Research status and progress of macular edema formation mechanism_Chinese Journal of Ocular Fundus Diseases

Authors：

Mei Xue , Zheng Honghua , Chen Xiaohong , Lei Yu ,  Chen Meizhu

China National People's Liberation Army Joint Service Forces Ninth Hospital, Xiamen University Affiliated Oriental Hospital, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou 320000, China;

Corresponding author：

Chen Meizhu, Email: jumychen@126.com

Keywords：

Macular edema; Review; Retinal water ion homeostasis

DOI：

10.3760/cma.j.cn511434-20181203-00413

Video：

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Abstract Full text Figures/Tables Video References Cited by

Macular edema is formed by the accumulation of extracellular fluid or intracellular fluid in the macular area of the retina. In a physiological state, the retina is kept relatively dehydrated and transparent, thereby ensuring the transmission of optical signals. This process requires multiple active or passive liquid transport systems to be performed together, and any of these process anomalies can disrupt the retinal water ion homeostasis, causing an imbalance between fluid entry and exit processes, leading to fluid formation. Macular edema is not an independent disease, it can occur in the process of many retinal diseases. It is the main cause of serious damage to the central vision, the main causes of diabetes, retinal vein occlusion, choroidal angiogenesis, uveitis, postoperative inflammation and tumor. This review mainly discusses the complex mechanism of macular edema caused by retinal barrier dysfunction when retinal water ion homeostasis is abnormal at the cellular and molecular levels. The purpose of this review is to provide a deeper overview of macular edema and its mechanisms of development, opening up new prospects for new prevention and treatment strategies for macular edema, a serious threat to vision.

Citation： Mei Xue, Zheng Honghua, Chen Xiaohong, Lei Yu, Chen Meizhu. Research status and progress of macular edema formation mechanism. Chinese Journal of Ocular Fundus Diseases, 2020, 36(5): 404-408. doi: 10.3760/cma.j.cn511434-20181203-00413 Copy

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1. Yanoff M, Fine BS, Brucker AJ, et al. Pathology of human cystoid macular edema[J]. Surv Ophthalmol, 1984, 28(Suppl): S505-511. DOI: 10.1016/0039-6257(84)90233-9.
2. Kohno T, Ishibashi T, Inomata H, et al. Experimental macular edema of commotio retinae: preliminary report[J]. Jpn J Ophthalmol, 1983, 27(1): 149-156.
3. Sun JK, Radwan SH, Soliman AZ, et al. Neural retinal disorganization as a robust marker of visual acuity in current and resolved diabetic macular edema[J]. Diabetes, 2015, 64(7): 2560-2570. DOI: 10.2337/db14-0782.
4. Radius RL, Anderson DR. Distribution of albumin in the normal monkey eye as revealed by Evans blue fluorescence microscopy[J]. Invest Ophthalmol Vis Sci, 1980, 19(3): 238-243.
5. Antonetti DA, Barber AJ, Hollinger LA, et al. 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[J]. J Biol Chem, 1999, 274(33): 23463-23467. DOI: 10.1074/jbc.274.33.23463.
6. Saker S, Stewart EA, Browning AC, et al. The effect of hyperglycaemia on permeability and the expression of junctional complex molecules in human retinal and choroidal endothelial cells[J]. Exp Eye Res, 2014, 121: 161-167. DOI: 10.1016/j.exer.2014.02.016.
7. Stewart EA, Saker S, Amoaku WM. Dexamethasone reverses the effects of high glucose on human retinal endothelial cell permeability and proliferation in vitro[J]. Exp Eye Res, 2016, 151: 75-81. DOI: 10.1016/j.exer.2016.08.005.
8. Tien T, Barrette KF, Chronopoulos A, et al. Effects of high glucose-induced Cx43 downregulation on occludin and ZO-1 expression and tight junction barrier function in retinal endothelial cells[J]. Invest Ophthalmol Vis Sci, 2013, 54(10): 6518-6525. DOI: 10.1167/iovs.13-11763.
9. Rangasamy S, Srinivasan R, Maestas J, et al. A potential role for angiopoietin 2 in the regulation of the blood-retinal barrier in diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2010, 52(6): 3784-3791. DOI: 10.1167/iovs.10-6386.
10. Aveleira CA, Lin CM, Abcouwer SF, et al. TNF-α signals through PKCζ/NF-κB to alter the tight junction complex and increase retinal endothelial cell permeability[J]. Diabetes, 2010, 59(11): 2872-2882. DOI: 10.2337/db09-1606.
11. Huang H, He J, Johnson D, et al. Deletion of placental growth factor prevents diabetic retinopathy and is associated with Akt activation and HIF1α-VEGF pathway inhibition[J]. Diabetes, 2015, 64(1): 200-212. DOI: 10.2337/db14-0016.
12. Liu X, Dreffs A, Díaz-Coránguez M, et al. Occludin S490 phosphorylation regulates vascular endothelial growth factor-induced retinal neovascularization[J]. Am J Pathol, 2016, 186(9): 2486-2499. DOI: 10.1016/j.ajpath.2016.04.018.
13. Murakami T, Frey T, Lin C, et al. Protein kinase cβ phosphorylates occludin regulating tight junction trafficking in vascular endothelial growth factor-induced permeability in vivo[J]. Diabetes, 2012, 61(6): 1573-1583. DOI: 10.2337/db11-1367.
14. Scheppke L, Aguilar E, Gariano RF, et al. Retinal vascular permeability suppression by topical application of a novel VEGFR2/Src kinase inhibitor in mice and rabbits[J]. J Clin Invest, 2008, 118(6): 2337-2346. DOI: 10.1172/JCI33361.
15. Hofman P, Blaauwgeers HG, Tolentino MJ, et al. VEGF-A induced hyperpermeability of blood-retinal barrier endothelium in vivo is predominantly associated with pinocytotic vesicular transport and not with formation of fenestrations[J]. Curr Eye Res, 2000, 21(2): 637-645. DOI: 10.1076/0271-3683(200008)2121-VFT637.
16. Wisniewska-Kruk J, van der Wijk AE, van Veen HA, et al. Plasmalemma vesicle-associated protein has a key role in blood-retinal barrier loss[J]. Am J Pathol, 2016, 186(4): 1044-1054. DOI: 10.1016/j.ajpath.2015.11.019.
17. Gu X, Fliesler SJ, Zhao YY, et al. Loss of caveolin-1 causes blood-retinal barrier breakdown, venous enlargement, and mural cell alteration[J]. Am J Pathol, 2014, 184(2): 541-555. DOI: 10.1016/j.ajpath.2013.10.022.
18. De Bock M, Van Haver V, Vandenbroucke RE, et al. Into rather unexplored terrain-transcellular transport across the blood-brain barrier[J]. Glia, 2016, 64(7): 1097-1123. DOI: 10.1002/glia.22960.
19. Dominguez E, Raoul W, Calippe B, et al. Experimental branch retinal vein occlusion induces upstream pericyte loss and vascular destabilization[J/OL]. PLoS One, 2015, 10(7): 0132644[2015-07-24]. http://dx.plos.org/10.1371/journal.pone.0132644. DOI: 10.1371/journal.pone.0132644.
20. Joussen AM, Poulaki V, Qin W, et al. 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[J]. Am J Pathol, 2002, 160(2): 501-509. DOI: 10.1016/S0002-9440(10)64869-9.
21. Behl Y, Krothapalli P, Desta T, et al. Diabetes-enhanced tumor necrosis factor-alpha production promotes apoptosis and the loss of retinal microvascular cells in type 1 and type 2 models of diabetic retinopathy[J]. Am J Pathol, 2008, 172(5): 1411-1418. DOI: 10.2353/ajpath.2008.071070.
22. Muto T, Tien T, Kim D, et al. High glucose alters Cx43 expression and gap junction intercellular communication in retinal Müller cells: promotes Müller cell and pericyte apoptosis[J]. Invest Ophthalmol Vis Sci, 2014, 55(11): 4327-4337. DOI: 10.1167/iovs.14-14606.
23. Tonade D, Liu H, Kern TS. Photoreceptor cells produce inflammatory mediators that contribute to endothelial cell death in diabetes[J]. Invest Ophthalmol Vis Sci, 2016, 57(14): 4264-4271. DOI: 10.1167/iovs.16-19859.
24. Gorp RM, Broers JL, Reutelingsperger CP, et al. Peroxide-induced membrane blebbing in endothelial cells associated with glutathione oxidation but not apoptosis[J]. Am J Physiol, 1999, 277(1): 20-28. DOI: 10.1152/ajpcell.1999.277.1.C20.
25. Rothschild PR, Salah S, Berdugo M, et al. ROCK-1 mediates diabetes-induced retinal pigment epithelial and endothelial cell blebbing: contribution to diabetic retinopathy[J]. Sci Rep, 2017, 7(1): 8834. DOI: 10.1038/s41598-017-07329-y.
26. Li W, Liu X, Yanoff M, et al. Cultured retinal capillary pericytes die by apoptosis after an abrupt fluctuation from high to low glucose levels: a comparative study with retinal capillary endothelial cells[J]. Diabetologia, 1996, 39(5): 537-547. DOI: 10.1007/BF00403300.
27. Shojaee N, Patton WF, Hechtman HB, et al. Myosin translocation in retinal pericytes during free-radical induced apoptosis[J]. Cell Biochem, 1999, 75(1): 118-129. DOI: 10.1002/(SICI)1097-4644(19991001)75:1<118::AID-JCB12>3.0.CO;2-U.
28. Kim YH, Kim YS, Park SY, et al. CaMKⅡ regulates pericyte loss in the retina of early diabetic mouse[J]. Mol Cells, 2011, 31(3): 289-293. DOI: 10.1007/s10059-011-0038-2.
29. Betts-Obregon BS, Mondragon AA, Mendiola AS, et al. TGFβ induces BIGH3 expression and human retinal pericyte apoptosis: a novel pathway of diabetic retinopathy[J]. Eye (Lond), 2016, 30(12): 1639-1647. DOI: 10.1038/eye.2016.179.
30. Yang R, Liu H, Williams I, et al. Matrix metalloproteinase-2 expression and apoptogenic activity in retinal pericytes: implications in diabetic retinopathy[J]. Ann N Y Acad Sci, 2007, 1103: 196-201. DOI: 10.1196/annals.1394.000.
31. Omri S, Behar-Cohen F, Rothschild PR, et al. PKCζ mediates breakdown of outer blood-retinal barriers in diabetic retinopathy[J/OL]. PLoS One, 2013, 8(11): 81600[2013-11-29]. http://dx.plos.org/10.1371/journal.pone.0081600. DOI: 10.1371/journal.pone.0081600.
32. Xu HZ, Song Z, Fu S, et al. RPE barrier breakdown in diabetic retinopathy: seeing is believing[J]. J Ocul Biol Dis Infor, 2011, 4(1-2): 83-92. DOI: 10.1007/s12177-011-9068-4.
33. Grajewski RS, Boelke AC, Adler W, et al. Spectral-domain optical coherence tomography findings of the macula in 500 consecutive patients with uveitis[J]. Eye (Lond), 2016, 30(11): 1415-1423. DOI: 10.1038/eye.2016.133.
34. Celık E, Doğan E, Turkoglu EB, et al. Serous retinal detachment in patients with macular edema secondary to branch retinal vein occlusion[J]. Arq Bras Oftalmol, 2016, 79(1): 9-11. DOI: 10.5935/0004-2749.20160004.
35. Shereef H, Comyn O, Sivaprasad S, et al. Differences in the topographic profiles of retinal thickening in eyes with and without serous macular detachment associated with diabetic macular oedema[J]. Br J Ophthalmol, 2014, 98(2): 182-187. DOI: 10.1136/bjophthalmol-2013-303095.
36. Vujosevic S, Torresin T, Berton M, et al. Diabetic macular edema with and without subfoveal neuroretinal detachment: two different morphological and functional entities[J]. Am J Ophthalmol, 2017, 181: 149-155. DOI: 10.1016/j.ajo.2017.06.026.
37. van Zeeburg EJ, Maaijwee KJ, Missotten TO, et al. A free retinal pigment epithelium-choroid graft in patients with exudative age-related macular degeneration: results up to 7 years[J]. Am J Ophthalmol, 2011, 153(1): 120-127. DOI: 10.1016/j.ajo.2011.06.007.
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