{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T22:11:02Z","timestamp":1792188662189,"version":"4.4.0"},"reference-count":130,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T00:00:00Z","timestamp":1616716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Diabetic macular edema (DME) is a critical complication of diabetic retinopathy, a condition that arises from the breakdown of the blood\u2013retinal barrier and the consequent increase in vascular permeability. Over the years, attempts have been made to treat DME by various approaches, including laser photocoagulation, steroid triamcinolone acetonide, and vitrectomy. However, treatment was unsatisfactory until research identified vascular endothelial growth factor (VEGF) as a factor in the pathogenesis of DME. Intraocular anti-VEGF agents show good efficacy in DME. Nevertheless, in some patients the condition recurs or becomes resistant to treatment, suggesting that other factors may be involved. Because inflammation and retinal hypoxia are seen in DME, research has examined the potential role of cytokines and other inflammatory mediators. In this review, we provide an overview of this research and describe feedback mechanisms that may represent a target for novel treatments.<\/jats:p>","DOI":"10.3390\/ijms22073427","type":"journal-article","created":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T13:17:53Z","timestamp":1616764673000},"page":"3427","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":106,"title":["Involvement of Cytokines in the Pathogenesis of Diabetic Macular Edema"],"prefix":"10.3390","volume":"22","author":[{"given":"Hidetaka","family":"Noma","sequence":"first","affiliation":[{"name":"Hachioji Medical Center, Department of Ophthalmology, Tokyo Medical University, 1163, Tatemachi, Hachioji, Tokyo 193-0998, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanako","family":"Yasuda","sequence":"additional","affiliation":[{"name":"Hachioji Medical Center, Department of Ophthalmology, Tokyo Medical University, 1163, Tatemachi, Hachioji, Tokyo 193-0998, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiko","family":"Shimura","sequence":"additional","affiliation":[{"name":"Hachioji Medical Center, Department of Ophthalmology, Tokyo Medical University, 1163, Tatemachi, Hachioji, Tokyo 193-0998, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"223","DOI":"10.3109\/08820539909069541","article-title":"The pathogenesis of edema in diabetic maculopathy","volume":"14","author":"Antcliff","year":"1999","journal-title":"Semin. Ophthalmol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000455264","article-title":"Macular edema: Definition and basic concepts","volume":"58","author":"Coscas","year":"2017","journal-title":"Dev. Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Early Treatment Diabetic Retinopathy Study Research Group (1985). Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch. Ophthalmol., 103, 1796\u20131806.","DOI":"10.1001\/archopht.1985.01050120030015"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/S0161-6420(92)31901-3","article-title":"Vitrectomy for diabetic macular traction and edema associated with posterior hyaloidal traction","volume":"99","author":"Lewis","year":"1992","journal-title":"Ophthalmology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/S0002-9394(14)72018-5","article-title":"Vitrectomy for diffuse macular edema in cases of diabetic retinopathy","volume":"122","author":"Tachi","year":"1996","journal-title":"Am. J. Ophthalmol"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/S0002-9394(01)01010-8","article-title":"Intraocular injection of crystalline cortisone as adjunctive treatment of diabetic macular edema","volume":"132","author":"Jonas","year":"2001","journal-title":"Am. J. Ophthalmol"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/S0002-9394(01)01269-7","article-title":"Increased levels of vascular endothelial growth factor and interleukin-6 in the aqueous humor of diabetics with macular edema","volume":"133","author":"Funatsu","year":"2002","journal-title":"Am. J. Ophthalmol"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1706","DOI":"10.1016\/j.ophtha.2006.04.033","article-title":"A pilot study of multiple intravitreal injections of ranibizumab in patients with center-involving clinically significant diabetic macular edema","volume":"113","author":"Chun","year":"2006","journal-title":"Ophthalmology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1016\/j.ajo.2006.06.068","article-title":"Vascular endothelial growth factor is a critical stimulus for diabetic macular edema","volume":"142","author":"Nguyen","year":"2006","journal-title":"Am. J. Ophthalmol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1056\/NEJMoa1414264","article-title":"Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema","volume":"372","author":"Wells","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/S0168-8227(98)00074-6","article-title":"Increased serum levels of advanced glycation end-products and diabetic complications","volume":"41","author":"Ono","year":"1998","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.mvr.2010.03.004","article-title":"Hyperglycemia attenuates acute permeability response to advanced glycation end products in retinal microvasculature","volume":"80","author":"Warboys","year":"2010","journal-title":"Microvasc. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1002\/1520-7560(0000)9999:9999<::AID-DMRR157>3.0.CO;2-G","article-title":"Role of vasoactive factors in the pathogenesis of early changes in diabetic retinopathy","volume":"16","author":"Chakrabarti","year":"2000","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_14","first-page":"830","article-title":"Comparison of aqueous humor cytokine and chemokine levels in diabetic patients with and without retinopathy","volume":"18","author":"Cheung","year":"2012","journal-title":"Mol. Vis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1177\/112067219800800301","article-title":"Diabetic macular edema","volume":"8","year":"1998","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1016\/j.ophtha.2014.02.023","article-title":"Proposed lexicon for anatomic landmarks in normal posterior segment spectral-domain optical coherence tomography: The IN\u2022OCT consensus","volume":"121","author":"Staurenghi","year":"2014","journal-title":"Ophthalmology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"L1332","DOI":"10.1152\/ajplung.00338.2006","article-title":"Dexamethasone prevents transport inhibition by hypoxia in rat lung and alveolar epithelial cells by stimulating activity and expression of Na+-K+-ATPase and epithelial Na+ channels","volume":"293","author":"Guney","year":"2007","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/S0140-6736(09)62124-3","article-title":"Diabetic retinopathy","volume":"376","author":"Cheung","year":"2010","journal-title":"Lancet"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1056\/NEJMra1005073","article-title":"Diabetic retinopathy","volume":"366","author":"Antonetti","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/CS20120588","article-title":"Advances in our understanding of diabetic retinopathy","volume":"125","author":"Stitt","year":"2013","journal-title":"Clin. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/S0014-5793(01)02110-X","article-title":"Unbalanced expression of VEGF and PEDF in ischemia-induced retinal neovascularization","volume":"489","author":"Gao","year":"2001","journal-title":"FEBS Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.exer.2006.01.016","article-title":"Oxygen-dependent diseases in the retina: Role of hypoxia-inducible factors","volume":"83","author":"Arjamaa","year":"2006","journal-title":"Exp. Eye Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.ajo.2009.07.007","article-title":"Intravitreous vascular endothelial growth factor and hypoxia-inducible factor 1a in patients with proliferative diabetic retinopathy","volume":"148","author":"Wang","year":"2009","journal-title":"Am. J. Ophthalmol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.1001\/archopht.1995.01100120068012","article-title":"Hypoxic regulation of vascular endothelial growth factor in retinal cells","volume":"113","author":"Aiello","year":"1995","journal-title":"Arch. Ophthalmol."},{"key":"ref_25","first-page":"1029","article-title":"Vascular permeability factor\/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis","volume":"146","author":"Dvorak","year":"1995","journal-title":"Am. J. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"23463","DOI":"10.1074\/jbc.274.33.23463","article-title":"Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1. A potential mechanism for vascular permeability in diabetic retinopathy and tumors","volume":"274","author":"Antonetti","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1159\/000267567","article-title":"Vascular endothelial growth factor plays a role in hyperpermeability of diabetic retinal vessels","volume":"27","author":"Murata","year":"1995","journal-title":"Ophthalmic Res."},{"key":"ref_28","first-page":"819","article-title":"The relation between expression of vascular endothelial growth factor and breakdown of the blood-retinal barrier in diabetic rat retinas","volume":"74","author":"Murata","year":"1996","journal-title":"Lab. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1159\/000337156","article-title":"Diabetic macular edema","volume":"1","author":"Lang","year":"2012","journal-title":"Ophthalmologica"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/S0002-9394(01)01381-2","article-title":"Pathologic features of vascular endothelial growth factor-induced retinopathy in the nonhuman primate","volume":"133","author":"Tolentino","year":"2002","journal-title":"Am. J. Ophthalmol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1016\/S0161-6420(03)00568-2","article-title":"Vitreous levels of interleukin-6 and vascular endothelial growth factor are related to diabetic macular edema","volume":"110","author":"Funatsu","year":"2003","journal-title":"Ophthalmology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1136\/bjophthalmol-2016-309953","article-title":"Aqueous cytokine and growth factor levels indicate response to ranibizumab for diabetic macular oedema","volume":"101","author":"Shimura","year":"2017","journal-title":"Br. J. Ophthalmol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.ophtha.2008.09.037","article-title":"Association of vitreous inflammatory factors with diabetic macular edema","volume":"116","author":"Funatsu","year":"2009","journal-title":"Ophthalmology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.1172\/JCI119006","article-title":"Characterization of vascular endothelial growth factor\u2019s effect on the activation of protein kinase C, its isoforms, and endothelial cell growth","volume":"98","author":"Xia","year":"1996","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"25130","DOI":"10.1074\/jbc.274.35.25130","article-title":"Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1\/KDR activation of c-Src","volume":"274","author":"He","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5096","DOI":"10.1074\/jbc.275.7.5096","article-title":"Utilization of distinct signaling pathways by receptors for vascular endothelial cell growth factor and other mitogens in the induction of endothelial cell proliferation","volume":"275","author":"Wu","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1159\/000475603","article-title":"Aqueous humor levels of soluble vascular endothelial growth factor receptor and inflammatory factors in diabetic macular edema","volume":"238","author":"Noma","year":"2017","journal-title":"Ophthalmologica"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"10705","DOI":"10.1073\/pnas.90.22.10705","article-title":"Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor","volume":"90","author":"Kendall","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/labinvest.3780050","article-title":"Release and complex formation of soluble VEGFR-1 from endothelial cells and biological fluids","volume":"80","author":"Hornig","year":"2000","journal-title":"Lab. Investig."},{"key":"ref_40","first-page":"469","article-title":"Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis","volume":"39","author":"Shibuya","year":"2006","journal-title":"J. Biochem. Mol. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"9267","DOI":"10.1073\/pnas.88.20.9267","article-title":"Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor","volume":"88","author":"Maglione","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S1050-1738(02)00168-8","article-title":"Structure and function of placental growth factor","volume":"12","author":"Gigante","year":"2002","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"17629","DOI":"10.1074\/jbc.271.30.17629","article-title":"The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis","volume":"271","author":"Clauss","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1182\/blood-2002-11-3423","article-title":"Mechanism of monocyte activation and expression of proinflammatory cytochemokines by placenta growth factor","volume":"102","author":"Selvaraj","year":"2003","journal-title":"Blood"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/S0006-291X(02)03033-4","article-title":"VEGFR-2-specific ligand VEGF-E induces non-edematous hyper-vascularization in mice","volume":"301","author":"Kiba","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1182\/blood-2006-04-016030","article-title":"Signaling of vascular endothelial growth factor receptor-1 tyrosine kinase promotes rheumatoid arthritis through activation of monocytes\/macrophages","volume":"108","author":"Murakami","year":"2006","journal-title":"Blood"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1074\/jbc.270.2.933","article-title":"Transcriptional regulation of the intercellular adhesion molecule-1 gene by inflammatory cytokines in human endothelial cells. Essential roles of a variant NF-kappa B site and p65 homodimers","volume":"270","author":"Ledebur","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1146\/annurev.immunol.14.1.649","article-title":"The NF-kappa B and I kappa B proteins: New discoveries and insights","volume":"14","author":"Baldwin","year":"1996","journal-title":"Annu. Rev. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2361","DOI":"10.1161\/01.CIR.96.7.2361","article-title":"Platelet-derived growth factor-stimulated superoxide anion production modulates activation of transcription factor NF-kappaB and expression of monocyte chemoattractant protein 1 in human aortic smooth muscle cells","volume":"96","author":"Marumo","year":"1997","journal-title":"Circulation"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2155","DOI":"10.1167\/iovs.02-0807","article-title":"VEGF164 is proinflammatory in the diabetic retina","volume":"44","author":"Ishida","year":"2003","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1016\/j.ophtha.2015.03.024","article-title":"Diabetic macular edema: Pathophysiology and novel therapeutic targets","volume":"122","author":"Das","year":"2015","journal-title":"Ophthalmology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1001\/jamaophthalmol.2017.4914","article-title":"Effect of adding dexamethasone to continued ranibizumab treatment in patients with persistent diabetic macular edema: A DRCR network phase 2 randomized clinical trial","volume":"136","author":"Maturi","year":"2018","journal-title":"JAMA Ophthalmol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1001\/jamaophthalmol.2015.5346","article-title":"Persistent macular thickening after ranibizumab treatment for diabetic macular edema with vision impairment","volume":"134","author":"Bressler","year":"2016","journal-title":"JAMA Ophthalmol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1056\/NEJM199412013312203","article-title":"Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders","volume":"331","author":"Aiello","year":"1994","journal-title":"N. Engl. J. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.2337\/dc06-0556","article-title":"Erythropoietin is expressed in the human retina and it is highly elevated in the vitreous fluid of patients with diabetic macular edema","volume":"29","author":"Fonollosa","year":"2006","journal-title":"Diabetes Care"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Yoshimura, T., Sonoda, K.H., Sugahara, M., Mochizuki, Y., Enaida, H., Oshima, Y., Ueno, A., Hata, Y., Yoshida, H., and Ishibashi, T. (2009). Comprehensive analysis of inflammatory immune mediators in vitreoretinal diseases. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0008158"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e245","DOI":"10.1111\/aos.12251","article-title":"Aqueous humour levels of placental growth factor in diabetic retinopathy","volume":"92","author":"Ando","year":"2014","journal-title":"Acta Ophthalmol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1596","DOI":"10.1016\/j.cellsig.2011.05.011","article-title":"Erythropoietin protects retinal pigment epithelial cells against the increase of permeability induced by diabetic conditions: Essential role of JAK2\/ PI3K signaling","volume":"23","author":"Villarroel","year":"2011","journal-title":"Cell Signal."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1111\/ceo.13619","article-title":"Erythropoietin protects outer blood-retinal barrier in experimental diabetic retinopathy by up-regulating ZO-1 and occludin","volume":"47","author":"Zhang","year":"2019","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_60","first-page":"66","article-title":"Retinal hemodynamics in proliferative diabetic retinopathy. A laser Doppler velocimetry study","volume":"34","author":"Grunwald","year":"1993","journal-title":"Invest. Ophthalmol Vis. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1136\/bjo.79.7.628","article-title":"Macular microcirculation in cystoid maculopathy of diabetic patients","volume":"79","author":"Arend","year":"1995","journal-title":"Br. J. Ophthalmol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/S0002-9394(00)00575-4","article-title":"Perifoveal microcirculation before and after vitrectomy for diabetic cystoid macular edema","volume":"130","author":"Kadonosono","year":"2000","journal-title":"Am. J. Ophthalmol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s10384-005-0266-0","article-title":"Tracing method in the assessment of retinal capillary blood flow velocity by fluorescein angiography with scanning laser ophthalmoscope","volume":"50","author":"Funatsu","year":"2006","journal-title":"Jpn. J. Ophthalmol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1016\/S0161-6420(91)32043-8","article-title":"Fluorescein fundus angiography with scanning laser ophthalmoscope. Visibility of leukocytes and platelets in perifoveal capillaries","volume":"98","author":"Tanaka","year":"1991","journal-title":"Ophthalmology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1016\/j.ophtha.2006.04.023","article-title":"Relationship between macular microcirculation and progression of diabetic macular edema","volume":"113","author":"Sakata","year":"2006","journal-title":"Ophthalmology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"21713","DOI":"10.1038\/s41598-020-78792-3","article-title":"Intravitreal ranibizumab reduced ocular blood flow and aqueous cytokine levels and improved retinal morphology in patients with diabetic macular edema","volume":"10","author":"Mizui","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"7717","DOI":"10.1074\/jbc.270.13.7717","article-title":"Purification and characterization of a naturally occurring vascular endothelial growth factor.placenta growth factor heterodimer","volume":"270","author":"DiSalvo","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"25646","DOI":"10.1016\/S0021-9258(18)47298-5","article-title":"Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1\/KDR","volume":"269","author":"Park","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"11709","DOI":"10.1073\/pnas.95.20.11709","article-title":"Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells","volume":"95","author":"Olofsson","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1159\/000119877","article-title":"PlGF-1 and VEGFR-1 pathway regulation of the external epithelial hemato-ocular barrier. A model for retinal edema","volume":"40","author":"Miyamoto","year":"2008","journal-title":"Ophthalmic Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1002\/(SICI)1097-4652(199801)174:1<66::AID-JCP8>3.0.CO;2-E","article-title":"Rapid disruption of gap junctional communication and phosphorylation of connexin43 by platelet-derived growth factor in T51B rat liver epithelial cells expressing platelet-derived growth factor receptor","volume":"174","author":"Hossain","year":"1998","journal-title":"J. Cell Physiol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"16439","DOI":"10.1038\/s41598-017-16610-z","article-title":"Discovery of high-affinity PDGF-VEGFR Interactions: Redefining RTK dynamics","volume":"7","author":"Mamer","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1126\/science.285.5425.245","article-title":"Pigment epithelium-derived factor: A potent inhibitor of angiogenesis","volume":"285","author":"Dawson","year":"1999","journal-title":"Science"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1007\/s00109-013-0993-5","article-title":"Ocular neovascularization","volume":"91","author":"Campochiaro","year":"2013","journal-title":"J. Mol. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1111\/j.1755-3768.2009.01661.x","article-title":"Vitreous and serum levels of vascular endothelial growth factor and platelet-derived growth factor and their correlation in patients with non-proliferative diabetic retinopathy and clinically significant macula oedema","volume":"89","author":"Praidou","year":"2011","journal-title":"Acta. Ophthalmol."},{"key":"ref_76","first-page":"710","article-title":"IL-6 increases endothelial permeability in vitro","volume":"131","author":"Maruo","year":"1992","journal-title":"Endocrinology"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"11463","DOI":"10.1074\/jbc.270.19.11463","article-title":"Induction of interleukin 6 (IL-6) by hypoxia in vascular cells. Central role of the binding site for nuclear factor-IL-6","volume":"270","author":"Yan","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_78","first-page":"L1057","article-title":"Endothelial permeability and IL-6 production during hypoxia: Role of ROS in signal transduction","volume":"277","author":"Ali","year":"1999","journal-title":"Am. J. Physiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1161\/01.ATV.0000012262.76205.6A","article-title":"Role of mitochondrial oxidant generation in endothelial cell responses to hypoxia","volume":"22","author":"Pearlstein","year":"2002","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_80","first-page":"6928524","article-title":"Aqueous humor mediator and cytokine aberrations in diabetic retinopathy and diabetic macular edema: A systematic review and meta-analysis","volume":"23","author":"Wu","year":"2019","journal-title":"Dis. Markers"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1172\/JCI117135","article-title":"Hypoxic induction of interleukin-8 gene expression in human endothelial cells","volume":"93","author":"Karakurum","year":"1994","journal-title":"J. Clin. Investig."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"4231","DOI":"10.1128\/MCB.16.8.4231","article-title":"Involvement of the transcription factor NF-kappaB in tubular morphogenesis of human microvascular endothelial cells by oxidative stress","volume":"16","author":"Shono","year":"1996","journal-title":"Mol. Cell Biol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1002\/jcp.10160","article-title":"Effects of interleukin-8 on granulation tissue maturation","volume":"193","author":"Moyer","year":"2002","journal-title":"J. Cell Physiol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"966","DOI":"10.7150\/ijbs.6996","article-title":"Interleukin-8 regulates endothelial permeability by down-regulation of tight junction but not dependent on integrins induced focal adhesions","volume":"9","author":"Yu","year":"2013","journal-title":"Int. J. Biol. Sci."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Kwon, J.W., and Jee, D. (2018). Aqueous humor cytokine levels in patients with diabetic macular edema refractory to anti-VEGF treatment. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0207902"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/S0021-9150(98)00285-8","article-title":"Monocyte chemotactic protein-1 gene and protein expression in atherogenesis of hypercholesterolemic rabbits","volume":"143","author":"Chen","year":"1999","journal-title":"Atherosclerosis"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/S0165-5728(01)00280-6","article-title":"Endothelin-1 and monocyte chemoattractant protein-1 modulation in ischemia and human brain-derived endothelial cell cultures","volume":"116","author":"Chen","year":"2001","journal-title":"J. Neuroimmunol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1093\/toxsci\/kfi101","article-title":"Oxidative stress mediates sodium arsenite-induced expression of heme oxygenase-1, monocyte chemoattractant protein-1, and interleukin-6 in vascular smooth muscle cells","volume":"85","author":"Lee","year":"2005","journal-title":"Toxicol Sci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"4615","DOI":"10.1242\/jcs.00755","article-title":"Potential role of MCP-1 in endothelial cell tight junction \u2018opening\u2019: Signaling via Rho and Rho kinase","volume":"116","author":"Stamatovic","year":"2003","journal-title":"J. Cell Sci."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"3623","DOI":"10.1099\/vir.0.82093-0","article-title":"MCP-1, a highly expressed chemokine in dengue haemorrhagic fever\/dengue shock syndrome patients, may cause permeability change, possibly through reduced tight junctions of vascular endothelium cells","volume":"87","author":"Lee","year":"2006","journal-title":"J. Gen. Virol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.ajo.2020.08.047","article-title":"Aqueous Cytokine Expression and Higher Order OCT Biomarkers: Assessment of the Anatomic-Biologic Bridge in the IMAGINE DME Study","volume":"222","author":"Abraham","year":"2021","journal-title":"Am. J. Ophthalmol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1245\/ASO.2006.03.038","article-title":"Interferon gamma-inducible protein 10 selectively inhibits proliferation and induces apoptosis in endothelial cells","volume":"13","author":"Feldman","year":"2006","journal-title":"Ann. Surg. Oncol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1161\/01.RES.0000209968.66606.10","article-title":"IP-10 blocks vascular endothelial growth factor-induced endothelial cell motility and tube formation via inhibition of calpain","volume":"98","author":"Bodnar","year":"2006","journal-title":"Circ. Res."},{"key":"ref_94","first-page":"200","article-title":"Modulation and function of intercellular adhesion molecule-1 (CD54) on human retinal pigment epithelial cells","volume":"66","author":"Elner","year":"1992","journal-title":"Lab. Investig."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"4931","DOI":"10.1167\/iovs.02-1324","article-title":"Upregulation of P-selectin and intercellular adhesion molecule-1 after retinal ischemia-reperfusion injury","volume":"44","author":"Nishiwaki","year":"2003","journal-title":"Invest. Ophthalmol Vis. Sci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1161\/01.HYP.0000123069.02156.8a","article-title":"In vivo evaluation of retinal injury after transient ischemia in hypertensive rats","volume":"43","author":"Hirose","year":"2004","journal-title":"Hypertension"},{"key":"ref_97","first-page":"642","article-title":"Enhanced expression of intracellular adhesion molecule-1 and P-selectin in the diabetic human retina and choroid","volume":"147","author":"McLeod","year":"1995","journal-title":"Am. J. Pathol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"10836","DOI":"10.1073\/pnas.96.19.10836","article-title":"Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition","volume":"96","author":"Miyamoto","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1016\/S0002-9440(10)65044-4","article-title":"Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-1)","volume":"156","author":"Miyamoto","year":"2000","journal-title":"Am. J. Pathol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/S0002-9440(10)64869-9","article-title":"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","volume":"160","author":"Joussen","year":"2002","journal-title":"Am. J. Pathol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"5198","DOI":"10.1167\/iovs.09-5144","article-title":"Delivery of SAR 1118 to the retina via ophthalmic drops and its effectiveness in a rat streptozotocin (STZ) model of diabetic retinopathy (DR)","volume":"51","author":"Rao","year":"2010","journal-title":"Invest. Ophthalmol Vis. Sci."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1001\/jamaophthalmol.2018.0179","article-title":"Aqueous humor cytokine levels and anatomic response to intravitreal ranibizumab in diabetic macular edema","volume":"136","author":"Hillier","year":"2018","journal-title":"JAMA Ophthalmol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1159\/000364955","article-title":"Role of inflammation in diabetic macular edema","volume":"232","author":"Noma","year":"2014","journal-title":"Ophthalmologica"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1016\/j.ophtha.2014.03.021","article-title":"Neutralization of vascular endothelial growth factor slows progression of retinal nonperfusion in patients with diabetic macular edema","volume":"121","author":"Campochiaro","year":"2014","journal-title":"Ophthalmology"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1016\/j.ophtha.2010.02.031","article-title":"Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema","volume":"117","author":"Elman","year":"2010","journal-title":"Ophthalmology"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/j.ophtha.2011.01.031","article-title":"The RESTORE study: Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema","volume":"118","author":"Mitchell","year":"2011","journal-title":"Ophthalmology"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.ophtha.2011.12.039","article-title":"Ranibizumab for diabetic macular edema: Results from 2 phase III randomized trials: RISE and RIDE","volume":"119","author":"Nguyen","year":"2012","journal-title":"Ophthalmology"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1016\/j.ophtha.2014.05.006","article-title":"Intravitreal aflibercept for diabetic macular edema","volume":"121","author":"Korobelnik","year":"2014","journal-title":"Ophthalmology"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1016\/j.ophtha.2015.02.006","article-title":"The REVEAL study: Ranibizumab monotherapy or combined with laser versus laser monotherapy in Asian patients with diabetic macular edema","volume":"122","author":"Ishibashi","year":"2015","journal-title":"Ophthalmology"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"2504","DOI":"10.1016\/j.ophtha.2015.08.006","article-title":"Outcomes with As-needed ranibizumab after initial monthly therapy: Long-term outcomes of the phase III RIDE and RISE trials","volume":"122","author":"Boyer","year":"2015","journal-title":"Ophthalmology"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.ophtha.2013.11.041","article-title":"Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: The RESTORE extension study","volume":"121","author":"Lang","year":"2014","journal-title":"Ophthalmology"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.ophtha.2014.08.047","article-title":"Intravitreal Ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results","volume":"122","author":"Elman","year":"2015","journal-title":"Ophthalmology"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1159\/000508953","article-title":"Anti-VEGF therapy reduces inflammation in diabetic macular edema","volume":"64","author":"Imazeki","year":"2021","journal-title":"Ophthalmic Res."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1016\/j.ophtha.2008.12.024","article-title":"Vitreous mediators after intravitreal bevacizumab or triamcinolone acetonide in eyes with proliferative diabetic retinopathy","volume":"116","author":"Arimura","year":"2009","journal-title":"Ophthalmology"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.ajo.2016.04.017","article-title":"Pro-permeability factors in diabetic macular edema. The Diabetic macular edema treated with ozurdex trial","volume":"168","author":"Campochiaro","year":"2016","journal-title":"Am. J. Ophthalmol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.ophtha.2010.12.033","article-title":"Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema","volume":"118","author":"Elman","year":"2011","journal-title":"Ophthalmology"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/s10384-016-0458-9","article-title":"Reduction in the frequency of intravitreal bevacizumab administrations achieved by posterior subtenon injection of triamcinolone acetonide in patients with diffuse diabetic macular edema","volume":"60","author":"Shimura","year":"2016","journal-title":"Jpn. J. Ophthalmol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1001\/jamaophthalmol.2013.4154","article-title":"Exploratory analysis of the effect of intravitreal ranibizumab or triamcinolone on worsening of diabetic retinopathy in a randomized clinical trial","volume":"131","author":"Bressler","year":"2013","journal-title":"JAMA Ophthalmol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.ophtha.2014.08.048","article-title":"Long-term effects of therapy with ranibizumab on diabetic retinopathy severity and baseline risk factors for worsening retinopathy","volume":"122","author":"Ip","year":"2015","journal-title":"Ophthalmology"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"2044","DOI":"10.1016\/j.ophtha.2015.06.017","article-title":"Intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies","volume":"122","author":"Brown","year":"2015","journal-title":"Ophthalmology"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1016\/j.ophtha.2018.10.041","article-title":"Durability of diabetic retinopathy improvement with as-needed ranibizumab: Open-label extension of RIDE and RISE studies","volume":"126","author":"Sun","year":"2019","journal-title":"Ophthalmology"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1016\/j.ophtha.2019.06.022","article-title":"Widefield OCT-angiography and fluorescein angiography assessments of nonperfusion in diabetic retinopathy and edema treated with anti-vascular endothelial growth factor","volume":"126","author":"Couturier","year":"2019","journal-title":"Ophthalmology"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"4741","DOI":"10.1167\/iovs.14-14682","article-title":"The effect of photocoagulation in ischemic areas to prevent recurrence of diabetic macular edema after intravitreal bevacizumab injection","volume":"55","author":"Takamura","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.ajo.2012.09.032","article-title":"Treatment of diabetic macular edema with a designed ankyrin repeat protein that binds vascular endothelial growth factor: A phase I\/II study","volume":"155","author":"Campochiaro","year":"2013","journal-title":"Am. J. Ophthalmol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"33","DOI":"10.2174\/1871523016666170502115816","article-title":"Designed ankyrin repeat proteins: A look at their evolving use in medicine with a focus on the treatment of chorioretinal vascular disorders","volume":"16","author":"Smithwick","year":"2017","journal-title":"Antiinflamm. Antiallergy Agents Med. Chem."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s12348-019-0182-y","article-title":"Interleukin-6 inhibition in the management of non-infectious uveitis and beyond","volume":"9","author":"Karkhur","year":"2019","journal-title":"J. Ophthalmic Inflamm. Infect."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"3873","DOI":"10.1016\/j.bmc.2013.04.011","article-title":"Novel 1H-imidazol-2-amine derivatives as potent and orally active vascular adhesion protein-1 (VAP-1) inhibitors for diabetic macular edema treatment","volume":"21","author":"Inoue","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s40942-019-0178-7","article-title":"Primary outcomes of the VIDI study: Phase 2, double-masked, randomized, active-controlled study of ASP8232 for diabetic macular edema","volume":"5","author":"Nguyen","year":"2019","journal-title":"Int. J. Retin. Vitr."},{"key":"ref_129","first-page":"2784","article-title":"Squalamine inhibits angiogenesis and solid tumor growth in vivo and perturbs embryonic vasculature","volume":"58","author":"Sills","year":"1998","journal-title":"Cancer Res."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"914","DOI":"10.3928\/23258160-20161004-04","article-title":"Topical squalamine 0.2% and intravitreal ranibizumab 0.5 mg as combination therapy for macular edema due to branch and central retinal vein occlusion: An open-label, randomized study","volume":"47","author":"Wroblewski","year":"2016","journal-title":"Ophthalmic. Surg. 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