Current Science

Open Access Open Access  Restricted Access Subscription Access

Role of Inflammation in Diabetic Retinopathy:Therapeutic Targets


Affiliations
1 Department of Surgery/Ophthalmology, University of New Mexico School of Medicine, MSC 10 8000, 1600 University Blvd. NE, Albuquerque, NM 87131, United States
2 Department of Cell Biology and Physiology, University of New Mexico School of Medicine, MSC 10 8000, 1600 University Blvd. NE, Albuquerque, NM 87131, United States
 

Inflammation plays a key role in the pathogenesis of diabetic retinopathy (DR), leading to alterations in the blood–retinal barrier and increased vascular permeability. Many anti-VEGF medications are now available for the treatment of DR, but response to these medications is not as robust in patients with diabetic macular oedema. Newer biologic agents are currently under study to improve the treatment of DR. These have shown promising results to both decrease the treatment burden of intravitreal injections and improve visual outcomes for diabetic patients.

Keywords

Chemokines, Cytokines, Diabetic Retinopathy, Drug Therapy, Inflammation.
User
Notifications
Font Size

  • IDF Diabetes Atlas, International Diabetes Federation, Brussels, Belgium, 2015, 7th edn.

  • Yau, J. W. Y. et al., Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care, 2012, 35(3), 556–564; doi:10.2337/dc11-1909.

  • Blindness caused by diabetes, Massachusetts, 1987–1994. JAMA. 1996, 276(23), 1865–1866.

  • Klein, R., Klein, B. E., Moss, S. E. and Cruickshanks, K. J., The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XVII. The 14-year incidence and progression of diabetic retinopathy and associated risk factors in type 1 diabetes. Ophthalmology, 1998, 105(10), 1801–1815; doi:10.1016/S0161-6420(98)91020-X.

  • Early Treatment Diabetic Retinopathy Study Research Group, Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study (ETDRS) report no. 1. Arch. Ophthalmol. Chic Ill, 1960. 1985, 103(12), 1796–1806.

  • Early photocoagulation for diabetic retinopathy. ETDRS report no. 9. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology (Suppl.), 1991, 98(5), 766–785.

  • Elman, M. J. et al., Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment. Ophthalmology, 2012, 119(11), 2312–2318; doi:10.1016/j.ophtha.2012.08.022.

  • Cunha-Vaz, J., Bernardes, R. and Lobo, C., Blood–retinal barrier. Eur. J. Ophthalmol., 2011, 21(Suppl 6), S3–S9; doi:10.5301/EJO.2010.6049.

  • Rangasamy, S., Srinivasan, R., Maestas, J., McGuire, P. G. and Das, A., A potential role for angiopoietin 2 in the regulation of the blood–retinal barrier in diabetic retinopathy. Invest. Opthalmol. Vis. Sci., 2011, 52(6), 3784; doi:10.1167/iovs.10-6386.

  • Das, A., McGuire, P. G. and Rangasamy, S., Diabetic macular edema: pathophysiology and novel therapeutic targets. Ophthalmology, 2015, 122(7), 1375–1394; doi:10.1016/j.ophtha.2015.03.024.

  • Zhang, C., Wang, H., Nie, J. and Wang, F., Protective factors in diabetic retinopathy: focus on blood–retinal barrier. Discov. Med., 2014, 18(98), 105–112.

  • Das, A., Frank, R. N., Weber, M. L., Kennedy, A., Reidy, C. A. and Mancini, M. A., ATP causes retinal pericytes to contract in vitro. Exp. Eye Res., 1988, 46(3), 349–362.

  • Orlidge, A. and D’Amore, P. A., Inhibition of capillary endothelial cell growth by pericytes and smooth muscle cells. J. Cell Biol., 1987, 105(3), 1455–1462.

  • Das, A., Frank, R. N., Zhang, N. L. and Samadani, E., Increases in collagen type IV and laminin in galactose-induced retinal capillary basement membrane thickening – prevention by an aldose reductase inhibitor. Exp. Eye Res., 1990, 50(3), 269–280.

  • Adamis, A. P. and Berman, A. J., Immunological mechanisms in the pathogenesis of diabetic retinopathy. Semin. Immunopathol., 2008, 30(2), 65–84; doi:10.1007/s00281-008-0111-x.

  • Brownlee, M., The pathobiology of diabetic complications: a unifying mechanism. Diabetes, 2005, 54(6), 1615–1625.

  • Tang, J. and Kern, T. S., Inflammation in diabetic retinopathy. Prog. Retin. Eye Res., 2011, 30(5), 343–358; doi:10.1016/j.preteyeres.2011.05.002.

  • Sheetz, M. J. and King, G. L., Molecular understanding of hyperglycaemia’s adverse effects for diabetic complications. JAMA, 2002, 288(20), 2579–2588.

  • Kumar, V., Abbas, A. K. and Aster, J. C. (eds), Robbins and Cotran Pathologic Basis of Disease, Elsevier/Saunders, Philadelphia, PA, USA, 2015, Ninth edn.

  • Joussen, A. M., Murata, T., Tsujikawa, A., Kirchhof, B., Bursell, S. E. and Adamis, A. P., Leukocyte-mediated endothelial cell injury and death in the diabetic retina. Am. J. Pathol., 2001, 158(1), 147–152; doi:10.1016/S0002-9440(10)63952-1.

  • Kim, S. Y., Johnson, M. A., McLeod, D. S., Alexander, T., Hansen, B. C. and Lutty, G. A., Neutrophils are associated with capillary closure in spontaneously diabetic monkey retinas. Diabetes, 2005, 54(5), 1534–1542.

  • Lutty, G. A., Cao, J. and McLeod, D. S., Relationship of polymorphonuclear leukocytes to capillary dropout in the human diabetic choroid. Am. J. Pathol., 1997, 151(3), 707–714.

  • Miyamoto, K. et al., Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition. Proc. Natl. Acad. Sci. USA, 1999, 96(19), 10836–10841.

  • Kowluru, R. A., Zhong, Q. and Kanwar, M., Metabolic memory and diabetic retinopathy: role of inflammatory mediators in retinal pericytes. Exp. Eye Res., 2010, 90(5), 617–623; doi:10.1016/j.exer.2010.02.006.

  • Wang, J.-J., Functions of Muller cell-derived vascular endothelial growth factor in diabetic retinopathy. World J. Diabetes, 2015, 6(5), 726; doi:10.4239/wjd.v6.i5.726.

  • Wang, J., Xu, X., Elliott, M. H., Zhu, M. and Le, Y.-Z. Müller cell-derived VEGF is essential for diabetes-induced retinal inflammation and vascular leakage. Diabetes, 2010, 59(9), 2297–2305; doi:10.2337/db09-1420.

  • Grigsby, J. G. et al., The role of microglia in diabetic retinopathy. J. Ophthalmol., 2014, 2014, 1–15; doi:10.1155/2014/705783.

  • Ibrahim, A. S. et al., Retinal microglial activation and inflammation induced by amadori-glycated albumin in a rat model of diabetes. Diabetes, 2011, 60(4), 1122–1133; doi:10.2337/db10-1160.

  • Funatsu, H., Yamashita, H., Ikeda, T., Mimura, T., Eguchi, S. and Hori, S., Vitreous levels of interleukin-6 and vascular endothelial growth factor are related to diabetic macular edema. Ophthalmology, 2003, 110(9), 1690–1696; doi:10.1016/S0161-6420(03)00568-2.

  • Funatsu, H. et al., Aqueous humor levels of cytokines are related to vitreous levels and progression of diabetic retinopathy in diabetic patients. Graefes Arch. Clin. Exp. Ophthalmol., 2005, 243(1), 3–8; doi:10.1007/s00417-004-0950-7.

  • Simo, R., Sundstrom, J. M. and Antonetti, D. A., Ocular antiVEGF therapy for diabetic retinopathy: the role of VEGF in the pathogenesis of diabetic retinopathy. Diabetes Care, 2014, 37(4), 893–899; doi:10.2337/dc13-2002.

  • Simo, R., Carrasco, E., Garcia-Ramirez, M. and Hernandez, C., Angiogenic and antiangiogenic factors in proliferative diabetic retinopathy. Curr. Diabetes Rev., 2006, 2(1), 71–98.

  • Penn, J. S., Madan, A., Caldwell, R. B., Bartoli, M., Caldwell, R. W. and Hartnett, M. E., Vascular endothelial growth factor in eye disease. Prog. Retin. Eye Res., 2008, 27(4), 331–371; doi:10.1016/j.preteyeres.2008.05.001.

  • Vincent, J. A. and Mohr, S., Inhibition of caspase-1/interleukin1beta signaling prevents degeneration of retinal capillaries in diabetes and galactosemia. Diabetes, 2007, 56(1), 224–230; doi:10.2337/db06-0427.

  • Rangasamy, S., McGuire, P. G., Franco Nitta, C., Monickaraj, F., Oruganti, S. R. and Das, A., Chemokine mediated monocyte trafficking into the retina: role of inflammation in alteration of the blood-retinal barrier in diabetic retinopathy. PLoS ONE, 2014, 9(10), e108508; doi:10.1371/journal.pone.0108508.

  • Garcia-Ramirez, M. et al., 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, 2007, 50(6), 1294–1303; doi:10.1007/s00125-007-0627-y.

  • Tikhonenko, M. et al., Remodeling of retinal fatty acids in an animal model of diabetes: a decrease in long-chain polyunsaturated fatty acids is associated with a decrease in fatty acid elongases Elovl2 and Elovl4. Diabetes, 2010, 59(1), 219–227; doi:10.2337/db09-0728.

  • Lyons, T. J. et al., Diabetic retinopathy and serum lipoprotein subclasses in the DCCT/EDIC cohort. Invest. Ophthalmol. Vis. Sci., 2004, 45(3), 910–918.

  • Madonna, R., Giovannelli, G., Confalone, P., Renna, F. V., Geng, Y.-J. and De Caterina, R., High glucose-induced hyperosmolarity contributes to COX-2 expression and angiogenesis: implications for diabetic retinopathy. Cardiovasc. Diabetol., 2016, 15, 18; doi:10.1186/s12933-016-0342-4.

  • Ayalasomayajula, S. P. and Kompella, U. B., 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., 2003, 458(3), 283–289.

  • Schwartzman, M. L. et al., Profile of lipid and protein autacoids in diabetic vitreous correlates with the progression of diabetic retinopathy. Diabetes, 2010, 59(7), 1780–1788; doi:10.2337/db10-0110.

  • Sala-Vila, A. et al., Dietary marine ω-3 fatty acids and incident sight-threatening retinopathy in middle-aged and older individuals with type 2 diabetes: prospective investigation from the PREDIMED Trial. JAMA Ophthalmol., 2016, doi:10.1001/jamaophthalmol.2016.2906.

  • Simopoulos, A. P., Omega-3 fatty acids in inflammation and autoimmune diseases. J. Am. Coll. Nutr., 2002, 21(6), 495–505.

  • The Diabetes Control and Complications Trial, The effect of intensive diabetes treatment on the progression of diabetic retinopathy in insulin-dependent diabetes mellitus. Arch. Ophthalmol. Chic. Ill 1960, 1995, 113(1), 36–51.

  • UK Prospective Diabetes Study (UKPDS) Group, Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet, 1998, 352(9131), 837–853.

  • Davis, M. D. et al., Risk factors for high-risk proliferative diabetic retinopathy and severe visual loss: Early Treatment Diabetic Retinopathy study report #18. Invest. Ophthalmol. Vis. Sci., 1998, 39(2), 233–252.

  • Avery, R. L. et al., Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology. 2006, 113(10), 1695, e1-e15; doi:10.1016/j.ophtha.2006.05.064.

  • Simunovic, M. P. and Maberley Dal, Anti-vascular endothelial growth factor therapy for proliferative diabetic retinopathy: a systematic review and meta-analysis. Retina, 2015, 35(10), 1931–1942; doi:10.1097/IAE.0000000000000723.

  • Writing Committee for the Diabetic Retinopathy Clinical Research Network and Gross, J. G. et al., Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial. JAMA, 2015, 314(20), 2137; doi:10.1001/jama.2015.15217.

  • Martinez-Zapata, M. J. et al., Anti-vascular endothelial growth factor for proliferative diabetic retinopathy. Cochrane Database Syst. Rev., 2014, 11, CD008721; doi:10.1002/14651858.CD008721.pub2.

  • Heier, J. S. et al., Comparison of aflibercept, bevacizumab, and ranibizumab for treatment of diabetic macular edema: extrapolation of data to clinical practice. JAMA Ophthalmol., 2016, 134(1), 95–99; doi:10.1001/jamaophthalmol.2015.4110.

  • Sepah, Y. J. et al., DoDV; READ-3 Study Group. Twenty-four month outcomes of the Ranibizumab for Edema of the Macula in diabetes – protocol 3 with high dose (READ-3) study. Ophthalmology, 2016, 123(12), 2581–2587; doi:10.1016/j.ophtha.2016.08.040.

  • Brown, D. M. et al., Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology, 2013, 120(10), 2013–2022; doi:10.1016/j.ophtha.2013.02.034.

  • Campochiaro, P. A. et al., Treatment of diabetic macular edema with a designed ankyrin repeat protein that binds vascular endothelial growth factor: a phase I/II study. Am. J. Ophthalmol., 2013, 155(4), 697–704; 704.e1-e2; doi:10.1016/j.ajo.2012.09.032.

  • Allergan, A study of abicipar pegol in patients with diabetic macular edema. In ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). 2000 (cited 20 August 2016); available from: https://clinicaltrials.gov/ct2/show/study/NCT02186119 NLM Identifier: NCT02186119.

  • OHR Pharmaceutical Inc. Product Portfolio: OHR-102 (Squalamine); http://www.ohrpharmaceutical.com/product-portfolio/squalamine; accessed on 20 August 2016.

  • Starr Muscle; Ohr Pharmaceutical Inc. Squalamine lactate eye drops in combination with ranibizumab in patients with diabetic macular edema (DME). In ClinicalTrials.gov (internet). Bethesda (MD): National Library of Medicine (US). 2000 (cited 20 August 2016); available from: https://clinicaltrials.gov/ct2/show/NCT02349516 NLM Identifier: NCT02349516.

  • Genentech, Inc. Study of the efficacy and safety of the ranibizumab port delivery system for sustained delivery of ranibizumab in participants with subfoveal neovascular age-related macular degeneration (LADDER). In ClinicalTrials.gov (internet). Bethesda (MD): National Library of Medicine (US). 2000 (cited 20 August 2016); available from: https://clinicaltrials.gov/ct2/show/NCT02510794 NLM Identifier: NCT02510794.

  • Neurotech Pharmaceuticals. Study of the intravitreal implantation of NT-503-3 encapsulated cell technology (ECT) for the treatment of recurrent choroidal neovascularization (CNV) secondary to agerelated macular degeneration (AMD). In ClinicalTrials.gov (internet). Bethesda (MD): National Library of Medicine (US), 2000 (cited 20 August 2016); available from: https://clinicaltrials.gov/ct2/show/NCT02228304 NLM Identifier: NCT02228304.

  • van der Velden, V. H. J., Glucocorticoids: mechanisms of action and anti-inflammatory potential in asthma. Mediat. Inflamm., 1998, 7(4), 229–237; doi:10.1080/09629359890910.

  • Dong, N., Xu, B., Wang, B. and Chu, L., Study of 27 aqueous humor cytokines in patients with type 2 diabetes with or without retinopathy. Mol. Vis., 2013, 19, 1734–1746.

  • Sohn, H. J. et al., Changes in aqueous concentrations of various cytokines after intravitreal triamcinolone versus bevacizumab for diabetic macular edema. Am. J. Ophthalmol., 2011, 152(4), 686–694; doi:10.1016/j.ajo.2011.03.033.

  • Bressler, S. B. et al., Five-year outcomes of ranibizumab with prompt or deferred laser versus laser or triamcinolone plus deferred ranibizumab for diabetic macular edema. Am. J. Ophthalmol., 2016, 164, 57–68; doi:10.1016/j.ajo.2015.12.025.

  • Boyer, D. S. et al., Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology, 2014, 121(10), 1904–1914; doi:10.1016/j.ophtha.2014.04.024.

  • Campochiaro, P. A. et al., Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema. Ophthalmology. 2011, 118(4), 626–635; e2. doi:10.1016/j.ophtha.2010.12.028.

  • Joussen, A. M. et al., Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression. FASEB J., 2002, 16(3), 438–440; doi:10.1096/fj.01-0707fje.

  • The DAMAD Study Group, Effect of aspirin alone and aspirin plus dipyridamole in early diabetic retinopathy. A multicenter randomized controlled clinical trial. Diabetes, 1989, 38(4), 491–498.

  • Early Treatment Diabetic Retinopathy Study Research Group. Effects of aspirin treatment on diabetic retinopathy. ETDRS report no. 8. Ophthalmology (Suppl.), 1991, 98(5), 757–765.

  • Friedman, S. M. et al., Topical nepafenec in eyes with noncentral diabetic macular edema. Retina, 2015, 35(5), 944–956; doi: 10.1097/IAE.0000000000000403.

  • Campochiaro, P. A. et al., Enhanced benefit in diabetic macular edema from AKB-9778 Tie2 activation combined with vascular endothelial growth factor suppression. Ophthalmology. 2016, 123(8), 1722–1730; doi:10.1016/j.ophtha.2016.04.025.

  • Hoffmann-La Roche. A phase 2 study of RO6867461 in participants with center-involving diabetic macular edema (CI-DME) (BOULEVARD). In ClinicalTrials.gov (internet), Bethesda (MD): National Library of Medicine (US). 2000 (cited 20 August 2016); available from: https://clinicaltrials.gov/ct2/show/NCT02699450 NLM Identifier: NCT02699450.

  • Sfikakis, P. P. et al., Infliximab for diabetic macular edema refractory to laser photocoagulation: a randomized, double-blind, placebocontrolled, crossover, 32-week study. Diabetes Care, 2010, 33(7), 1523–1528; doi:10.2337/dc09-2372.

  • Furfine, E. S. et al., Optimized intravitreal IL-6 antagonist for the treatment of diabetic macular edema and Uveitis. In Association for Research in Vision and Ophthalmology, Meeting, abstr., Seattle, WA, USA, 2016.

  • Das, A., McGuire, P. and Monickaraj, F., Novel pharmacotherapies in diabetic retinopathy: current status and what’s in the horizon? Indian J. Ophthalmol., 2016, 64(1), 4; doi:10.4103/0301-4738.178154.

  • Funatsu, H., Noma, H., Mimura, T., Eguchi, S. and Hori, S., Association of vitreous inflammatory factors with diabetic macular edema. Ophthalmology, 2009, 116(1), 73–79; doi:10.1016/j.ophtha.2008.09.037.

  • Pfizer. A phase 2 multi-center study to evaluate the efficacy and safety of a chemokine CCR2/5 receptor antagonist in adults with type 2 diabetes and overt nephropathy. In ClinicalTrials.gov (internet). Bethesda (MD): National Library of Medicine (US), 2000 (cited 20 August 2016); available from: https://clinicaltrials.gov/ct2/show/results/NCT01712061 NLM Identifier: NCT01712061.

  • Pfizer. A phase 2, multi-center study to compare the efficacy and safety of a chemokine CCR2/5 receptor antagonist with ranibizumab in adults with diabetic macular edema. In ClinicalTrials.gov (internet), Bethesda (MD), National Library of Medicine (US). 2000 (cited 20 August 2016); available from: https://clinicaltrials.gov/ct2/show/NCT01994291 NLM Identifier: NCT01994291.

  • Kita, T. et al., Plasma kallikrein–kinin system as a VEGF-independent mediator of diabetic macular edema. Diabetes, 2015, 64(10), 3588–3599; doi:10.2337/db15-0317.

  • KalVista Pharmaceuticals, Ltd, Juvenile Diabetes Research Foundation, A phase I single ascending dose study of the intravitreal plasma kallikrein inhibitor KVD001 in subjects with DME. In ClinicalTrials.gov (internet), Bethesda (MD), National Library of Medicine (US), 2000 (cited 20 August 2016); available from: https://clinicaltrials.gov/ct2/show/NCT02193113 NLM Identifier:NCT02193113.

  • Allegro Ophthalmics, LLC; Trial Runners, LLC; Duke University. A phase 2 randomized, controlled, double-masked, multicenter clinical trial designed to evaluate the safety and exploratory efficacy of Luminate® (ALG-1001) as compared to Avastin® and focal laser photocoagulation in the treatment of diabetic macular edema. In ClinicalTrials.gov (internet), Bethesda (MD), National Library of Medicine (US), 2000 (cited 20 August 2016); available from: https://clinicaltrials.gov/ct2/show/NCT02348918 NLM Identifier: NCT02348918.


Abstract Views: 479

PDF Views: 109




  • Role of Inflammation in Diabetic Retinopathy:Therapeutic Targets

Abstract Views: 479  |  PDF Views: 109

Authors

Samuel Hobbs
Department of Surgery/Ophthalmology, University of New Mexico School of Medicine, MSC 10 8000, 1600 University Blvd. NE, Albuquerque, NM 87131, United States
Finny Monickaraj
Department of Surgery/Ophthalmology, University of New Mexico School of Medicine, MSC 10 8000, 1600 University Blvd. NE, Albuquerque, NM 87131, United States
Paul McGuire
Department of Cell Biology and Physiology, University of New Mexico School of Medicine, MSC 10 8000, 1600 University Blvd. NE, Albuquerque, NM 87131, United States
Arup Das
Department of Surgery/Ophthalmology, University of New Mexico School of Medicine, MSC 10 8000, 1600 University Blvd. NE, Albuquerque, NM 87131, United States

Abstract


Inflammation plays a key role in the pathogenesis of diabetic retinopathy (DR), leading to alterations in the blood–retinal barrier and increased vascular permeability. Many anti-VEGF medications are now available for the treatment of DR, but response to these medications is not as robust in patients with diabetic macular oedema. Newer biologic agents are currently under study to improve the treatment of DR. These have shown promising results to both decrease the treatment burden of intravitreal injections and improve visual outcomes for diabetic patients.

Keywords


Chemokines, Cytokines, Diabetic Retinopathy, Drug Therapy, Inflammation.

References





DOI: https://doi.org/10.18520/cs%2Fv113%2Fi07%2F1287-1295