Correlation of aqueous humor cytokine profiles with disorganization of retinal inner layers and postoperative visual acuity in idiopathic epiretinal membrane_Chinese Journal of Ocular Fundus Diseases

Authors：

Zhang Shian ^1,2 , Huo Yu ^1,3 , Gao Xinyu ^1,3 , Zhao Yu ^1,4 , Chen Huan ^1,2 , Yu Jiafeng ^1,2 , Wu Sulan ^1,2 , Chen Yiqi ^1,2 ,  Mao Jianbo ^1,2 , Shen Lijun ^1,2,3

1. Ophthalmology Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310000, China;
2. Zhejiang Key Laboratory of Precision Medicine for Eye Diseases, Hangzhou 310000, China;
3. Postgraduate Training Base, Wenzhou Medical University (Zhejiang Provincial People’s Hospital), Hangzhou 310000, China;
4. School of Public Health, Hangzhou Medical College, Hangzhou 310000, China;

Corresponding author：

Mao Jianbo, Email: rocket222@sina.com

Keywords：

Epiretinal membrane; Cytokine; Swept-source optical coherence tomography; Ectopic inner foveal layers; Disorganization of retinal inner layer

DOI：

10.3760/cma.j.cn511434-20250507-00203

Video：

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Objective To observe and analyze the correlations between aqueous humor cytokine concentrations and disorganization of retinal inner layers (DRIL), as well as postoperative visual acuity, in patients with idiopathic epiretinal membrane (iERM). Methods A prospective clinical study. From November 2022 to October 2024, 40 eyes of 40 patients diagnosed with iERM at Ophthalmology Center of Zhejiang Provincial People's Hospital (Affiliated People's Hospital) underwent cataract surgery alone or combined with pars plana vitrectomy (iERM group) were enrolled; 19 eyes of 19 patients undergoing cataract surgery alone during the same period served as the control group. All eyes underwent best-corrected visual acuity (BCVA) testing and swept-source optical coherence tomography (SS-OCT). BCVA was assessed using a logarithmic visual acuity chart and converted to the logarithm of the minimum angle of resolution (logMAR) for statistical analysis. Central macular thickness (CMT) was measured using SS-OCT. The iERM group was further subdivided into DRIL-positive and DRIL-negative subgroups (21 eyes and 19 eyes, respectively), based on the presence or absence of DRIL. Aqueous humor samples were collected preoperatively from eyes in both the iERM and control groups. Concentrations of transforming growth factor (TGF)-β1, TGF-β2, TGF-β3, platelet-derived growth factor (PDGF)-AB, hepatocyte growth factor (HGF), fibroblast growth factor (FGF), vascular endothelial growth factor-A (VEGF-A), placental growth factor (PLGF), glial cell line-derived neurotrophic factor (GDNF), intercellular adhesion molecule-1 (ICAM-1), angiopoietin (Ang)-1, Ang-2, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were measured. Follow-up examinations using the same equipment and methods were performed at 1 month postoperatively. Aqueous cytokine levels were compared between the iERM group, control group, DRIL-positive subgroup, and DRIL-negative subgroup. Correlations between aqueous cytokine levels in the iERM group and BCVA or CMT were also analyzed. Intergroup comparisons utilized the Mann-Whitney U test; correlations between variables were assessed using Spearman's rank correlation analysis. Results Compared to the control group, the iERM group exhibited significantly higher aqueous concentrations of TGF-β1, TGF-β3, PDGF-AB, PLGF, GDNF, ICAM-1, Ang-1, and TNF-α (P＜0.05). Compared to the DRIL-negative subgroup, the DRIL-positive subgroup showed significantly elevated aqueous concentrations of TGF-β3, PDGF-AB, PLGF, GDNF, ICAM-1, Ang-1, Ang-2, TNF-α, and IL-6 (P＜0.05). Significant differences were observed in logMAR BCVA (P= 0.028) and CMT (P＜0.001) within the iERM group between preoperative and 1-month postoperative measurements. LogMAR BCVA differed significantly between the DRIL-positive and DRIL-negative subgroups (P=0.048). Correlation analysis revealed that baseline aqueous levels of VEGF-A and IL-6 in eyes with DRIL were positively correlated with postoperative BCVA (r=0.324, 0.452; P=0.042, 0.003). No significant correlation was found between CMT and any cytokine (P＞0.05). Conclusions Aqueous humor cytokines are closely associated with DRIL in iERM patients. IL-6 and VEGF-A may serve as potential predictive biomarkers for early postoperative visual recovery.

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2.	Fung AT, Galvin J, Tran T. Epiretinal membrane: a review[J]. Clin Exp Ophthalmol, 2021, 49(3): 289-308. DOI: 10.1111/ceo.13914.
3.	Harada C, Mitamura Y, Harada T. The role of cytokines and trophic factors in epiretinal membranes: involvement of signal transduction in glial cells[J]. Prog Retin Eye Res, 2006, 25(2): 149-164. DOI: 10.1016/j.preteyeres.2005.09.001.
4.	Pilli S, Lim P, Zawadzki RJ, et al. Fourier-domain optical coherence tomography of eyes with idiopathic epiretinal membrane: correlation between macular morphology and visual function[J]. Eye (Lond), 2011, 25(6): 775-783. DOI: 10.1038/eye.2011.55.
5.	Myojin S, Yoshimura T, Yoshida S, et al. Gene expression analysis of the irrigation solution samples collected during vitrectomy for idiopathic epiretinal membrane[J/OL]. PLoS One, 2016, 11(10): e0164355[2016-10-13]. https://pubmed.ncbi.nlm.nih.gov/27736918/. DOI: 10.1371/journal.pone.0164355.
6.	Zandi S, Tappeiner C, Pfister IB, et al. Vitreal cytokine profile differences between eyes with epiretinal membranes or macular holes[J]. Invest Ophthalmol Vis Sci, 2016, 57(14): 6320-6326. DOI: 10.1167/iovs.16-20657.
7.	Mao J, Zhang C, Zhang S, et al. Predictors of anti-VEGF efficacy in chronic central serous chorioretinopathy based on intraocular cytokine levels and pigment epithelium detachment subtypes[J/OL]. Acta Ophthalmol, 2022, 100(7): e1385-e1394[2022-02-04]. https://pubmed.ncbi.nlm.nih.gov/35122421/. DOI: 10.1111/aos.15109.
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10.	Song P, Li P, Geng W, et al. Cytokines possibly involved in idiopathic epiretinal membrane progression after uncomplicated cataract surgery[J/OL]. Exp Eye Res, 2022, 217: 108957[2022-01-22]. https://pubmed.ncbi.nlm.nih.gov/35077755/. DOI: 10.1016/j.exer.2022.108957.
11.	Chen L, Zhang W, Xie P, et al. Comparisons of vitreal angiogenic, inflammatory, profibrotic cytokines, and chemokines profile between patients with epiretinal membrane and macular hole[J/OL]. J Ophthalmol, 2021, 2021: 9947250[2021-07-13]. https://pubmed.ncbi.nlm.nih.gov/34336263/. DOI: 10.1155/2021/9947250.
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13.	González-Saldivar G, Berger A, Wong D, et al. Ectopic inner foveal layer classification scheme predicts visual outcomes after epiretinal membrane surgery[J]. Retina, 2020, 40(4): 710-717. DOI: 10.1097/iae.0000000000002486.
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16.	Kanda A, Noda K, Hirose I, et al. TGF-β-SNAIL axis induces Müller glial-mesenchymal transition in the pathogenesis of idiopathic epiretinal membrane[J/OL]. Sci Rep, 2019, 9(1): 673[2019-01-24]. https://pubmed.ncbi.nlm.nih.gov/30679596/. DOI: 10.1038/s41598-018-36917-9.
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18.	Mirshahi A, Hoehn R, Lorenz K, et al. Anti-tumor necrosis factor alpha for retinal diseases: current knowledge and future concepts[J]. J Ophthalmic Vis Res, 2012, 7(1): 39-44.
19.	Harjunpää H, Llort Asens M, Guenther C, et al. Cell adhesion molecules and their roles and regulation in the immune and tumor microenvironment[J/OL]. Front Immunol, 2019, 10: 1078[2019-05-22]. https://pubmed.ncbi.nlm.nih.gov/31231358/. DOI: 10.3389/fimmu.2019.01078.
20.	Srejovic JV, Muric MD, Jakovljevic VL, et al. Molecular and cellular mechanisms involved in the pathophysiology of retinal vascular disease-interplay between inflammation and oxidative stress[J/OL]. Int J Mol Sci, 2024, 25(21): 11850[2024-11-04]. https://pubmed.ncbi.nlm.nih.gov/39519401/. DOI: 10.3390/ijms252111850.

1. Govetto A, Lalane RA 3rd, Sarraf D, et al. Insights into epiretinal membranes: presence of ectopic inner foveal layers and a new optical coherence tomography staging scheme[J]. Am J Ophthalmol, 2017, 175: 99-113. DOI: 10.1016/j.ajo.2016.12.006.
2. Fung AT, Galvin J, Tran T. Epiretinal membrane: a review[J]. Clin Exp Ophthalmol, 2021, 49(3): 289-308. DOI: 10.1111/ceo.13914.
3. Harada C, Mitamura Y, Harada T. The role of cytokines and trophic factors in epiretinal membranes: involvement of signal transduction in glial cells[J]. Prog Retin Eye Res, 2006, 25(2): 149-164. DOI: 10.1016/j.preteyeres.2005.09.001.
4. Pilli S, Lim P, Zawadzki RJ, et al. Fourier-domain optical coherence tomography of eyes with idiopathic epiretinal membrane: correlation between macular morphology and visual function[J]. Eye (Lond), 2011, 25(6): 775-783. DOI: 10.1038/eye.2011.55.
5. Myojin S, Yoshimura T, Yoshida S, et al. Gene expression analysis of the irrigation solution samples collected during vitrectomy for idiopathic epiretinal membrane[J/OL]. PLoS One, 2016, 11(10): e0164355[2016-10-13]. https://pubmed.ncbi.nlm.nih.gov/27736918/. DOI: 10.1371/journal.pone.0164355.
6. Zandi S, Tappeiner C, Pfister IB, et al. Vitreal cytokine profile differences between eyes with epiretinal membranes or macular holes[J]. Invest Ophthalmol Vis Sci, 2016, 57(14): 6320-6326. DOI: 10.1167/iovs.16-20657.
7. Mao J, Zhang C, Zhang S, et al. Predictors of anti-VEGF efficacy in chronic central serous chorioretinopathy based on intraocular cytokine levels and pigment epithelium detachment subtypes[J/OL]. Acta Ophthalmol, 2022, 100(7): e1385-e1394[2022-02-04]. https://pubmed.ncbi.nlm.nih.gov/35122421/. DOI: 10.1111/aos.15109.
8. Ożóg MK, Nowak-Wąs M, Rokicki W. Pathophysiology and clinical aspects of epiretinal membrane-review[J/OL]. Front Med (Lausanne), 2023, 10: 1121270[2023-08-10]. https://pubmed.ncbi.nlm.nih.gov/37636571/. DOI: 10.3389/fmed.2023.1121270.
9. Pollreisz A, Funk M, Breitwieser FP, et al. Quantitative proteomics of aqueous and vitreous fluid from patients with idiopathic epiretinal membranes[J]. Exp Eye Res, 2013, 108: 48-58. DOI: 10.1016/j.exer.2012.11.010.
10. Song P, Li P, Geng W, et al. Cytokines possibly involved in idiopathic epiretinal membrane progression after uncomplicated cataract surgery[J/OL]. Exp Eye Res, 2022, 217: 108957[2022-01-22]. https://pubmed.ncbi.nlm.nih.gov/35077755/. DOI: 10.1016/j.exer.2022.108957.
11. Chen L, Zhang W, Xie P, et al. Comparisons of vitreal angiogenic, inflammatory, profibrotic cytokines, and chemokines profile between patients with epiretinal membrane and macular hole[J/OL]. J Ophthalmol, 2021, 2021: 9947250[2021-07-13]. https://pubmed.ncbi.nlm.nih.gov/34336263/. DOI: 10.1155/2021/9947250.
12. Govetto A, Virgili G, Rodriguez FJ, et al. Functional and anatomical significance of the ectopic inner foveal layers in eyes with idiopathic epiretinal membranes: surgical results at 12 months[J]. Retina, 2019, 39(2): 347-357. DOI: 10.1097/iae.0000000000001940.
13. González-Saldivar G, Berger A, Wong D, et al. Ectopic inner foveal layer classification scheme predicts visual outcomes after epiretinal membrane surgery[J]. Retina, 2020, 40(4): 710-717. DOI: 10.1097/iae.0000000000002486.
14. Bianchi L, Altera A, Barone V, et al. Untangling the extracellular matrix of idiopathic epiretinal membrane: a path winding among structure, interactomics and translational medicine[J/OL]. Cells, 2022, 11(16): 2531[2022-08-15]. https://pubmed.ncbi.nlm.nih.gov/36010606/. DOI: 10.3390/cells11162531.
15. Lennikov A, Mukwaya A, Fan L, et al. Synergistic interactions of PlGF and VEGF contribute to blood-retinal barrier breakdown through canonical NFκB activation[J/OL]. Exp Cell Res, 2020, 397(2): 112347[2020-12-15]. https://pubmed.ncbi.nlm.nih.gov/33130176/. DOI: 10.1016/j.yexcr.2020.112347.
16. Kanda A, Noda K, Hirose I, et al. TGF-β-SNAIL axis induces Müller glial-mesenchymal transition in the pathogenesis of idiopathic epiretinal membrane[J/OL]. Sci Rep, 2019, 9(1): 673[2019-01-24]. https://pubmed.ncbi.nlm.nih.gov/30679596/. DOI: 10.1038/s41598-018-36917-9.
17. Joussen AM, Ricci F, Paris LP, et al. Angiopoietin/Tie2 signalling and its role in retinal and choroidal vascular diseases: a review of preclinical data[J]. Eye (Lond), 2021, 35(5): 1305-1316. DOI: 10.1038/s41433-020-01377-x.
18. Mirshahi A, Hoehn R, Lorenz K, et al. Anti-tumor necrosis factor alpha for retinal diseases: current knowledge and future concepts[J]. J Ophthalmic Vis Res, 2012, 7(1): 39-44.
19. Harjunpää H, Llort Asens M, Guenther C, et al. Cell adhesion molecules and their roles and regulation in the immune and tumor microenvironment[J/OL]. Front Immunol, 2019, 10: 1078[2019-05-22]. https://pubmed.ncbi.nlm.nih.gov/31231358/. DOI: 10.3389/fimmu.2019.01078.
20. Srejovic JV, Muric MD, Jakovljevic VL, et al. Molecular and cellular mechanisms involved in the pathophysiology of retinal vascular disease-interplay between inflammation and oxidative stress[J/OL]. Int J Mol Sci, 2024, 25(21): 11850[2024-11-04]. https://pubmed.ncbi.nlm.nih.gov/39519401/. DOI: 10.3390/ijms252111850.

Chinese Journal of Ocular Fundus Diseases

Latest ArticlesCorrelation of aqueous humor cytokine profiles with disorganization of retinal inner layers and postoperative visual acuity in idiopathic epiretinal membrane

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