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Comparison of the cytokines levels in aqueous humor in vitrectomized eyes versus non-vitrectomized eyes with diabetic macular edema

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Abstract

Background

This study was conducted to compare concentrations of VEGF family growth factors, inflammation-related factors, and adhesion molecules in the aqueous humor of eyes with diabetic macular edema (DME), with and without prior vitrectomy.

Methods

A total of 31 eyes were included, 11 with DME that had undergone vitrectomy, 9 with DME but without vitrectomy, and 11 from age-related cataract patients as controls. The concentrations of cytokines including TNF-α, IL-6, IL-8, IP-10, MCP-1, IFN-γ, MIP-1 α, MIP-1 β, PECAM-1, MIF, VCAM-1, ICAM-1, PIGF were quantified using Luminex Human Discovery Assay. Central macular thickness (CMT) values of all eyes were measured using optical coherence tomography (OCT).

Results

(1) Vitrectomized DME eyes exhibited significantly higher levels of IL-6 and IL-8 compared to non-vitrectomized eyes (P < 0.05). (2) In vitrectomized group, after Benjamini–Hochberg correction, there was a significant positive correlation between the levels of VEGF and PlGF (rs = 0.855, P < 0.05), as well as the levels of TNF-α and IFN-γ (rs = 0.858, P < 0.05). In non-vitrectomized group, significant positive correlations were found between VEGF and PlGF levels after correcting for multiple comparisons (rs = 0.9, P < 0.05). (3) In non-vitrectomized group, the concentrations of VEGF and PlGF in aqueous humor were significantly positively correlated with CMT values (rs = 0.95, P < 0.05; rs = 0.9, P < 0.05, respectively).

Conclusions

The concentrations of IL-6 and IL-8 in the aqueous humor were significantly higher in vitrectomized DME eyes compared to nonvitrectomized DME eyes and the levels of VEGF were similar in the two groups, suggesting that inflammation after vitrectomy may be a key factor in the occurrence and development of DME.

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Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

Abbreviations

TNF-α:

Tumor necrosis factor alpha

IL-6:

Interleukin-6

IL-8:

Interleukin-8

IP-10:

Interferon-inducible protein 10

MCP-1:

Monocyte chemotactic protein 1

IFN-γ:

Interferon gamma

MIP-1 α:

Macrophage inflammatory protein-1 alpha

MIP-1 β:

Macrophage inflammatory protein-1 beta

PECAM-1:

Platelet endothelial cell adhesion molecule-1

MIF:

Macrophage migration inhibitory factor

VCAM-1:

Vascular cell adhesion molecule-1

ICAM-1:

Intercellular adhesion molecule-1

PIGF:

Placental growth factor

VEGF:

Vascular endothelial growth factor

CMT:

Central macular thickness

DME:

Diabetic macular edema

DR:

Diabetic retinopathy

BRB:

Blood-retinal barrier

OCT:

Optical coherence tomography

References

  1. Glassman AR, Wells JA 3rd, Josic K, Maguire MG, Antoszyk AN, Baker C, Beaulieu WT, Elman MJ, Jampol LM, Sun JK (2020) Five-year outcomes after initial aflibercept, bevacizumab, or ranibizumab treatment for diabetic macular edema (Protocol T Extension Study). Ophthalmology 127:1201–1210

    Article  PubMed  Google Scholar 

  2. Liu K, Wang H, He W, Ye J, Song Y, Wang Y, Liu X, Wu Z, Chen S, Fan K et al (2022) Intravitreal conbercept for diabetic macular oedema: 2-year results from a randomised controlled trial and open-label extension study. Br J Ophthalmol 106:1436–1443

    Article  PubMed  Google Scholar 

  3. Yoshida S, Kubo Y, Kobayashi Y, Zhou Y, Nakama T, Yamaguchi M, Tachibana T, Ishikawa K, Arita R, Nakao S et al (2015) Increased vitreous concentrations of MCP-1 and IL-6 after vitrectomy in patients with proliferative diabetic retinopathy: Possible association with postoperative macular oedema. Br J Ophthalmol 99:960–966

    Article  PubMed  Google Scholar 

  4. Yanyali A, Aytug B, Horozoglu F, Nohutcu AF (2007) Bevacizumab (Avastin) for diabetic macular edema in previously vitrectomized eyes. Am J Ophthalmol 144:124–126

    Article  CAS  PubMed  Google Scholar 

  5. Koyanagi Y, Yoshida S, Kobayashi Y, Kubo Y, Yamaguchi M, Nakama T, Nakao S, Ikeda Y, Ohshima Y, Ishibashi T et al (2016) Comparison of the effectiveness of intravitreal ranibizumab for diabetic macular edema in vitrectomized and nonvitrectomized eyes. Ophthalmologica 236:67–73

    Article  PubMed  Google Scholar 

  6. Chen YY, Chen PY, Chen FT, Chen YJ, Wang JK (2018) Comparison of efficacy of intravitreal ranibizumab between non-vitrectomized and vitrectomized eyes with diabetic macular edema. Int Ophthalmol 38:293–299

    PubMed  Google Scholar 

  7. Funatsu H, Yamashita H, Noma H, Mimura T, Nakamura S, Sakata K, Hori S (2005) Aqueous humor levels of cytokines are related to vitreous levels and progression of diabetic retinopathy in diabetic patients. Graefe’s Arch Clin Exp Ophthalmol 243:3–8

    Article  CAS  Google Scholar 

  8. Lee SS, Ghosn C, Yu Z, Zacharias LC, Kao H, Lanni C, Abdelfattah N, Kuppermann B, Csaky KG, D’Argenio DZ et al (2010) Vitreous VEGF clearance is increased after vitrectomy. Investig Ophthalmol Vis Sci 51:2135–2138

    Article  Google Scholar 

  9. Niwa Y, Kakinoki M, Sawada T, Wang X, Ohji M (2015) Ranibizumab and aflibercept: intraocular pharmacokinetics and their effects on aqueous VEGF level in vitrectomized and nonvitrectomized macaque eyes. Investig Ophthalmol Vis Sci 56:6501–6505

    Article  CAS  Google Scholar 

  10. Kakinoki M, Sawada O, Sawada T, Saishin Y, Kawamura H, Ohji M (2012) Effect of vitrectomy on aqueous VEGF concentration and pharmacokinetics of bevacizumab in macaque monkeys. Investig Ophthalmol Vis Sci 53:5877–5880

    Article  CAS  Google Scholar 

  11. Dvorak HF, Brown LF, Detmar M, Dvorak AM (1995) Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146:1029–1039

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Miyamoto K, Khosrof S, Bursell SE, Moromizato Y, Aiello LP, Ogura Y, Adamis AP (2000) Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-1). Am J Pathol 156:1733–1739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. De Falco S, Gigante B, Persico MG (2002) Structure and function of placental growth factor. Trends Cardiovasc Med 12:241–246

    Article  PubMed  Google Scholar 

  14. DiSalvo J, Bayne ML, Conn G, Kwok PW, Trivedi PG, Soderman DD, Palisi TM, Sullivan KA, Thomas KA (1995) Purification and characterization of a naturally occurring vascular endothelial growth factor·placenta growth factor heterodimer. J Biol Chem 270:7717–7723

    Article  CAS  PubMed  Google Scholar 

  15. Noma H, Mimura T, Yasuda K, Motohashi R, Kotake O, Shimura M (2017) Aqueous humor levels of soluble vascular endothelial growth factor receptor and inflammatory factors in diabetic macular edema. Ophthalmologica 238:81–88

    Article  CAS  PubMed  Google Scholar 

  16. Bressler SB, Melia M, Glassman AR, Almukhtar T, Jampol LM, Shami M, Berger BB, Bressler NM (2015) Ranibizumab plus prompt or deferred laser for diabetic macular edema in eyes with vitrectomy before anti-vascular endothelial growth factor therapy. Retina 35(12):2516–2528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn E (2004) Vascular endothelial growth factor and angiogenesis. Pharmacol Rev 56:549–580

    Article  CAS  PubMed  Google Scholar 

  18. Ferrara N, Gerber HP, LeCouter J (1995) The biology of VEGF and its receptors. Nat Med 9:669–676

    Article  Google Scholar 

  19. Wang H, Lafdil F, Kong X, Gao B (2011) Signal transducer and activator of transcription 3 in liver diseases: a novel therapeutic target. Int J Biol Sci 7:536–550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ebihara N, Matsuda A, Nakamura S, Matsuda H, Murakami A (2011) Role of the IL-6 classic-and trans-signaling pathways in corneal sterile inflammation and wound healing. Investig Ophthalmol Vis Sci 52:8549–8557

    Article  CAS  Google Scholar 

  21. Funatsu H, Yamashita H, Ikeda T, Mimura T, Eguchi S, Hori S (2003) Vitreous levels of interleukin-6 and vascular endothelial growth factor are related to diabetic macular edema. Ophthalmology 110:1690–1696

    Article  PubMed  Google Scholar 

  22. Roh MI, Kim HS, Song JH, Lim JB, Kwon OW (2009) Effect of intravitreal bevacizumab injection on aqueous humor cytokine levels in clinically significant macular edema. Ophthalmology 116:80–86

    Article  PubMed  Google Scholar 

  23. Jo N, Wu GS, Rao NA (2003) Upregulation of chemokine expression in the retinal vasculature in ischemia-reperfusion injury. Investig Ophthalmol Vis Sci 44:4054–4060

    Article  Google Scholar 

  24. Funk M, Schmidinger G, Maar N, Bolz M, Benesch T, Zlabinger GJ, Schmidt-Erfurth UM (2010) Angiogenic and inflammatory markers in the intraocular fluid of eyes with diabetic macular edema and influence of therapy with bevacizumab. Retina 30:1412–1419

    Article  PubMed  Google Scholar 

  25. Ide N, Hirase T, Nishimoto-Hazuku A, Ikeda Y, Node K (2008) Angiotensin II increases expression of IP-10 and the renin-angiotensin system in endothelial cells. Hypertens Res 31:1257–1267

    Article  CAS  PubMed  Google Scholar 

  26. Yoshimura T (2018) The chemokine MCP-1 (CCL2) in the host interaction with cancer: a foe or ally? Cell Mol Immunol 15:335–345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hong KH, Ryu J, Han KH (2005) Monocyte chemoattractant protein-1-induced angiogenesis is mediated by vascular endothelial growth factor-A. Blood 105:1405–1407

    Article  CAS  PubMed  Google Scholar 

  28. Gu R, Zhou M, Jiang C, Yu J, Xu G (2016) Elevated concentration of cytokines in aqueous in post-vitrectomy eyes. Clin Exp Ophthalmol 44:128–134

    Article  PubMed  Google Scholar 

  29. Park YG, Jee D, Kwon J (2019) Aqueous humor cytokine levels in diabetic macular edema patients with cotton-wool spots. J Diabetes Res 2019:1–9

    Article  CAS  Google Scholar 

  30. Tang J, Kern TS (2011) Inflammation in diabetic retinopathy. Prog Retin Eye Res 30:343–358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Joussen AM, Poulaki V, Qin W, Kirchhof B, Mitsiades N, Wiegand SJ, Rudge J, Yancopoulos GD, Adamis AP (2002) 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. Am J Pathol 160:501–509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hillier RJ, Ojaimi E, Wong DT, Mak MY, Berger AR, Kohly RP, Kertes PJ, Forooghian F, Boyd SR, Eng K et al (2017) Aqueous humor cytokine levels as biomarkers of disease severity in diabetic macular edema. Retina 37:761–769

    Article  CAS  PubMed  Google Scholar 

  33. Oh IK, Kim SW, Oh J, Lee TS, Huh K (2010) Inflammatory and angiogenic factors in the aqueous humor and the relationship to diabetic retinopathy. Curr Eye Res 35:1116–1127

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This research was funded by the National Natural Science Foundation of China (No. 82000917). Yuzhi Ding has been supported by the “Best Young Scholars” Fellowship from Southeast University.

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Author notes

  1. Yiheng Wang, Yuzhi Ding have contributed equally to this work.

Authors and Affiliations

  1. Department of Ophthalmology, Zhongda Hospital, Southeast University, Nanjing, 210009, Jiangsu Province, China

    Yiheng Wang, Yuzhi Ding, Qiuyu Zhuang & Jie Luan

  2. School of Medicine, Southeast University, Nanjing, 210009, Jiangsu Province, China

    Yiheng Wang & Qiuyu Zhuang

Authors
  1. Yiheng Wang
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Contributions

Examined and analyzed the aqueous humor data, and was a major contributor in writing the manuscript: YHW, YZD. Optimization of the manuscript: QYZ. Design of the study and final review of the manuscript: JL. All authors (YHW, YZD, QYZ, JL) read and approved the final manuscript.

Corresponding author

Correspondence to Jie Luan.

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Competing interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical approval and consent to participate

This study was approved by the Clinical research ethics committee of Zhongda Hospital, Affiliated with Southeast University, Nanjing, Jiangsu Province, China (approval number: 2022ZDSYLL112-P01). All methods were carried out in accordance with relevant guidelines and regulations. All patients provided a written informed consent before enrollment.

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Wang, Y., Ding, Y., Zhuang, Q. et al. Comparison of the cytokines levels in aqueous humor in vitrectomized eyes versus non-vitrectomized eyes with diabetic macular edema. Int Ophthalmol 44, 220 (2024). https://doi.org/10.1007/s10792-024-03136-3

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