Vitreous levels of Lipocalin-2 on patients with primary rhegmatogenous retinal detachment

English version

Autoři: Georgios Batsos ^aff001; Eleni Christodoulou ^aff001; Georgios Vartholomatos ^aff002; Petros Galanis ^aff003; Maria Stefaniotou ^aff001
Působiště autorů: Ophthalmology Department, University Hospital Of Ioannina, Ioannina, Greece ^aff001; Haematology Laboratory Unit of Molecular Biology, University Hospital Of Ioannina, Ioannina, Greece ^aff002; Center for Health Services Management and Evaluation, National and Kapodistrian University of Athens (NKUA), Athens, Greece ^aff003
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0227266

Souhrn

Purpose

To measure vitreous levels of Lipocalin2 (LCN2) in patients with rhegmatogenous retinal detachment (RRD) and investigate potential association with presence of proliferative vitreoretinopathy (PVR).

Materials and methods

Collection of undiluted vitreous samples from 24 patients suffering from RRD and 10 control patients undergoing vitrectomy for: vitreomacular traction (VMT) (n = 2), idiopathic epiretinal membrane (iERM) (n = 6) and full thickness macular hole (FTMH) (n = 2). Quantitative analysis of LCN2 has been made with flow cytometry. Lens status, duration of symptoms, quadrants of detachment, as well as level of PVR, were assessed. Statistical analysis included Mann-Whitney test, Kruskal-Wallis test, t-test, Spearman’s correlation coefficient and Fisher's exact test.

Results

Median LCN2 was significantly higher in the RRD group as compared to control (p<0.001). Within the RRD group there was a positive correlation between LCN2 and PVR grade (r_s = 0.94, p<0.001). Median LCN2 was 35,759 pg/ml (IR = 55,347) in grade C PVR, 9,387 pg/ml (IR = 3721) in grade B, 4,917 pg/ml (IR = non computable) in grade A and 3,921 pg/ml (2132) in the no PVR group. Median LCN2 was also significantly higher in pseudophakic patients as compared to phakic patients (p = 0.007). LCN2 also correlates with the extend of detachment (≤2 vs >2 quadrants, p<0.001) as well as with duration of symptoms (r_s = 0.87, p<0.001). After multivariate linear regression analysis, only PVR was independently related with LCN2 concentration. In particular, increased PVR grading was associated with increased LCN2 concentration (coefficient b = 2.97, 95% confidence interval = 1.89 to 4.67, p<0.001).

Conclusion

A positive correlation between vitreous levels of LCN2 and PVR grading reveals a potential role in the pathogenesis and progression of PVR. Further studies could elucidate if LCN2 could be a therapeutic target.

Klíčová slova:

Inflammation – Biomarkers – Surgical and invasive medical procedures – Inflammatory diseases – Retinal detachment – Retina – Vitreoretinal surgery

Zdroje

1. Mohamed YH, Ono K, Kinoshita H, et al. Success Rates of Vitrectomy in Treatment of Rhegmatogenous Retinal Detachment. Journal of ophthalmology. 2016;2016:2193518.

2. The Royal College of Ophthalmologists. National Electronic Retinal Detachment Surgery Audit: Feasibility Report. 2017 [cited 2019 10 Aug]; https://www.nodaudit.org.uk/u/docs/20/kxmnfevalz/RetinalDetachmentSurgeryAuditFeasibilityReport.pdf.

3. 2018 MEAEDoO. Quality and Outcomes. 2018 [cited 2019 10 Aug]; https://www.masseyeandear.org/assets/MEE/pdfs/about/ophthalmology-quality-2018.pdf.

4. Schaal S, Sherman MP, Barr CC, et al. Primary retinal detachment repair: comparison of 1-year outcomes of four surgical techniques. Retina (Philadelphia, Pa). 2011;31(8):1500–4.

5. Enders P, Schick T, Schaub F, et al. Risk of Multiple Recurring Retinal Detachment after Primary Rhegmatogenous Retinal Detachment Repair. Retina (Philadelphia, Pa). 2017;37(5):930–5.

6. Charteris DG, Downie J, Aylward GW, et al. Intraretinal and periretinal pathology in anterior proliferative vitreoretinopathy. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2007;245(1):93–100. doi: 10.1007/s00417-006-0323-5 16612635

7. Pastor JC, Rojas J, Pastor-Idoate S, et al. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical consequences. Progress in retinal and eye research. 2016;51:125–55. doi: 10.1016/j.preteyeres.2015.07.005 26209346

8. Sadaka A, Giuliari GP. Proliferative vitreoretinopathy: current and emerging treatments. Clin Ophthalmol. 2012;6:1325–33. doi: 10.2147/OPTH.S27896 22942638

9. Pennock S, Haddock LJ, Eliott D, et al. Is neutralizing vitreal growth factors a viable strategy to prevent proliferative vitreoretinopathy? Progress in retinal and eye research. 2014;40:16–34. doi: 10.1016/j.preteyeres.2013.12.006 24412519

10. Rouberol F, Chiquet C. [Proliferative vitreoretinopathy: pathophysiology and clinical diagnosis]. Journal francais d'ophtalmologie. 2014;37(7):557–65. doi: 10.1016/j.jfo.2014.04.001 24997864

11. Pastor JC. Proliferative vitreoretinopathy: an overview. Survey of ophthalmology. 1998;43(1):3–18. doi: 10.1016/s0039-6257(98)00023-x 9716190

12. Pastor JC, de la Rua ER, Martin F. Proliferative vitreoretinopathy: risk factors and pathobiology. Progress in retinal and eye research. 2002;21(1):127–44. doi: 10.1016/s1350-9462(01)00023-4 11906814

13. Leaver PK. Proliferative vitreoretinopathy. The British journal of ophthalmology. 1995;79(10):871–2. doi: 10.1136/bjo.79.10.871 7488570

14. Laqua H, Machemer R. Glial cell proliferation in retinal detachment (massive periretinal proliferation). American journal of ophthalmology. 1975;80(4):602–18. doi: 10.1016/0002-9394(75)90390-6 810029

15. Moysidis SN, Thanos A, Vavvas DG. Mechanisms of inflammation in proliferative vitreoretinopathy: from bench to bedside. Mediators of inflammation. 2012;2012:815937.

16. Khan MA, Brady CJ, Kaiser RS. Clinical management of proliferative vitreoretinopathy: an update. Retina (Philadelphia, Pa). 2015;35(2):165–75.

17. Ricker LJ, Kessels AG, de Jager W, et al. Prediction of proliferative vitreoretinopathy after retinal detachment surgery: potential of biomarker profiling. American journal of ophthalmology. 2012;154(2):347–54 e2. doi: 10.1016/j.ajo.2012.02.004 22541653

18. Wang F, Yu J, Qiu QH, et al. [Kininogen-1 and insulin-like growth factor binding protein-6 as serum biomarkers for proliferative vitreoretinopathy]. [Zhonghua yan ke za zhi] Chinese journal of ophthalmology. 2010;46(7):609–14. 21054968

19. Zandi S, Pfister IB, Traine PG, et al. Biomarkers for PVR in rhegmatogenous retinal detachment. PloS one. 2019;14(4):e0214674. doi: 10.1371/journal.pone.0214674 30943234

20. Tosi GM, Marigliani D, Romeo N, et al. Disease pathways in proliferative vitreoretinopathy: an ongoing challenge. Journal of cellular physiology. 2014;229(11):1577–83. doi: 10.1002/jcp.24606 24604697

21. Charteris DG, Sethi CS, Lewis GP, et al. Proliferative vitreoretinopathy-developments in adjunctive treatment and retinal pathology. Eye (London, England). 2002;16(4):369–74.

22. Salom D, Sanz-Marco E, Mullor JL, et al. Aqueous humor neutrophil gelatinase-associated lipocalin levels in patients with idiopathic acute anterior uveitis. Molecular vision. 2010;16:1448–52. 20680102

23. Koban Y, Sahin S, Boy F, et al. Elevated lipocalin-2 level in aqueous humor of patients with central retinal vein occlusion. International ophthalmology. 2018.

24. Wilson R, Belluoccio D, Little CB, et al. Proteomic characterization of mouse cartilage degradation in vitro. Arthritis and rheumatism. 2008;58(10):3120–31. doi: 10.1002/art.23789 18821673

25. Chakraborty S, Kaur S, Guha S, et al. The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer. Biochimica et biophysica acta. 2012;1826(1):129–69. doi: 10.1016/j.bbcan.2012.03.008 22513004

26. Lindberg S, Jensen JS, Mogelvang R, et al. Plasma neutrophil gelatinase-associated lipocalinin in the general population: association with inflammation and prognosis. Arteriosclerosis, thrombosis, and vascular biology. 2014;34(9):2135–42. doi: 10.1161/ATVBAHA.114.303950 24969771

27. Bolignano D, Donato V, Coppolino G, et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a marker of kidney damage. American journal of kidney diseases: the official journal of the National Kidney Foundation. 2008;52(3):595–605.

28. Brunner HI, Bennett MR, Mina R, et al. Association of noninvasively measured renal protein biomarkers with histologic features of lupus nephritis. Arthritis and rheumatism. 2012;64(8):2687–97. doi: 10.1002/art.34426 22328173

29. Chassaing B, Srinivasan G, Delgado MA, et al. Fecal lipocalin 2, a sensitive and broadly dynamic non-invasive biomarker for intestinal inflammation. PloS one. 2012;7(9):e44328. doi: 10.1371/journal.pone.0044328 22957064

30. Berard JL, Zarruk JG, Arbour N, et al. Lipocalin 2 is a novel immune mediator of experimental autoimmune encephalomyelitis pathogenesis and is modulated in multiple sclerosis. Glia. 2012;60(7):1145–59. doi: 10.1002/glia.22342 22499213

31. Jang Y, Lee JH, Wang Y, et al. Emerging clinical and experimental evidence for the role of lipocalin-2 in metabolic syndrome. Clinical and experimental pharmacology & physiology. 2012;39(2):194–9.

32. Abella V, Scotece M, Conde J, et al. The potential of lipocalin-2/NGAL as biomarker for inflammatory and metabolic diseases. Biomarkers: biochemical indicators of exposure, response, and susceptibility to chemicals. 2015;20(8):565–71.

33. Zhang J, Wu Y, Zhang Y, et al. The role of lipocalin 2 in the regulation of inflammation in adipocytes and macrophages. Mol Endocrinol. 2008;22(6):1416–26. doi: 10.1210/me.2007-0420 18292240

34. Machemer R, Aaberg TM, Freeman HM, et al. An updated classification of retinal detachment with proliferative vitreoretinopathy. American journal of ophthalmology. 1991;112(2):159–65. doi: 10.1016/s0002-9394(14)76695-4 1867299

35. The classification of retinal detachment with proliferative vitreoretinopathy. Ophthalmology. 1983;90(2):121–5. doi: 10.1016/s0161-6420(83)34588-7 6856248

36. Lean JS, Stern WH, Irvine AR, et al. Classification of proliferative vitreoretinopathy used in the silicone study. The Silicone Study Group. Ophthalmology. 1989;96(6):765–71. doi: 10.1016/s0161-6420(89)32821-1 2662099

37. Parmar T, Parmar VM, Perusek L, et al. Lipocalin 2 Plays an Important Role in Regulating Inflammation in Retinal Degeneration. J Immunol. 2018;200(9):3128–41. doi: 10.4049/jimmunol.1701573 29602770

38. Parmar T, Parmar VM, Arai E, et al. Acute Stress Responses Are Early Molecular Events of Retinal Degeneration in Abca4-/-Rdh8-/- Mice After Light Exposure. Investigative ophthalmology & visual science. 2016;57(7):3257–67.

39. Valapala M, Edwards M, Hose S, et al. Increased Lipocalin-2 in the retinal pigment epithelium of Cryba1 cKO mice is associated with a chronic inflammatory response. Aging cell. 2014;13(6):1091–4. doi: 10.1111/acel.12274 25257511

40. Hofmaier F, Hauck SM, Amann B, et al. Changes in matrix metalloproteinase network in a spontaneous autoimmune uveitis model. Investigative ophthalmology & visual science. 2011;52(5):2314–20.

41. Kubben FJ, Sier CF, Hawinkels LJ, et al. Clinical evidence for a protective role of lipocalin-2 against MMP-9 autodegradation and the impact for gastric cancer. Eur J Cancer. 2007;43(12):1869–76. doi: 10.1016/j.ejca.2007.05.013 17604154

42. Yan L, Borregaard N, Kjeldsen L, et al. The high molecular weight urinary matrix metalloproteinase (MMP) activity is a complex of gelatinase B/MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL). Modulation of MMP-9 activity by NGAL. The Journal of biological chemistry. 2001;276(40):37258–65. doi: 10.1074/jbc.M106089200 11486009

43. Kobayashi T, Kim H, Liu X, et al. Matrix metalloproteinase-9 activates TGF-beta and stimulates fibroblast contraction of collagen gels. American journal of physiology Lung cellular and molecular physiology. 2014;306(11):L1006–15. doi: 10.1152/ajplung.00015.2014 24705725

44. Symeonidis C, Papakonstantinou E, Souliou E, et al. Correlation of matrix metalloproteinase levels with the grade of proliferative vitreoretinopathy in the subretinal fluid and vitreous during rhegmatogenous retinal detachment. Acta ophthalmologica. 2011;89(4):339–45. doi: 10.1111/j.1755-3768.2009.01701.x 19764916

45. Kon CH, Occleston NL, Charteris D, et al. A prospective study of matrix metalloproteinases in proliferative vitreoretinopathy. Investigative ophthalmology & visual science. 1998;39(8):1524–9.

46. Zeng J, Jiang D, Zhu X, et al. [A quantitative study of matrix metalloproteinases in proliferative vitreoretinopathy]. Yan ke xue bao = Eye science. 2003;19(2):130–2. 12870353

47. Tassoni A, Gutteridge A, Barber AC, et al. Molecular Mechanisms Mediating Retinal Reactive Gliosis Following Bone Marrow Mesenchymal Stem Cell Transplantation. Stem cells (Dayton, Ohio). 2015;33(10):3006–16.

48. Lee S, Park JY, Lee WH, et al. Lipocalin-2 is an autocrine mediator of reactive astrocytosis. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2009;29(1):234–49.

49. Eastlake K, Heywood WE, Banerjee P, et al. Comparative proteomic analysis of normal and gliotic PVR retina and contribution of Muller glia to this profile. Experimental eye research. 2018;177:197–207. doi: 10.1016/j.exer.2018.08.016 30176221

50. Eastlake K, Banerjee PJ, Angbohang A, et al. Muller glia as an important source of cytokines and inflammatory factors present in the gliotic retina during proliferative vitreoretinopathy. Glia. 2016;64(4):495–506. doi: 10.1002/glia.22942 26556395