Research advances in the mechanism of subthreshold micropulse laser in diabetic macular edema_Chinese Journal of Ocular Fundus Diseases

Authors：

Wang Tingli , Zhou Huaiyu , Yin Xinxuan ,  Li Zhiqing

Tianjin Key Laboratory of Retinal Functions and Diseases,Tianjin International Joint Research and Development Centre of Ophthalmology and Vision Science, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, China;

Corresponding author：

Li Zhiqing, Email: lzhqyk@163.com

Keywords：

Diabetic retinopathy; Macular edema; Laser coagulation; Review

DOI：

10.3760/cma.j.cn511434-20200114-00022

Video：

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Abstract Full text Figures/Tables Video References Cited by

In recent years, the subthreshold micropulse laser is a kind of laser mode which is characterized by long intermittence. It achieves effective therapeutic effect while minimizes the damage to tissues. At present, it has been used to treat diabetic macular edema. Early studies suggested that the laser selectively acts on retinal pigment epithelial cells to reduce macular edema by regulating the expression of inflammatory biomarkers, growth factors, heat shock proteins and other substances. In recent years, with the development of research, more and more emphasis has been placed on the role of retinal glial cells. Müller cells are also considered as one of the target cells affected by micropulse laser, but there is no evidence of direct or indirect effects of micropulse laser on Müller cells. In the near future, it is expected that we will have more clinical evidence to confirm the target cells of the micropulse laser, which may be further confirmed by in vitro experiments through Müller cells or Müller cells co-cultured with retina pigment epithelium cells, so as to make a more detailed statement on the mechanism of it.

Citation： Wang Tingli, Zhou Huaiyu, Yin Xinxuan, Li Zhiqing. Research advances in the mechanism of subthreshold micropulse laser in diabetic macular edema. Chinese Journal of Ocular Fundus Diseases, 2021, 37(1): 73-77. doi: 10.3760/cma.j.cn511434-20200114-00022 Copy

1.	Su D, Hubschman JP. A review of subthreshold micropulse laser and recent advances in retinal laser technology[J]. Ophthalmol Ther, 2017, 6(1): 1-6. DOI: 10.1007/s40123-017-0077-7.
2.	Scholz P, Altay L, Fauser S. A review of subthreshold micropulse laser for treatment of macular disorders[J]. Adv Ther, 2017, 34(7): 1528-1555. DOI: 10.1007/s12325-017-0559-y.
3.	Luttrull JK, Dorin G. Subthreshold diode micropulse laser photocoagulation (SDM) as invisible retinal phototherapy for diabetic macular edema: a review[J]. Curr Diabetes Rev, 2012, 8(4): 274-284. DOI: 10.2174/157339912800840523.
4.	Ambiya V, Goud A, Mathai A, et al. Microsecond yellow laser for subfoveal leaks in central serous chorioretinopathy[J]. Clin Ophthalmol, 2016, 10: 1513-1519. DOI: 10.2147/opth.S112431.
5.	Inagaki K, Ohkoshi K, Ohde S, et al. Subthreshold micropulse photocoagulation for persistent macular edema secondary to branch retinal vein occlusion including best-corrected visual acuity greater than 20/40[J/OL]. J Ophthalmol, 2014, 2014: 251257[2014-09-04]. https://pubmed.ncbi.nlm.nih.gov/25276413/. DOI: 10.1155/2014/251257.
6.	Yadav NK, Jayadev C, Mohan A, et al. Subthreshold micropulse yellow laser (577 nm) in chronic central serous chorioretinopathy: safety profile and treatment outcome[J]. Eye (Lond), 2015, 29(2): 258-264. DOI: 10.1038/eye.2014.315.
7.	Chen G, Tzekov R, Li W, et al. Subthreshold micropulse diode laser versus conventional laser photocoagulation for diabetic macular edema: a meta-analysis of randomized controlled trials[J]. Retina, 2016, 36(11): 2059-2065. DOI: 10.1097/iae.0000000000001053.
8.	Simó R, Hernández C, European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR). Neurodegeneration in the diabetic eye: new insights and therapeutic perspectives[J]. Trends Endocrinol Metab, 2014, 25(1): 23-33. DOI: 10.1016/j.tem.2013.09.005.
9.	Chhablani J, Roh YJ, Jobling AI, et al. Restorative retinal laser therapy: present state and future directions[J]. Surv Ophthalmol, 2018, 63(3): 307-328. DOI: 10.1016/j.survophthal.2017.09.008.
10.	Midena E, Bini S. Multimodal retinal imaging of diabetic macular edema: toward new paradigms of pathophysiology[J]. Graefe's Arch Clin Exp Ophthalmol, 2016, 254(9): 1661-1668. DOI: 10.1007/s00417-016-3361-7.
11.	Midena E, Pilotto E. Emerging insights into pathogenesis[J]. Dev Ophthalmol, 2017, 60: 16-27. DOI: 10.1159/000459687.
12.	Grigsby JG, Cardona SM, Pouw CE, et al. The role of microglia in diabetic retinopathy[J/OL]. J Ophthalmol, 2014, 2014: 705783[2014-08-31]. https://pubmed.ncbi.nlm.nih.gov/25258680/. DOI: 10.1155/2014/705783.
13.	Bringmann A, Wiedemann P. Müller glial cells in retinal disease[J]. Ophthalmologica, 2012, 227(1): 1-19. DOI: 10.1159/000328979.
14.	Telegina DV, Kozhevnikova OS, Kolosova NG. Changes in retinal glial cells with age and during development of age-related macular degeneration[J]. Biochemistry (Mosc), 2018, 83(9): 1009-1017. DOI: 10.1134/s000629791809002x.
15.	Li L, Eter N, Heiduschka P. The microglia in healthy and diseased retina[J]. Exp Eye Res, 2015, 136: 116-130. DOI: 10.1016/j.exer.2015.04.020.
16.	Midena E, Micera A, Frizziero L, et al. Sub-threshold micropulse laser treatment reduces inflammatory biomarkers in aqueous humour of diabetic patients with macular edema[J/OL]. Sci Rep, 2019, 9(1): 10034[2019-07-11]. https://pubmed.ncbi.nlm.nih.gov/31296907/. DOI 10.1038/s41598-019-46515-y.
17.	Bringmann A, Pannicke T, Grosche J, et al. Müller cells in the healthy and diseased retina[J]. Prog Retin Eye Res, 2006, 25(4): 397-424. DOI: 10.1016/j.preteyeres.2006.05.003.
18.	Midena E, Bini S, Martini F, et al. Changes of aqueous humor Müller cells' biomarkers in human patients affected by diabetic macular edema after subthreshold micropulse laser treament[J]. Retina, 2020, 40(1): 126-134. DOI: 10.1097/iae.0000000000002356.
19.	Vujosevic S, Midena E. Retinal layers changes in human preclinical and early clinical diabetic retinopathy support early retinal neuronal and Müller cells alterations[J/OL]. J Diabetes Res, 2013, 2013: 905058[2013-06-12]. https://pubmed.ncbi.nlm.nih.gov/23841106/. DOI: 10.1155/2013/905058.
20.	Rungger-Brändle E, Dosso AA, Leuenberger PM. Glial reactivity, an early feature of diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2000, 41(7): 1971-1980.
21.	Sarthy V. Focus on molecules: glial fibrillary acidic protein (GFAP)[J]. Exp Eye Res, 2007, 84(3): 381-382. DOI: 10.1016/j.exer.2005.12.014.
22.	Hibino H, Inanobe A, Furutani K, et al. Inwardly rectifying potassium channels: their structure, function, and physiological roles[J]. Physiol Rev, 2010, 90(1): 291-366. DOI: 10.1152/physrev.00021.2009.
23.	Zhang Y, Xu G, Ling Q, et al. Expression of aquaporin 4 and Kir4.1 in diabetic rat retina: treatment with minocycline[J]. J Int Med Res, 2011, 39(2): 464-479. DOI: 10.1177/147323001103900214.
24.	Coughlin BA, Feenstra DJ, Mohr S. Müller cells and diabetic retinopathy[J]. Vision Res, 2017, 139: 93-100. DOI: 10.1016/j.visres.2017.03.013.
25.	Pannicke T, Iandiev I, Wurm A, et al. Diabetes alters osmotic swelling characteristics and membrane conductance of glial cells in rat retina[J]. Diabetes, 2006, 55(3): 633-639. DOI: 10.2337/diabetes.55.03.06.db05-1349.
26.	Zhao M, Valamanesh F, Celerier I, et al. The neuroretina is a novel mineralocorticoid target: aldosterone up-regulates ion and water channels in Müller glial cells[J]. FASEB J, 2010, 24(9): 3405-3415. DOI: 10.1096/fj.09-154344.
27.	Ponnalagu M, Subramani M, Jayadev C, et al. Retinal pigment epithelium-secretome: a diabetic retinopathy perspective[J]. Cytokine, 2017, 95: 126-135. DOI: 10.1016/j.cyto.2017.02.013.
28.	Wang JJ, Zhu M, Le YZ. Functions of Müller cell-derived vascular endothelial growth factor in diabetic retinopathy[J]. World J Diabetes, 2015, 6(5): 726-733. DOI: 10.4239/wjd.v6.i5.726.
29.	Wang J, Xu X, Elliott MH, et al. Müller cell-derived VEGF is essential for diabetes-induced retinal inflammation and vascular leakage[J]. Diabetes, 2010, 59(9): 2297-2305. DOI: 10.2337/db09-1420.
30.	Obert E, Strauss R, Brandon C, et al. Targeting the tight junction protein, zonula occludens-1, with the connexin43 mimetic peptide, αCT1, reduces VEGF-dependent RPE pathophysiology[J]. J Mol Med (Berl), 2017, 95(5): 535-552. DOI: 10.1007/s00109-017-1506-8.
31.	Rodrigues M, Xin X, Jee K, et al. VEGF secreted by hypoxic Müller cells induces MMP-2 expression and activity in endothelial cells to promote retinal neovascularization in proliferative diabetic retinopathy[J]. Diabetes, 2013, 62(11): 3863-3873. DOI: 10.2337/db13-0014.
32.	Mohammad G, Kowluru RA. Matrix metalloproteinase-2 in the development of diabetic retinopathy and mitochondrial dysfunction[J]. Lab Invest, 2010, 90(9): 1365-1372. DOI: 10.1038/labinvest.2010.89.
33.	Kowluru RA, Zhong Q, Santos JM. Matrix metalloproteinases in diabetic retinopathy: potential role of MMP-9[J]. Expert Opin Investig Drugs, 2012, 21(6): 797-805. DOI: 10.1517/13543784.2012.681043.
34.	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.
35.	王海青, 牛国桢, 张晓波, 等. RPE细胞的正常功能及其在眼科疾病中的作用[J]. 生命科学, 2013, 25(9): 878-885.Wang HQ, Niu GZ, Zhang XB, et al. The normal functions of RPE cell and its roles in eye disease[J]. Chinese Bulletin of Life Sciences, 2013, 25(9): 878-885.
36.	Tababat-Khani P, Berglund LM, Agardh CD, et al. Photocoagulation of human retinal pigment epithelial cells in vitro: evaluation of necrosis, apoptosis, cell migration, cell proliferation and expression of tissue repairing and cytoprotective genes[J/OL]. PLoS One, 2013, 8(8): e70465[2013-08-01]. https://pubmed.ncbi.nlm.nih.gov/23936435/. DOI: 10.1371/journal.pone.0070465.
37.	Inagaki K, Shuo T, Katakura K, et al. Sublethal photothermal stimulation with a micropulse laser induces heat shock protein expression in ARPE-19 cells[J/OL]. J Ophthalmol, 2015, 2015: 729792[2015-11-30]. https://pubmed.ncbi.nlm.nih.gov/26697211/. DOI: 10.1155/2015/729792.
38.	Ji Cho M, Yoon SJ, Kim W, et al. Oxidative stress-mediated TXNIP loss causes RPE dysfunction[J]. Exp Mol Med, 2019, 51(10): 1-13. DOI: 10.1038/s12276-019-0327-y.
39.	Zhang SX, Wang JJ, Gao G, et al. Pigment epithelium-derived factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF-VEGF receptor 2 binding in diabetic retinopathy[J]. J Mol Endocrinol, 2006, 37(1): 1-12. DOI: 10.1677/jme.1.02008.
40.	Li Z, Song Y, Chen X, et al. Biological modulation of mouse RPE cells in response to subthreshold diode micropulse laser treatment[J]. Cell Biochem Biophys, 2015, 73(2): 545-552. DOI: 10.1007/s12013-015-0675-8.
41.	García-Ramírez M, Hernández C, Simó R. Expression of erythropoietin and its receptor in the human retina: a comparative study of diabetic and nondiabetic subjects[J]. Diabetes Care, 2008, 31(6): 1189-1194. DOI: 10.2337/dc07-2075.
42.	Midena E, Bini S, Frizziero L, et al. Aqueous humour concentrations of PEDF and erythropoietin are not influenced by subthreshold micropulse laser treatment of diabetic macular edema[J/OL]. Biosci Rep, 2019, 39(6): BSR20190328[2019-06-18]. https://pubmed.ncbi.nlm.nih.gov/31138761/. DOI: 10.1042/bsr20190328.
43.	Garcia-Ramírez M, Hernández C, Ruiz-Meana M, et al. Erythropoietin protects retinal pigment epithelial cells against the increase of permeability induced by diabetic conditions: essential role of JAK2/ PI3K signaling[J]. Cell Signal, 2011, 23(10): 1596-1602. DOI: 10.1016/j.cellsig.2011.05.011.
44.	García-Arumí J, Fonollosa A, Macià C, et al. Vitreous levels of erythropoietin in patients with macular oedema secondary to retinal vein occlusions: a comparative study with diabetic macular oedema[J]. Eye (Lond), 2009, 23(5): 1066-1071. DOI: 10.1038/eye.2008.230.
45.	Mitsuhashi J, Morikawa S, Shimizu K, et al. Intravitreal injection of erythropoietin protects against retinal vascular regression at the early stage of diabetic retinopathy in streptozotocin-induced diabetic rats[J]. Exp Eye Res, 2013, 106: 64-73. DOI: 10.1016/j.exer.2012.11.001.
46.	Yenari MA, Liu J, Zheng Z, et al. Antiapoptotic and anti-inflammatory mechanisms of heat-shock protein protection[J]. Ann N Y Acad Sci, 2005, 1053: 74-83. DOI: 10.1196/annals.1344.007.
47.	Luttrull JK, Chang DB, Margolis BW, et al. Laser resensitization of medically unresponsive neovascular age-related macular degeneration: efficacy and implications[J]. Retina, 2015, 35(6): 1184-1194. DOI: 10.1097/iae.0000000000000458.
48.	Sramek C, Mackanos M, Spitler R, et al. Non-damaging retinal phototherapy: dynamic range of heat shock protein expression[J]. Invest Ophthalmol Vis Sci, 2011, 52(3): 1780-1787. DOI: 10.1167/iovs.10-5917.

1. Su D, Hubschman JP. A review of subthreshold micropulse laser and recent advances in retinal laser technology[J]. Ophthalmol Ther, 2017, 6(1): 1-6. DOI: 10.1007/s40123-017-0077-7.
2. Scholz P, Altay L, Fauser S. A review of subthreshold micropulse laser for treatment of macular disorders[J]. Adv Ther, 2017, 34(7): 1528-1555. DOI: 10.1007/s12325-017-0559-y.
3. Luttrull JK, Dorin G. Subthreshold diode micropulse laser photocoagulation (SDM) as invisible retinal phototherapy for diabetic macular edema: a review[J]. Curr Diabetes Rev, 2012, 8(4): 274-284. DOI: 10.2174/157339912800840523.
4. Ambiya V, Goud A, Mathai A, et al. Microsecond yellow laser for subfoveal leaks in central serous chorioretinopathy[J]. Clin Ophthalmol, 2016, 10: 1513-1519. DOI: 10.2147/opth.S112431.
5. Inagaki K, Ohkoshi K, Ohde S, et al. Subthreshold micropulse photocoagulation for persistent macular edema secondary to branch retinal vein occlusion including best-corrected visual acuity greater than 20/40[J/OL]. J Ophthalmol, 2014, 2014: 251257[2014-09-04]. https://pubmed.ncbi.nlm.nih.gov/25276413/. DOI: 10.1155/2014/251257.
6. Yadav NK, Jayadev C, Mohan A, et al. Subthreshold micropulse yellow laser (577 nm) in chronic central serous chorioretinopathy: safety profile and treatment outcome[J]. Eye (Lond), 2015, 29(2): 258-264. DOI: 10.1038/eye.2014.315.
7. Chen G, Tzekov R, Li W, et al. Subthreshold micropulse diode laser versus conventional laser photocoagulation for diabetic macular edema: a meta-analysis of randomized controlled trials[J]. Retina, 2016, 36(11): 2059-2065. DOI: 10.1097/iae.0000000000001053.
8. Simó R, Hernández C, European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR). Neurodegeneration in the diabetic eye: new insights and therapeutic perspectives[J]. Trends Endocrinol Metab, 2014, 25(1): 23-33. DOI: 10.1016/j.tem.2013.09.005.
9. Chhablani J, Roh YJ, Jobling AI, et al. Restorative retinal laser therapy: present state and future directions[J]. Surv Ophthalmol, 2018, 63(3): 307-328. DOI: 10.1016/j.survophthal.2017.09.008.
10. Midena E, Bini S. Multimodal retinal imaging of diabetic macular edema: toward new paradigms of pathophysiology[J]. Graefe's Arch Clin Exp Ophthalmol, 2016, 254(9): 1661-1668. DOI: 10.1007/s00417-016-3361-7.
11. Midena E, Pilotto E. Emerging insights into pathogenesis[J]. Dev Ophthalmol, 2017, 60: 16-27. DOI: 10.1159/000459687.
12. Grigsby JG, Cardona SM, Pouw CE, et al. The role of microglia in diabetic retinopathy[J/OL]. J Ophthalmol, 2014, 2014: 705783[2014-08-31]. https://pubmed.ncbi.nlm.nih.gov/25258680/. DOI: 10.1155/2014/705783.
13. Bringmann A, Wiedemann P. Müller glial cells in retinal disease[J]. Ophthalmologica, 2012, 227(1): 1-19. DOI: 10.1159/000328979.
14. Telegina DV, Kozhevnikova OS, Kolosova NG. Changes in retinal glial cells with age and during development of age-related macular degeneration[J]. Biochemistry (Mosc), 2018, 83(9): 1009-1017. DOI: 10.1134/s000629791809002x.
15. Li L, Eter N, Heiduschka P. The microglia in healthy and diseased retina[J]. Exp Eye Res, 2015, 136: 116-130. DOI: 10.1016/j.exer.2015.04.020.
16. Midena E, Micera A, Frizziero L, et al. Sub-threshold micropulse laser treatment reduces inflammatory biomarkers in aqueous humour of diabetic patients with macular edema[J/OL]. Sci Rep, 2019, 9(1): 10034[2019-07-11]. https://pubmed.ncbi.nlm.nih.gov/31296907/. DOI 10.1038/s41598-019-46515-y.
17. Bringmann A, Pannicke T, Grosche J, et al. Müller cells in the healthy and diseased retina[J]. Prog Retin Eye Res, 2006, 25(4): 397-424. DOI: 10.1016/j.preteyeres.2006.05.003.
18. Midena E, Bini S, Martini F, et al. Changes of aqueous humor Müller cells' biomarkers in human patients affected by diabetic macular edema after subthreshold micropulse laser treament[J]. Retina, 2020, 40(1): 126-134. DOI: 10.1097/iae.0000000000002356.
19. Vujosevic S, Midena E. Retinal layers changes in human preclinical and early clinical diabetic retinopathy support early retinal neuronal and Müller cells alterations[J/OL]. J Diabetes Res, 2013, 2013: 905058[2013-06-12]. https://pubmed.ncbi.nlm.nih.gov/23841106/. DOI: 10.1155/2013/905058.
20. Rungger-Brändle E, Dosso AA, Leuenberger PM. Glial reactivity, an early feature of diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2000, 41(7): 1971-1980.
21. Sarthy V. Focus on molecules: glial fibrillary acidic protein (GFAP)[J]. Exp Eye Res, 2007, 84(3): 381-382. DOI: 10.1016/j.exer.2005.12.014.
22. Hibino H, Inanobe A, Furutani K, et al. Inwardly rectifying potassium channels: their structure, function, and physiological roles[J]. Physiol Rev, 2010, 90(1): 291-366. DOI: 10.1152/physrev.00021.2009.
23. Zhang Y, Xu G, Ling Q, et al. Expression of aquaporin 4 and Kir4.1 in diabetic rat retina: treatment with minocycline[J]. J Int Med Res, 2011, 39(2): 464-479. DOI: 10.1177/147323001103900214.
24. Coughlin BA, Feenstra DJ, Mohr S. Müller cells and diabetic retinopathy[J]. Vision Res, 2017, 139: 93-100. DOI: 10.1016/j.visres.2017.03.013.
25. Pannicke T, Iandiev I, Wurm A, et al. Diabetes alters osmotic swelling characteristics and membrane conductance of glial cells in rat retina[J]. Diabetes, 2006, 55(3): 633-639. DOI: 10.2337/diabetes.55.03.06.db05-1349.
26. Zhao M, Valamanesh F, Celerier I, et al. The neuroretina is a novel mineralocorticoid target: aldosterone up-regulates ion and water channels in Müller glial cells[J]. FASEB J, 2010, 24(9): 3405-3415. DOI: 10.1096/fj.09-154344.
27. Ponnalagu M, Subramani M, Jayadev C, et al. Retinal pigment epithelium-secretome: a diabetic retinopathy perspective[J]. Cytokine, 2017, 95: 126-135. DOI: 10.1016/j.cyto.2017.02.013.
28. Wang JJ, Zhu M, Le YZ. Functions of Müller cell-derived vascular endothelial growth factor in diabetic retinopathy[J]. World J Diabetes, 2015, 6(5): 726-733. DOI: 10.4239/wjd.v6.i5.726.
29. Wang J, Xu X, Elliott MH, et al. Müller cell-derived VEGF is essential for diabetes-induced retinal inflammation and vascular leakage[J]. Diabetes, 2010, 59(9): 2297-2305. DOI: 10.2337/db09-1420.
30. Obert E, Strauss R, Brandon C, et al. Targeting the tight junction protein, zonula occludens-1, with the connexin43 mimetic peptide, αCT1, reduces VEGF-dependent RPE pathophysiology[J]. J Mol Med (Berl), 2017, 95(5): 535-552. DOI: 10.1007/s00109-017-1506-8.
31. Rodrigues M, Xin X, Jee K, et al. VEGF secreted by hypoxic Müller cells induces MMP-2 expression and activity in endothelial cells to promote retinal neovascularization in proliferative diabetic retinopathy[J]. Diabetes, 2013, 62(11): 3863-3873. DOI: 10.2337/db13-0014.
32. Mohammad G, Kowluru RA. Matrix metalloproteinase-2 in the development of diabetic retinopathy and mitochondrial dysfunction[J]. Lab Invest, 2010, 90(9): 1365-1372. DOI: 10.1038/labinvest.2010.89.
33. Kowluru RA, Zhong Q, Santos JM. Matrix metalloproteinases in diabetic retinopathy: potential role of MMP-9[J]. Expert Opin Investig Drugs, 2012, 21(6): 797-805. DOI: 10.1517/13543784.2012.681043.
34. 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.
35. 王海青, 牛国桢, 张晓波, 等. RPE细胞的正常功能及其在眼科疾病中的作用[J]. 生命科学, 2013, 25(9): 878-885.Wang HQ, Niu GZ, Zhang XB, et al. The normal functions of RPE cell and its roles in eye disease[J]. Chinese Bulletin of Life Sciences, 2013, 25(9): 878-885.
36. Tababat-Khani P, Berglund LM, Agardh CD, et al. Photocoagulation of human retinal pigment epithelial cells in vitro: evaluation of necrosis, apoptosis, cell migration, cell proliferation and expression of tissue repairing and cytoprotective genes[J/OL]. PLoS One, 2013, 8(8): e70465[2013-08-01]. https://pubmed.ncbi.nlm.nih.gov/23936435/. DOI: 10.1371/journal.pone.0070465.
37. Inagaki K, Shuo T, Katakura K, et al. Sublethal photothermal stimulation with a micropulse laser induces heat shock protein expression in ARPE-19 cells[J/OL]. J Ophthalmol, 2015, 2015: 729792[2015-11-30]. https://pubmed.ncbi.nlm.nih.gov/26697211/. DOI: 10.1155/2015/729792.
38. Ji Cho M, Yoon SJ, Kim W, et al. Oxidative stress-mediated TXNIP loss causes RPE dysfunction[J]. Exp Mol Med, 2019, 51(10): 1-13. DOI: 10.1038/s12276-019-0327-y.
39. Zhang SX, Wang JJ, Gao G, et al. Pigment epithelium-derived factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF-VEGF receptor 2 binding in diabetic retinopathy[J]. J Mol Endocrinol, 2006, 37(1): 1-12. DOI: 10.1677/jme.1.02008.
40. Li Z, Song Y, Chen X, et al. Biological modulation of mouse RPE cells in response to subthreshold diode micropulse laser treatment[J]. Cell Biochem Biophys, 2015, 73(2): 545-552. DOI: 10.1007/s12013-015-0675-8.
41. García-Ramírez M, Hernández C, Simó R. Expression of erythropoietin and its receptor in the human retina: a comparative study of diabetic and nondiabetic subjects[J]. Diabetes Care, 2008, 31(6): 1189-1194. DOI: 10.2337/dc07-2075.
42. Midena E, Bini S, Frizziero L, et al. Aqueous humour concentrations of PEDF and erythropoietin are not influenced by subthreshold micropulse laser treatment of diabetic macular edema[J/OL]. Biosci Rep, 2019, 39(6): BSR20190328[2019-06-18]. https://pubmed.ncbi.nlm.nih.gov/31138761/. DOI: 10.1042/bsr20190328.
43. Garcia-Ramírez M, Hernández C, Ruiz-Meana M, et al. Erythropoietin protects retinal pigment epithelial cells against the increase of permeability induced by diabetic conditions: essential role of JAK2/ PI3K signaling[J]. Cell Signal, 2011, 23(10): 1596-1602. DOI: 10.1016/j.cellsig.2011.05.011.
44. García-Arumí J, Fonollosa A, Macià C, et al. Vitreous levels of erythropoietin in patients with macular oedema secondary to retinal vein occlusions: a comparative study with diabetic macular oedema[J]. Eye (Lond), 2009, 23(5): 1066-1071. DOI: 10.1038/eye.2008.230.
45. Mitsuhashi J, Morikawa S, Shimizu K, et al. Intravitreal injection of erythropoietin protects against retinal vascular regression at the early stage of diabetic retinopathy in streptozotocin-induced diabetic rats[J]. Exp Eye Res, 2013, 106: 64-73. DOI: 10.1016/j.exer.2012.11.001.
46. Yenari MA, Liu J, Zheng Z, et al. Antiapoptotic and anti-inflammatory mechanisms of heat-shock protein protection[J]. Ann N Y Acad Sci, 2005, 1053: 74-83. DOI: 10.1196/annals.1344.007.
47. Luttrull JK, Chang DB, Margolis BW, et al. Laser resensitization of medically unresponsive neovascular age-related macular degeneration: efficacy and implications[J]. Retina, 2015, 35(6): 1184-1194. DOI: 10.1097/iae.0000000000000458.
48. Sramek C, Mackanos M, Spitler R, et al. Non-damaging retinal phototherapy: dynamic range of heat shock protein expression[J]. Invest Ophthalmol Vis Sci, 2011, 52(3): 1780-1787. DOI: 10.1167/iovs.10-5917.

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