322195)
103. Tawfik A, Sanders T, Kahook K, Akeel S, Elmarakby A, Al-Shabrawey M: Suppression of retinal peroxisome proliferator-activated receptor g in experimental diabetes and oxygen-induced retinopathy: role of NADPH oxidase. Invest. Ophthalmol. Vis. Sci. 50(2), 878-884 (2009).
104. Al-Shabrawey M, Rojas M, Sanders T et al.: Role of NADPH oxidase in retinal vascular inflammation. Invest. Ophthalmol. Vis. Sci. 49(7), 3239-3244 (2008).
105. Al-Shabrawey M, Bartoli M, El-Remessy AB et al.: Inhibition of NAD(P)H oxidase activity blocks vascular endothelial growth factor overexpression and neovascularization during ischemic retinopathy. Am. J. Pathol. 167(2), 599-607 (2005). (Pubitemid 43026113)
106. Zhang W, Baban B, Rojas M et al.: Arginase activity mediates retinal inflammation in endotoxin-induced uveitis. Am. J. Pathol. 175(2), 891-902 (2009).
107. Caldwell RB, Zhang W, Romero MJ, Caldwell RW: Vascular dysfunction in retinopathy-an emerging role for arginase. Brain Res. Bull. 81(2-3), 303-309 (2010).
108. Kubes P, Suzuki M, Granger DN: Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc. Natl Acad. Sci. USA 88(11), 4651-4655 (1991). (Pubitemid 21914599)
109. Li Q, Verma A, Han PY et al.: Diabetic eNOS knockout mice develop accelerated retinopathy. Invest. Ophthalmol. Vis. Sci. 51(10), 5240-5246 (2010).
110. Leal EC, Manivannan A, Hosoya K et al.: Inducible nitric oxide synthase isoform is a key mediator of leukostasis and blood-retinal barrier breakdown in diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 48(11), 5257-5265 (2007). (Pubitemid 351260939)
111. Pacher P, Beckman JS, Liaudet L: Nitric oxide and peroxynitrite in health and disease. Physiol. Rev. 87(1), 315-424 (2007). (Pubitemid 46217686)
112. Wu G, Morris SM Jr: Arginine metabolism: nitric oxide and beyond. Biochem. J. 336(Pt 1), 1-17 (1998). (Pubitemid 28532555)
113. Nagaoka T, Kuo L, Ren Y, Yoshida A, Hein TW: C-reactive protein inhibits endothelium-dependent nitric oxide-mediated dilation of retinal arterioles via enhanced superoxide production. Invest. Ophthalmol. Vis. Sci. 49(5), 2053-2060 (2008).
114. Kelleher ZT, Matsumoto A, Stamler JS, Marshall HE: NOS2 regulation of NF-kB by S-nitrosylation of p65. J. Biol. Chem. 282(42), 30667-30672 (2007). (Pubitemid 350035227)
115. Marshall HE, Stamler JS: Inhibition of NF-kB by S-nitrosylation. Biochemistry 40(6), 1688-1693 (2001).
116. Barile GR, Schmidt AM: RAGE and its ligands in retinal disease. Curr. Mol. Med. 7(8), 758-765 (2007).
117. Bierhaus A, Humpert PM, Morcos M et al.: Understanding RAGE, the receptor for advanced glycation end products. J. Mol. Med. 83(11), 876-886 (2005). (Pubitemid 41598688)
118. Moore TC, Moore JE, Kaji Y et al.: The role of advanced glycation end products in retinal microvascular leukostasis. Invest. Ophthalmol. Vis. Sci. 44(10), 4457-4464 (2003). (Pubitemid 37186283)
119. Kaji Y, Usui T, Ishida S et al.: Inhibition of diabetic leukostasis and blood-retinal barrier breakdown with a soluble form of a receptor for advanced glycation end products. Invest. Ophthalmol. Vis. Sci. 48(2), 858-865 (2007). (Pubitemid 351260723)
120. Silva KC, Pinto CC, Biswas SK, de Faria JB, de Faria JM: Hypertension increases retinal inflammation in experimental diabetes: a possible mechanism for aggravation of diabetic retinopathy by hypertension. Curr. Eye Res. 32(6), 533-541 (2007). (Pubitemid 47039108)
121. Marchesi C, Paradis P, Schiffrin EL: Role of the renin-angiotensin system in vascular inflammation. Trends Pharmacol. Sci. 29(7), 367-374 (2008).
122. Garrido AM, Griendling KK: NADPH oxidases and angiotensin II receptor signaling. Mol. Cell Endocrinol. 302(2), 148-158 (2009).
123. Miller AG, Tan G, Binger KJ et al.: Candesartan attenuates diabetic retinal vascular pathology by restoring glyoxalase-I function. Diabetes 59(12), 3208-3215 (2010).
124. Wagner J, Jan Danser AH, Derkx FH et al.: Demonstration of renin mRNA, angiotensinogen mRNA, and angiotensin converting enzyme mRNA expression in the human eye: evidence for an intraocular renin-angiotensin system. Br. J. Ophthalmol. 80(2), 159-163 (1996). (Pubitemid 26058551)
125. Wheeler-Schilling TH, Kohler K, Sautter M, Guenther E: Angiotensin II receptor subtype gene expression and cellular localization in the retina and non-neuronal ocular tissues of the rat. Eur. J. Neurosci. 11(10), 3387-3394 (1999). (Pubitemid 29484235)
126. Silva KC, Pinto CC, Biswas SK, Souza DS, de Faria JB, de Faria JM: Prevention of hypertension abrogates early inflammatory events in the retina of diabetic hypertensive rats. Exp. Eye Res. 85(1), 123-129 (2007). (Pubitemid 47017272)
127. Chen P, Guo AM, Edwards PA, Trick G, Scicli AG: Role of NADPH oxidase and ANG II in diabetes-induced retinal leukostasis. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293(4), R1619-R1629 (2007). (Pubitemid 47535780)
128. Rojas M, Zhang W, Lee DL et al.: Role of IL-6 in angiotensin II-induced retinal vascular inflammation. Invest. Ophthalmol. Vis. Sci. 51(3), 1709-1718 (2010).
129. Birukov KG: Cyclic stretch, reactive oxygen species, and vascular remodeling. Antioxid. Redox. Signal 11(7), 1651-1667 (2009).
130. Masuzawa K, Goto K, Jesmin S et al.: An endothelin type A receptor antagonist reverses upregulated VEGF and ICAM-1 levels in streptozotocin-induced diabetic rat retina. Curr. Eye Res. 31(1), 79-89 (2006). (Pubitemid 43155547)
131. Gustavsson C, Agardh CD, Zetterqvist AV, Nilsson J, Agardh E, Gomez MF: Vascular cellular adhesion molecule-1 (VCAM-1) expression in mice retinal vessels is affected by both hyperglycemia and hyperlipidemia. PLoS One 5(9), E12699 (2010).
132. Rosen ED, Spiegelman BM: PPAR-g: a nuclear regulator of metabolism, differentiation, and cell growth. J. Biol. Chem. 276(41), 37731-37734 (2001).
133. Sung B, Park S, Yu BP, Chung HY: Amelioration of age-related inflammation and oxidative stress by PPAR-g activator: suppression of NF-kB by 2,4-thiazolidinedione. Exp. Gerontol. 41(6), 590-599 (2006). (Pubitemid 43867228)
134. Muranaka K, Yanagi Y, Tamaki Y et al.: Effects of peroxisome proliferator-activated receptor g and its ligand on blood-retinal barrier in a streptozotocin-induced diabetic model. Invest. Ophthalmol. Vis. Sci. 47(10), 4547-4552 (2006). (Pubitemid 46579384)
135. Zhang W, Rojas M, Lilly B et al.: NAD(P)H oxidase-dependent regulation of CCL2 production during retinal inflammation. Invest. Ophthalmol. Vis. Sci. 50(6), 3033-3040 (2009).
136. Cunningham MA, Edelman JL, Kaushal S: Intravitreal steroids for macular edema: the past, the present, and the future. Surv. Ophthalmol. 53(2), 139-149 (2008). (Pubitemid 351391933)
137. De Bosscher K, Haegeman G, Elewaut D: Targeting inflammation using selective glucocorticoid receptor modulators. Curr. Opin. Pharmacol. 10(4), 497-504 (2010).
138. Tamura H, Miyamoto K, Kiryu J et al.: Intravitreal injection of corticosteroid attenuates leukostasis and vascular leakage in experimental diabetic retina. Invest. Ophthalmol. Vis. Sci. 46(4), 1440-1444 (2005). (Pubitemid 41685887)
139. Beer PM, Bakri SJ, Singh RJ, Liu W, Peters GB 3rd, Miller M: Intraocular concentration and pharmacokinetics of triamcinolone acetonide after a single intravitreal injection. Ophthalmology 110(4), 681-686 (2003). (Pubitemid 36520063)
140. Jonas JB, Sofker A: Intraocular injection of crystalline cortisone as adjunctive treatment of diabetic macular edema. Am. J. Ophthalmol. 132(3), 425-427 (2001). (Pubitemid 32768624)
141. El-Asrar AM, Al-Mezaine HS, Ola MS: Changing paradigms in the treatment of diabetic retinopathy. Curr. Opin. Ophthalmol. 20(6), 532-538 (2009).
142. Kim SJ, Flach AJ, Jampol LM: Nonsteroidal anti-inflammatory drugs in ophthalmology. Surv. Ophthalmol. 55(2), 108-133 (2010).
143. Wang D, DuBois RN: Pro-inflammatory prostaglandins and progression of colorectal cancer. Cancer Lett. 267(2), 197-203 (2008).
144. Surh YJ, Chun KS, Cha HH et al.: Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kB activation. Mutat. Res. 480-481, 243-268 (2001).
145. Du Y, Sarthy VP, Kern TS: Interaction between NO and COX pathways in retinal cells exposed to elevated glucose and retina of diabetic rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 287(4), R735-R741 (2004). (Pubitemid 39280457)
146. Johnson EI, Dunlop ME, Larkins RG: Increased vasodilatory prostaglandin production in the diabetic rat retinal vasculature. Curr. Eye Res. 18(2), 79-82 (1999). (Pubitemid 29137563)
147. Ayalasomayajula SP, Amrite AC, Kompella UB: Inhibition of cyclooxygenase-2, but not cyclooxygenase-1, reduces prostaglandin E2 secretion from diabetic rat retinas. Eur. J. Pharmacol. 498(1-3), 275-278 (2004). (Pubitemid 39208089)
148. Ayalasomayajula SP, Kompella UB: Celecoxib, a selective cyclooxygenase-2 inhibitor, inhibits retinal vascular endothelial growth factor expression and vascular leakage in a streptozotocin-induced diabetic rat model. Eur. J. Pharmacol. 458(3), 283-289 (2003). (Pubitemid 36009467)
149. Sun W, Gerhardinger C, Dagher Z, Hoehn T, Lorenzi M: Aspirin at low-intermediate concentrations protects retinal vessels in experimental diabetic retinopathy through non-platelet-mediated effects. Diabetes 54(12), 3418-3426 (2005). (Pubitemid 43334331)
150. Kern TS, Engerman RL: Pharmacological inhibition of diabetic retinopathy: aminoguanidine and aspirin. Diabetes 50(7), 1636-1642 (2001). (Pubitemid 33639605)
151. Amrite AC, Ayalasomayajula SP, Cheruvu NP, Kompella UB: Single periocular injection of celecoxib-PLGA microparticles inhibits diabetes-induced elevations in retinal PGE2, VEGF, and vascular leakage. Invest. Ophthalmol. Vis. Sci. 47(3), 1149-1160 (2006). (Pubitemid 46768351)
152. Kern TS, Miller CM, Du Y et al.: Topical administration of nepafenac inhibits diabetes-induced retinal microvascular disease and underlying abnormalities of retinal metabolism and physiology. Diabetes 56(2), 373-379 (2007).
153. Powell ED, Field RA: Diabetic retinopathy and rheumatoid arthritis. Lancet 2(7349), 17-18 (1964).
154. Effects of aspirin treatment on diabetic retinopathy. ETDRS report number 8. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 98(Suppl. 5), 757-765 (1991).
155. Effect of aspirin alone and aspirin plus dipyridamole in early diabetic
156. Scott DL: Etanercept in arthritis. Int. J. Clin. Pract. 59(1), 114-118 (2005). (Pubitemid 40267631)
157. Kleinbongard P, Schulz R, Heusch G: TNFa in myocardial ischemia/reperfusion, remodeling and heart failure. Heart Fail. Rev. 16(1), 49-69 (2011).
158. Joussen AM, Doehmen S, Le ML et al.: TNF-α mediated apoptosis plays an important role in the development of early diabetic retinopathy and long-term histopathological alterations. Mol. Vis. 15, 1418-1428 (2009).
159. Sfikakis PP, Markomichelakis N, Theodossiadis GP, Grigoropoulos V, Katsilambros N, Theodossiadis PG: Regression of sight-threatening macular edema in Type 2 diabetes following treatment with the anti-tumor necrosis factor monoclonal antibody infliximab. Diabetes Care 28(2), 445-447 (2005). (Pubitemid 40170961)
160. Rao VR, Prescott E, Shelke NB et al.: Delivery of SAR 1118 to retina via ophthalmic drops and its effectiveness in reduction of retinal leukostasis and vascular leakiness in rat streptozotocin (STZ) model of diabetic retinopathy (DR).Invest. Ophthalmol. Vis. Sci. 51(10), 5198-5204 (2010).
161. Iliaki E, Poulaki V, Mitsiades N, Mitsiades CS, Miller JW, Gragoudas ES: Role of a 4 integrin (CD49d) in the pathogenesis of diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 50(10), 4898-4904 (2009).
162. Barile GR, Pachydaki SI, Tari SR et al.: The RAGE axis in early diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 46(8), 2916-2924 (2005). (Pubitemid 43086714)
163. Bhatwadekar A, Glenn JV, Figarola JL et al.: A new advanced glycation inhibitor, LR-90, prevents experimental diabetic retinopathy in rats. Br. J. Ophthalmol. 92(4), 545-547 (2008). (Pubitemid 351497988)
164. Kowluru RA, Tang J, Kern TS: Abnormalities of retinal metabolism in diabetes and experimental galactosemia. VII. Effect of long-term administration of antioxidants on the development of retinopathy. Diabetes 50(8), 1938-1942 (2001). (Pubitemid 33641616)
165. Bursell SE, King GL: Can protein kinase C inhibition and vitamin E prevent the development of diabetic vascular complications? Diabetes Res. Clin. Pract. 45(2-3), 169-182 (1999). (Pubitemid 29457765)
166. Ali TK, El-Remessy AB: Diabetic retinopathy: current management and experimental therapeutic targets. Pharmacotherapy 29(2), 182-192 (2009).
167. Zhang JZ, Xi X, Gao L, Kern TS: Captopril inhibits capillary degeneration in the early stages of diabetic retinopathy. Curr. Eye Res. 32(10), 883-889 (2007). (Pubitemid 350034786)
168. Nagai N, Izumi-Nagai K, Oike Y et al.: Suppression of diabetes-induced retinal inflammation by blocking the angiotensin II type 1 receptor or its downstream nuclear factor-kB pathway. Invest. Ophthalmol. Vis. Sci. 48(9), 4342-4350 (2007). (Pubitemid 351261068)
169. Yamagishi S, Matsui T, Nakamura K et al.: Olmesartan blocks inflammatory reactions in endothelial cells evoked by advanced glycation end products by suppressing generation of reactive oxygen species. Ophthalmic. Res. 40(1), 10-15 (2008). (Pubitemid 350308297)
170. Mauer M, Zinman B, Gardiner R et al.: Renal and retinal effects of enalapril and losartan in Type 1 diabetes. N. Engl. J. Med. 361(1), 40-51 (2009).
171. Chaturvedi N, Porta M, Klein R et al.: Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in Type 1 diabetes: randomised, placebo-controlled trials. Lancet 372(9647), 1394-1402 (2008).
172. Sjolie AK, Klein R, Porta M et al.: Effect of candesartan on progression and regression of retinopathy in Type 2 diabetes (DIRECT Protect 2): a randomised placebo-controlled trial. Lancet 372(9647), 1385-1393 (2008).