Changes and correlation analysis of cytokines in aqueous humor before and after intravitreal injection of conbercept treatment in patients with proliferative diabetic retinopathy_Chinese Journal of Ocular Fundus Diseases

Authors：

Zeng Xiaoting ^1,2 , Teng Yue ¹ ,  Yu Xiaoyi ¹ , Guan Guohua ¹

1. Department of Ophthalmology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China;
2. Department of Ophthalmology, Guangdong Provincial Second Hospital of Traditional Chinese Medicine, Guangzhou 510095, China;

Corresponding author：

Yu Xiaoyi, Email: gzdryxy@163.com

Keywords：

Diabetic retinopathy; Vascular endothelial growth factors; Angiogenesis inhibitors; Aqueous humor; Cytokines

DOI：

10.3760/cma.j.cn511434-20200428-00186

Video：

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Objective To study the changes and correlation of cytokines in aqueous humor before and after intravitreal injection of conbercept (IVC) treatment in patients with proliferative diabetic retinopathy (PDR).Methods A prospective clinical study. From March to December 2019, 36 patients (42 eyes) of PDR patients treated with IVC combined with pars plana vitrectomy (PPV) (the observation group) and 27 patients (31 eyes) underwent cataract surgery in the same period (control group) in Department of Ophthalmology of the First Affiliated Hospital of Guangzhou University of Chinese Medicine were included in this study. Before PPV 5-7 days, IVC treatment was performed, and the aqueous humor were extracted during IVC and second-stage PPV in the observation group. The aqueous humor was extracted during cataract surgery in the control group. Luminex assay was used to detect VEGF-A, placental growth factor (PLGF), platelet-derived growth factor-AA (PDGF-AA), platelet-derived growth factor-BB (PDGF-BB), angiopoietin-like protein 4 (ANGPTL4), IL-6, IL-8, IL-1β, monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α) cytokine expression. For normally distributed data, the independent sample t test was used for comparison between two independent samples; for non-normally distributed data, the Wilcoxon rank sum test was used for comparison between two independent samples. The correlation analysis used Spearman rank correlation test.Results Before IVC treatment, the concentrations of VEGF-A, PLGF, PDGF-AA, ANGPTL4, IL-6, IL-8, MCP-1 and ICAM-1 in the aqueous humor of PDR patients were significantly higher than those in the control group (P＜0.05). After IVC treatment, the concentration of VEGF-A in the aqueous humor was significantly lower than that before treatment, and the concentrations of ANGPTL4 and IL-8 were significantly higher than those before treatment (P＜0.05). There were no significant differences in the concentrations of PLGF, PDGF-AA, PDGF-BB, IL-6, IL-1β, MCP-1, ICAM-1 and TNF-α before and after IVC treatment (P＞0.05). Before IVC treatment, the concentration of VEGF-A was positively correlated with PLGF, PDGF-AA, PDGF-BB, ANGPTL4, IL-6, IL-8, MCP-1 and TNF-α (P＜0.05).Conclusions IVC treatment can reduce the concentration of VEGF-A and increase the concentrations of ANGPTL4 and IL-8 in aqueous humor in PDR patients before PPV.

Citation： Zeng Xiaoting, Teng Yue, Yu Xiaoyi, Guan Guohua. Changes and correlation analysis of cytokines in aqueous humor before and after intravitreal injection of conbercept treatment in patients with proliferative diabetic retinopathy. Chinese Journal of Ocular Fundus Diseases, 2020, 36(12): 948-953. doi: 10.3760/cma.j.cn511434-20200428-00186 Copy

1.	Adamis AP. Is diabetic retinopathy an inflammatory disease?[J]. Br J Ophthalmol, 2002, 86(4): 363-365. DOI: 10.1136/bjo.86.4.363.
2.	马燕. 炎症反应和炎性因子与糖尿病视网膜病变的研究进展[J]. 中华实验眼科杂志, 2013, 31(1): 86-90. DOI: 10.3760/cma.j.issn.2095-0160.2013.01.021.Ma Y. Research advance in the relationship of inflammatory reaction and inflammatory factor with diabetic retinopathy[J]. Chin J Exp Ophthalmol, 2013, 31(1): 86-90. DOI: 10.3760/cma.j.issn.2095-0160.2013.01.021.
3.	温德佳, 任新军, 郑传珍, 等. 玻璃体液中细胞因子表达水平与糖尿病视网膜病变发病关系的研究进展[J]. 中华眼底病杂志, 2020, 36(2): 151-155. DOI: 10.3760/cma.j.issn.1005-1015.2020.02.016.Wen DJ, Ren XJ, Zheng CZ, et al. Research progress of cytokines in vitreous of diabetic retinopathy[J]. Chin J Ocul Fundus Dis, 2020, 36(2): 151-155. DOI: 10.3760/cma.j.issn.1005-1015.2020.02.016.
4.	陈小红, 陈梅珠, 王云鹏. 增生型糖尿病视网膜病变患眼玻璃体腔注射雷珠单抗治疗前后房水血管内皮生长因子和色素上皮衍生因子的浓度变化[J]. 中华眼底病杂志, 2015, 31(6): 560-563. DOI: 10.3760/cma.j.issn.1005-1015.2015.06.012.Chen XH, Chen MZ, Wang YP. Quantitative analysis of vascular endothelial growth factor and pigment epithelium-derived factor in aqueous humor before and after intravitreal injection of ranibizumab in proliferative diabetic retinopathy[J]. Chin J Ocul Fundus Dis, 2015, 31(6): 560-563. DOI: 10.3760/cma.j.issn.1005-1015.2015.06.012.
5.	王友, 邓铂林, 黄健, 等. 玻璃体腔注射雷珠单抗治疗严重增生型糖尿病视网膜病变后玻璃体细胞因子的变化[J]. 中华眼底病杂志, 2014, 30(5): 484-487. DOI: 10.3760/cma.j.issn.1005-1015.2014.05.014.Wang Y, Deng BL, Huang J, et al. Concentration of the inflammatory cytokines in vitreous of severe proliferative diabetic retinopathy after intravitreal ranibizumab injection[J]. Chin J Ocul Fundus Dis, 2014, 30(5): 484-487. DOI: 10.3760/cma.j.issn.1005-1015.2014.05.014.
6.	严励. 糖尿病[M]//葛均波. 内科学. 8版. 北京: 人民卫生出版社, 2013: 741-742.Yan L. Diabetes[M]//Ge JB. Internal medicine. 8th ed. Beijing: People's Medical Publishing House, 2013: 741-742.
7.	马景学. 糖尿病性视网膜病变[M]//赵堪兴. 眼科学. 8版. 北京: 人民卫生出版社, 2013: 217-219.Ma JX. Diabetic retinopathy[M]//Zhao KX. Ophthalmology. 8th ed. Beijing: People's Medical Publishing House, 2013: 217-219.
8.	中华医学会眼科学会眼底病学组. 我国糖尿病视网膜病变临床诊疗指南(2014年)[J]. 中华眼科杂志, 2014, 50(11): 851-865. DOI: 10.3760/cma.j.issn.0412-4081.2014.11.014.Fundus Disease Group of Ophthalmology Association of Chinese Medical Association. Guidelines for clinical diagnosis and treatment of diabetic retinopathy in China (2014)[J]. Chin J Ophthalmol, 2014, 50(11): 851-865. DOI: 10.3760/cma.j.issn.0412-4081.2014.11.014.
9.	Affleck DG, Bull DA, Bailey SH, et al. PDGF(BB) increases myocardial production of VEGF: shift in VEGF mRNA splice variants after direct injection of bFGF, PDGF(BB), and PDGF(AB)[J]. J Surg Res, 2002, 107(2): 203-209. DOI: 10.1006/jsre.2002.6510.
10.	Cohen T, Nahari D, Cerem LW, et al. Interleukin 6 induces the expression of vascular endothelial growth factor[J]. J Biol Chem, 1996, 271(2): 736-741. DOI: 10.1074/jbc.271.2.736.
11.	Marumo T, Schini-Kerth VB, Busse R. Vascular endothelial growth factor activates nuclear factor-kappaB and induces monocyte chemoattractant protein-1 in bovine retinal endothelial cells[J]. Diabetes, 1999, 48(5): 1131-1137. DOI: 10.2337/diabetes.48.5.1131.
12.	Li H, Lei N, Zhang M, et al. Pharmacokinetics of a long-lasting anti-VEGF fusion protein in rabbit[J]. Exp Eye Res, 2012, 97(1): 154-159. DOI: 10.1016/j.exer.2011.09.002.
13.	Semeraro F, Cancarini A, Morescalchi F, et al. Serum and intraocular concentrations of erythropoietin and vascular endothelial growth factor in patients with type 2 diabetes and proliferative retinopathy[J]. Diabetes Metab, 2014, 40(6): 445-451. DOI: 10.1016/j.diabet.2014.04.005.
14.	Behl T, Kotwani A. Exploring the various aspects of the pathological role of vascular endothelial growth factor (VEGF) in diabetic retinopathy[J]. Pharmacol Res, 2015, 99: 137-148. DOI: 10.1016/j.phrs.2015.05.013.
15.	Klaassen I, de Vries EW, Vogels IMC, et al. Identification of proteins associated with clinical and pathological features of proliferative diabetic retinopathy in vitreous and fibrovascular membranes[J/OL]. PLoS One, 2017, 12(11):e187304[2017-11-02]. https://doi.org/10.1371/journal.pone.0187304. DOI: 10.1371/journal.pone.0187304.
16.	Van Bergen T, Hu TT, Etienne I, et al. Neutralization of placental growth factor as a novel treatment option in diabetic retinopathy[J]. Exp Eye Res, 2017, 165: 136-150. DOI: 10.1016/j.exer.2017.09.012.
17.	Zhang X, Wu J, Wu C, et al. Comparison of aqueous humor levels of PlGF and VEGF in proliferative diabetic retinopathy before and after intravitreal conbercept injection[J/OL]. Diabetes Res Clin Pract, 2020, 162: 108083[2020-02-11]. https://pubmed.ncbi.nlm.nih.gov/27586653/. DOI: 10.1016/j.diabres.2020.108083.
18.	Ishii Y, Hamashima T, Yamamoto S, et al. Pathogenetic significance and possibility as a therapeutic target of platelet derived growth factor[J]. Pathol Int, 2017, 67(5): 235-246. DOI: 10.1111/pin.12530.
19.	Mori K, Gehlbach P, Ando A, et al. Retina-specific expression of PDGF-B versus PDGF-A: vascular versus nonvascular proliferative retinopathy[J]. Invest Ophthalmol Vis Sci, 2002, 43(6): 2001-2006.
20.	Yu SY, Nam DH, Lee DY. Changes in aqueous concentrations of various cytokines after intravitreal bevacizumab and subtenon triamcinolone injection for diabetic macular edema[J]. Graefe's Arch Clin Exp Ophthalmol, 2018, 256(1): 39-47. DOI: 10.1007/s00417-017-3819-2.
21.	Praidou A, Papakonstantinou E, Androudi S, et al. 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[J]. Acta Ophthalmol, 2011, 89(3): 248-254. DOI: 10.1111/j.1755-3768.2009.01661.x.
22.	Yang X, Cheng Y, Su G. A review of the multifunctionality of angiopoietin-like 4 in eye disease[J/OL]. Biosci Rep, 2018, 38(5): BSR20180557[2018-09-14]. https://doi.org/10.1042/BSR20180557. DOI: 10.1042/BSR20180557.
23.	Yokouchi H, Eto K, Nishimura W, et al. Angiopoietin-like protein 4(ANGPTL4) is induced by high glucose in retinal pigment epithelial cells and exhibits potent angiogenic activity on retinal endothelial cells[J/OL]. Acta Ophthalmol, 2013, 91(4): e289-297[2013-02-07]. https://doi.org/10.1111/aos.12097. DOI: 10.1111/aos.12097.
24.	Kim JH, Shin JP, Kim IT, et al. Angiopoietin-like 4 correlates with response to intravitreal ranibizumab injections in neovascular age-related macular degeneration[J]. Retina, 2018, 38(3): 523-530. DOI: 10.1097/IAE.0000000000001554.
25.	Babapoor-Farrokhran S, Jee K, Puchner B, et al. Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy[J/OL]. Proc Natl Acad Sci USA, 2015, 112(23): e3030-3039[2015-05-26]. https://doi.org/10.1073/pnas.1423765112. DOI: 10.1073/pnas.1423765112.
26.	Higgins GT, Wang JH, Dockery P, et al. Induction of angiogenic cytokine expression in cultured RPE by ingestion of oxidized photoreceptor outer segments[J]. Invest Ophthalmol Vis Sci, 2003, 44(4): 1775-1782. DOI: 10.1167/iovs.02-0742.
27.	Harada C, Harada T, Mitamura Y, et al. Diverse NF-kappaB expression in epiretinal membranes after human diabetic retinopathy and proliferative vitreoretinopathy[J]. Mol Vis, 2004, 10: 31-36.
28.	Forooghian F, Kertes PJ, Eng KT, et al. Alterations in the intraocular cytokine milieu after intravitreal bevacizumab[J]. Invest Ophthalmol Vis Sci, 2010, 51(5): 2388-2392. DOI: 10.1167/iovs.09-4065.
29.	Futakuchi A, Inoue T, Wei FY, et al. YAP/TAZ are essential for TGF-β2-mediated conjunctival fibrosis[J]. Invest Ophthalmol Vis Sci, 2018, 59(7): 3069-3078. DOI: 10.1167/iovs.18-24258.
30.	Casanovas O, Hicklin DJ, Bergers G, et al. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors[J]. Cancer Cell, 2005, 8(4): 299-309. DOI: 10.1016/j.ccr.2005.09.005.
31.	Tam BY, Wei K, Rudge JS, et al. VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis[J]. Nat Med, 2006, 12(7): 793-800. DOI: 10.1038/nm1428.
32.	Ellis LM, Hicklin DJ. Pathways mediating resistance to vascular endothelial growth factor-targeted therapy[J]. Clin Cancer Res, 2008, 14(20): 6371-6375. DOI: 10.1158/1078-0432.CCR-07-5287.
33.	Carmeliet P. Angiogenesis in life, disease and medicine[J]. Nature, 2005, 438(7070): 932-936. DOI: 10.1038/nature04478.
34.	Jeon S, Lee WK. Intravitreal bevacizumab increases intraocular interleukin-6 levels at 1 day after injection in patients with proliferative diabetic retinopathy[J]. Cytokine, 2012, 60(2): 535-539. DOI: 10.1016/j.cyto.2012.07.005.
35.	Hombrebueno JR, Ali IH, Xu H, et al. Sustained intraocular VEGF neutralization results in retinal neurodegeneration in the Ins2(Akita) diabetic mouse[J/OL]. Sci Rep, 2015, 5: 18316[2015-12-16]. https://www.nature.com/articles/srep18316. DOI: 10.1038/srep18316.
36.	Fong DS, Aiello L, Gardner TW, et al. Retinopathy in diabetes[J]. Diabetes Care, 2004, 27(Suppl 1): S84-87. DOI: 10.2337/diacare.27.2007.s84.

1. Adamis AP. Is diabetic retinopathy an inflammatory disease?[J]. Br J Ophthalmol, 2002, 86(4): 363-365. DOI: 10.1136/bjo.86.4.363.
2. 马燕. 炎症反应和炎性因子与糖尿病视网膜病变的研究进展[J]. 中华实验眼科杂志, 2013, 31(1): 86-90. DOI: 10.3760/cma.j.issn.2095-0160.2013.01.021.Ma Y. Research advance in the relationship of inflammatory reaction and inflammatory factor with diabetic retinopathy[J]. Chin J Exp Ophthalmol, 2013, 31(1): 86-90. DOI: 10.3760/cma.j.issn.2095-0160.2013.01.021.
3. 温德佳, 任新军, 郑传珍, 等. 玻璃体液中细胞因子表达水平与糖尿病视网膜病变发病关系的研究进展[J]. 中华眼底病杂志, 2020, 36(2): 151-155. DOI: 10.3760/cma.j.issn.1005-1015.2020.02.016.Wen DJ, Ren XJ, Zheng CZ, et al. Research progress of cytokines in vitreous of diabetic retinopathy[J]. Chin J Ocul Fundus Dis, 2020, 36(2): 151-155. DOI: 10.3760/cma.j.issn.1005-1015.2020.02.016.
4. 陈小红, 陈梅珠, 王云鹏. 增生型糖尿病视网膜病变患眼玻璃体腔注射雷珠单抗治疗前后房水血管内皮生长因子和色素上皮衍生因子的浓度变化[J]. 中华眼底病杂志, 2015, 31(6): 560-563. DOI: 10.3760/cma.j.issn.1005-1015.2015.06.012.Chen XH, Chen MZ, Wang YP. Quantitative analysis of vascular endothelial growth factor and pigment epithelium-derived factor in aqueous humor before and after intravitreal injection of ranibizumab in proliferative diabetic retinopathy[J]. Chin J Ocul Fundus Dis, 2015, 31(6): 560-563. DOI: 10.3760/cma.j.issn.1005-1015.2015.06.012.
5. 王友, 邓铂林, 黄健, 等. 玻璃体腔注射雷珠单抗治疗严重增生型糖尿病视网膜病变后玻璃体细胞因子的变化[J]. 中华眼底病杂志, 2014, 30(5): 484-487. DOI: 10.3760/cma.j.issn.1005-1015.2014.05.014.Wang Y, Deng BL, Huang J, et al. Concentration of the inflammatory cytokines in vitreous of severe proliferative diabetic retinopathy after intravitreal ranibizumab injection[J]. Chin J Ocul Fundus Dis, 2014, 30(5): 484-487. DOI: 10.3760/cma.j.issn.1005-1015.2014.05.014.
6. 严励. 糖尿病[M]//葛均波. 内科学. 8版. 北京: 人民卫生出版社, 2013: 741-742.Yan L. Diabetes[M]//Ge JB. Internal medicine. 8th ed. Beijing: People's Medical Publishing House, 2013: 741-742.
7. 马景学. 糖尿病性视网膜病变[M]//赵堪兴. 眼科学. 8版. 北京: 人民卫生出版社, 2013: 217-219.Ma JX. Diabetic retinopathy[M]//Zhao KX. Ophthalmology. 8th ed. Beijing: People's Medical Publishing House, 2013: 217-219.
8. 中华医学会眼科学会眼底病学组. 我国糖尿病视网膜病变临床诊疗指南(2014年)[J]. 中华眼科杂志, 2014, 50(11): 851-865. DOI: 10.3760/cma.j.issn.0412-4081.2014.11.014.Fundus Disease Group of Ophthalmology Association of Chinese Medical Association. Guidelines for clinical diagnosis and treatment of diabetic retinopathy in China (2014)[J]. Chin J Ophthalmol, 2014, 50(11): 851-865. DOI: 10.3760/cma.j.issn.0412-4081.2014.11.014.
9. Affleck DG, Bull DA, Bailey SH, et al. PDGF(BB) increases myocardial production of VEGF: shift in VEGF mRNA splice variants after direct injection of bFGF, PDGF(BB), and PDGF(AB)[J]. J Surg Res, 2002, 107(2): 203-209. DOI: 10.1006/jsre.2002.6510.
10. Cohen T, Nahari D, Cerem LW, et al. Interleukin 6 induces the expression of vascular endothelial growth factor[J]. J Biol Chem, 1996, 271(2): 736-741. DOI: 10.1074/jbc.271.2.736.
11. Marumo T, Schini-Kerth VB, Busse R. Vascular endothelial growth factor activates nuclear factor-kappaB and induces monocyte chemoattractant protein-1 in bovine retinal endothelial cells[J]. Diabetes, 1999, 48(5): 1131-1137. DOI: 10.2337/diabetes.48.5.1131.
12. Li H, Lei N, Zhang M, et al. Pharmacokinetics of a long-lasting anti-VEGF fusion protein in rabbit[J]. Exp Eye Res, 2012, 97(1): 154-159. DOI: 10.1016/j.exer.2011.09.002.
13. Semeraro F, Cancarini A, Morescalchi F, et al. Serum and intraocular concentrations of erythropoietin and vascular endothelial growth factor in patients with type 2 diabetes and proliferative retinopathy[J]. Diabetes Metab, 2014, 40(6): 445-451. DOI: 10.1016/j.diabet.2014.04.005.
14. Behl T, Kotwani A. Exploring the various aspects of the pathological role of vascular endothelial growth factor (VEGF) in diabetic retinopathy[J]. Pharmacol Res, 2015, 99: 137-148. DOI: 10.1016/j.phrs.2015.05.013.
15. Klaassen I, de Vries EW, Vogels IMC, et al. Identification of proteins associated with clinical and pathological features of proliferative diabetic retinopathy in vitreous and fibrovascular membranes[J/OL]. PLoS One, 2017, 12(11):e187304[2017-11-02]. https://doi.org/10.1371/journal.pone.0187304. DOI: 10.1371/journal.pone.0187304.
16. Van Bergen T, Hu TT, Etienne I, et al. Neutralization of placental growth factor as a novel treatment option in diabetic retinopathy[J]. Exp Eye Res, 2017, 165: 136-150. DOI: 10.1016/j.exer.2017.09.012.
17. Zhang X, Wu J, Wu C, et al. Comparison of aqueous humor levels of PlGF and VEGF in proliferative diabetic retinopathy before and after intravitreal conbercept injection[J/OL]. Diabetes Res Clin Pract, 2020, 162: 108083[2020-02-11]. https://pubmed.ncbi.nlm.nih.gov/27586653/. DOI: 10.1016/j.diabres.2020.108083.
18. Ishii Y, Hamashima T, Yamamoto S, et al. Pathogenetic significance and possibility as a therapeutic target of platelet derived growth factor[J]. Pathol Int, 2017, 67(5): 235-246. DOI: 10.1111/pin.12530.
19. Mori K, Gehlbach P, Ando A, et al. Retina-specific expression of PDGF-B versus PDGF-A: vascular versus nonvascular proliferative retinopathy[J]. Invest Ophthalmol Vis Sci, 2002, 43(6): 2001-2006.
20. Yu SY, Nam DH, Lee DY. Changes in aqueous concentrations of various cytokines after intravitreal bevacizumab and subtenon triamcinolone injection for diabetic macular edema[J]. Graefe's Arch Clin Exp Ophthalmol, 2018, 256(1): 39-47. DOI: 10.1007/s00417-017-3819-2.
21. Praidou A, Papakonstantinou E, Androudi S, et al. 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[J]. Acta Ophthalmol, 2011, 89(3): 248-254. DOI: 10.1111/j.1755-3768.2009.01661.x.
22. Yang X, Cheng Y, Su G. A review of the multifunctionality of angiopoietin-like 4 in eye disease[J/OL]. Biosci Rep, 2018, 38(5): BSR20180557[2018-09-14]. https://doi.org/10.1042/BSR20180557. DOI: 10.1042/BSR20180557.
23. Yokouchi H, Eto K, Nishimura W, et al. Angiopoietin-like protein 4(ANGPTL4) is induced by high glucose in retinal pigment epithelial cells and exhibits potent angiogenic activity on retinal endothelial cells[J/OL]. Acta Ophthalmol, 2013, 91(4): e289-297[2013-02-07]. https://doi.org/10.1111/aos.12097. DOI: 10.1111/aos.12097.
24. Kim JH, Shin JP, Kim IT, et al. Angiopoietin-like 4 correlates with response to intravitreal ranibizumab injections in neovascular age-related macular degeneration[J]. Retina, 2018, 38(3): 523-530. DOI: 10.1097/IAE.0000000000001554.
25. Babapoor-Farrokhran S, Jee K, Puchner B, et al. Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy[J/OL]. Proc Natl Acad Sci USA, 2015, 112(23): e3030-3039[2015-05-26]. https://doi.org/10.1073/pnas.1423765112. DOI: 10.1073/pnas.1423765112.
26. Higgins GT, Wang JH, Dockery P, et al. Induction of angiogenic cytokine expression in cultured RPE by ingestion of oxidized photoreceptor outer segments[J]. Invest Ophthalmol Vis Sci, 2003, 44(4): 1775-1782. DOI: 10.1167/iovs.02-0742.
27. Harada C, Harada T, Mitamura Y, et al. Diverse NF-kappaB expression in epiretinal membranes after human diabetic retinopathy and proliferative vitreoretinopathy[J]. Mol Vis, 2004, 10: 31-36.
28. Forooghian F, Kertes PJ, Eng KT, et al. Alterations in the intraocular cytokine milieu after intravitreal bevacizumab[J]. Invest Ophthalmol Vis Sci, 2010, 51(5): 2388-2392. DOI: 10.1167/iovs.09-4065.
29. Futakuchi A, Inoue T, Wei FY, et al. YAP/TAZ are essential for TGF-β2-mediated conjunctival fibrosis[J]. Invest Ophthalmol Vis Sci, 2018, 59(7): 3069-3078. DOI: 10.1167/iovs.18-24258.
30. Casanovas O, Hicklin DJ, Bergers G, et al. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors[J]. Cancer Cell, 2005, 8(4): 299-309. DOI: 10.1016/j.ccr.2005.09.005.
31. Tam BY, Wei K, Rudge JS, et al. VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis[J]. Nat Med, 2006, 12(7): 793-800. DOI: 10.1038/nm1428.
32. Ellis LM, Hicklin DJ. Pathways mediating resistance to vascular endothelial growth factor-targeted therapy[J]. Clin Cancer Res, 2008, 14(20): 6371-6375. DOI: 10.1158/1078-0432.CCR-07-5287.
33. Carmeliet P. Angiogenesis in life, disease and medicine[J]. Nature, 2005, 438(7070): 932-936. DOI: 10.1038/nature04478.
34. Jeon S, Lee WK. Intravitreal bevacizumab increases intraocular interleukin-6 levels at 1 day after injection in patients with proliferative diabetic retinopathy[J]. Cytokine, 2012, 60(2): 535-539. DOI: 10.1016/j.cyto.2012.07.005.
35. Hombrebueno JR, Ali IH, Xu H, et al. Sustained intraocular VEGF neutralization results in retinal neurodegeneration in the Ins2(Akita) diabetic mouse[J/OL]. Sci Rep, 2015, 5: 18316[2015-12-16]. https://www.nature.com/articles/srep18316. DOI: 10.1038/srep18316.
36. Fong DS, Aiello L, Gardner TW, et al. Retinopathy in diabetes[J]. Diabetes Care, 2004, 27(Suppl 1): S84-87. DOI: 10.2337/diacare.27.2007.s84.

Chinese Journal of Ocular Fundus Diseases

Changes and correlation analysis of cytokines in aqueous humor before and after intravitreal injection of conbercept treatment in patients with proliferative diabetic retinopathy

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