Concentration of the inflammatory cytokines in vitreous of severe proliferative diabetic retinopathy after intravitreal ranibizumab injection_Chinese Journal of Ocular Fundus Diseases

Authors：

WangYou , DengBolin , 黄健 ,  AnGang

Department of ophthalmology, Central Hospital of Jinzhou in Liaoning Province, Jinzhou 121001, China;

Corresponding author：

AnGang, Email: 97545208@qq.com

Keywords：

Diabetic retinopathy/therapy; Angiogenesis inhibitors/therapeutic use; Antibodies,monoclonal/therapeutic use; Vascular endothelial growth factors; Chemokines

DOI：

10.3760/cma.j.issn.1005-1015.2014.05.014

Video：

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Objective To observe the concentration of the inflammatory cytokines in vitreous of severe proliferative diabetic retinopathy (PDR) after intravitreal ranibizumab injection (IVR). Methods A total of 80 PDR patients (80 eyes) were enrolled in this study. The patients were randomly divided into vitrectomy group (group A) and IVR combined with vitrectomy group (group B), 40 eyes in each group. The differences of sex (χ²=0.05), age (t=0.59), duration of diabetes (t=0.36), HbA1c (t=0.13) and intraocular pressure (F=0.81) between two groups were not significant (P>0.05). The eyes in group B received 0.5 mg (0.05 ml) ranibizumab injection at 7 days before operation. The vitreous samples (0.4 ml) were obtained before operation. The concentration of vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-8, intercellular adhesion molecule-1 (ICAM-1) and connective tissue growth factor (CTGF) were measured by enzyme-linked immunosorbent assays. Results The concentration of VEGF and ICAM-1 were (10.70±3.60), (224.64±90.32) pg/L in group B and (72.38±23.59), (665.61±203.34) pg/L in group A. The differences of VEGF and ICAM-1 concentration between two groups was significant (t=16.34, 12.53; P<0.001). The concentration of IL-6 and IL-8 were (210.64±80.27), (156.00±57.74) pg/L in group B and (45.78±33.82), (41.07±13.82) pg/L in group A. The differences of IL-6 and IL-8 concentration between two groups was significant (t=11.97, 12.24; P<0.001). There was no difference of CTGF concentration between two groups (t=1.39, P=0.17). The CTGF/VEGF in group B was higher than that in group A (t=14.75, P<0.001). Conclusions One week after IVR, the concentration of VEGF and ICAM-1 are decreased, while IL-6 and IL-8 increased. There is no obvious change in CTGF, but CTGF/VEGF is increased.

Citation： WangYou, DengBolin, AnGang. Concentration of the inflammatory cytokines in vitreous of severe proliferative diabetic retinopathy after intravitreal ranibizumab injection. Chinese Journal of Ocular Fundus Diseases, 2014, 30(5): 484-487. doi: 10.3760/cma.j.issn.1005-1015.2014.05.014 Copy

1.	Rizzo S, Genovesi-Ebert F, di Bartolo E,et al. Injection of intravitreal bevacizumab (Avastin) as a preoperative adjunct before vitrectomy surgery in the treatment of severe proliferative diabetic retinopathy (PDR)[J]. Graefe's Arch Clin Exp Ophthalmol, 2008, 246:837-842.
2.	Ahmadieh H, Shoeibi N, Entezari M, et al. Intravitreal bevacizumab for prevention of early postvitrectomy hemorrhage in diabetic patients:a randomized clinical trial[J]. Ophthalmology, 2009,116:1943-1948.
3.	da R Lucena D, Ribeiro JA, Costa RA,et al. Intraoperative bleeding during vitrectomy for diabetic tractional retinal detachment with versus without preoperative intravitreal bevacizumab (IBeTra study)[J]. Br J Ophthalmol, 2009, 93:688-691.
4.	Romano MR, Gibran SK, Marticorena J, et al. Can a preoperative bevacizumab injection prevent recurrent postvitrectomy diabetic vitreous haemorrhage?[J]. Eye (London),2009,23:1698-1701.
5.	di Lauro R, De Ruggiero P, di Lauro R, et al. Intravitreal bevacizumab for surgical treatment of severe proliferative diabetic retinopathy[J]. Graefe's Arch Clin Exp Ophthalmol, 2010,248:785-791.
6.	Forooghian F, Kertes PJ, Eng KT, et al. Alterations in the intraocular cytokine milieu after intravitreal bevacizumab[J].Invest Ophthalmol Vis Sci,2010,51:2388-2392.
7.	Wilkinson CP, Ferris FL 3rd, Klein RE,et al. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales[J]. Ophthalmology,2003,110:1677-1682.
8.	Diabetic Retinopathy Study Research Group.Diabetic retinopathy study:report number. 6:design,methods, and baseline results; report number 7:a modification of the Airlie House classification of diabetic retinopathy[J]. Invest Ophthalmol Vis Sci,1981,21(1 Pt 2):1-226.
9.	Avitabile T, Bonfiglio V, Castiglione F, et al. Severe proliferative diabetic retinopathy treated with vitrectomy or panretinal photocoagulation:a monocenter randomized controlled clinical trial[J]. Can J Ophthalmol, 2011,46:345-351.
10.	Miller JW, Adamis AP, Aiello LP. Vascular endothelial growth factor in ocular neovascularization and proliferative diabetic retinopathy[J]. Diabete Metab Rev,1997,13:37-50.
11.	Adamis AP, Berman AJ. Immunological mechanisms in the pathogenesis of diabetic retinopathy[J].Semin Immunopathol,2008,30:65-84.
12.	Lu M, Perez VL, Ma N, et al. VEGF increases retinal vascular ICAM-1 expression in vivo[J]. Invest Ophthalmol Vis Sci,1999,40:1808-1812.
13.	Ishida S, Usui T, Yamashiro K, et al. VEGF164(165) as the pathological isoform:differential leukocyte and endothelial responses through VEGFR1 and VEGFR2[J]. Invest Ophthalmol Vis Sci,2004,45:368-374.
14.	Ip MS, Domalpally A, Hopkins JJ,et al. Long-term effects of ranibizumab on diabetic retinopathy severity and progression[J]. Arch Ophthalmol,2012,130:1145-1152.
15.	Yan SF, Tritto I, Pinsky D,et al. Induction of interleukin-6 (IL-6) by hypoxia in vascular cells. Central role of the binding site for nuclear factor-IL-6[J]. J Biol Chem,1995,270:11463-11471.
16.	Cohen T, Nahari D, Cerem LW, et al. Interleukin 6 induces the expression of vascular endothelial growth factor[J].J Biol Chem,1996,271:736-741.
17.	Taub DD, Anver M, Oppenheim JJ,et al. T lymphocyte recruitment by interleukin-8 (IL-8). IL-8-induced degranulation of neutrophils releases potent chemoattractants for human T lymphocytes both in vitro and in vivo[J]. J Clin Invest,1996,97:1931-1941.
18.	Luster AD, Greenberg SM, Leder P. The IP-10 chemokine binds to a specific cell surface heparan sulfate site shared with platelet factor 4 and inhibits endothelial cell proliferation[J]. J Exp Med,1995,182:219-231.
19.	Jeon S, Lee WK. Intravitreal bevacizumab increases intraocular interleukin-6 levels at 1 day after injection in patients with proliferative diabetic retinopathy[J]. Cytokine, 2012,60:535-539.
20.	Petrovi AčG MG, Korošec P, Košnik M,et al. Association of preoperative vitreous IL-8 and VEGF levels with visual acuity after vitrectomy in proliferative diabetic retinopathy[J]. Acta Ophthalmol, 2010,88:311-316.
21.	Joussen AM, Poulaki V, Le ML,et al. A central role for inflammation in the pathogenesis of diabetic retinopathy[J]. FASEB J, 2004,18:1450-1452.
22.	Limb GA, Hickman-Casey J, Hollifield RD, et al. Vascular adhesion molecules in vitreous from eyes with proliferative diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 1999,40:2453-2457.
23.	Yuuki T, Kanda T, Kimura Y, et al. Inflammatory cytokines in vitreous fluid and serum of patients with diabetic vitreoretinopathy[J]. J Diabetes Complications, 2001,15:257-259.
24.	Jonas JB, Jonas RA, Neumaier M, et al. Cytokine concentration in aqueous humor of eyes with diabetic macular edema[J]. Retina, 2012,32:2150-2157.
25.	Hinton DR, He S, Jin ML, et al. Novel growth factors involved in the pathogenesis of proliferative vitreoretinopathy[J]. Eye (Lond), 2002,16:422-428.
26.	Abu El-Asrar AM, van den Steen PE, Al-Amro SA,et al. Expression of angiogenic and fibrogenic factors in proliferative vitreoretinal disorders[J]. Int Ophthalmol, 2007,27:11-22.
27.	Yang H, Huang Y, Chen X,et al.The role of CTGF in the diabetic rat retina and its relationship with VEGF and TGF-β(2), elucidated by treatment with CTGFsiRNA[J]. Acta Ophthalmol, 2010,88:652-659.
28.	Arevalo JF, Maia M, Flynn HW Jr, et al. Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy[J]. Br J Ophthalmol, 2008,92:213-216.
29.	Kuiper EJ, van Nieuwenhoven FA, de Smet MD, et al. The angio-fibrotic switch of VEGF and CTGF in proliferative diabetic retinopathy. PLoS One, 2008,3:2675.[2008-07-16]http://www.biomedsearch.com/nih/angio-fibrotic-switch-VEGF-CTGF/18628999.html.

1. Rizzo S, Genovesi-Ebert F, di Bartolo E,et al. Injection of intravitreal bevacizumab (Avastin) as a preoperative adjunct before vitrectomy surgery in the treatment of severe proliferative diabetic retinopathy (PDR)[J]. Graefe's Arch Clin Exp Ophthalmol, 2008, 246:837-842.
2. Ahmadieh H, Shoeibi N, Entezari M, et al. Intravitreal bevacizumab for prevention of early postvitrectomy hemorrhage in diabetic patients:a randomized clinical trial[J]. Ophthalmology, 2009,116:1943-1948.
3. da R Lucena D, Ribeiro JA, Costa RA,et al. Intraoperative bleeding during vitrectomy for diabetic tractional retinal detachment with versus without preoperative intravitreal bevacizumab (IBeTra study)[J]. Br J Ophthalmol, 2009, 93:688-691.
4. Romano MR, Gibran SK, Marticorena J, et al. Can a preoperative bevacizumab injection prevent recurrent postvitrectomy diabetic vitreous haemorrhage?[J]. Eye (London),2009,23:1698-1701.
5. di Lauro R, De Ruggiero P, di Lauro R, et al. Intravitreal bevacizumab for surgical treatment of severe proliferative diabetic retinopathy[J]. Graefe's Arch Clin Exp Ophthalmol, 2010,248:785-791.
6. Forooghian F, Kertes PJ, Eng KT, et al. Alterations in the intraocular cytokine milieu after intravitreal bevacizumab[J].Invest Ophthalmol Vis Sci,2010,51:2388-2392.
7. Wilkinson CP, Ferris FL 3rd, Klein RE,et al. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales[J]. Ophthalmology,2003,110:1677-1682.
8. Diabetic Retinopathy Study Research Group.Diabetic retinopathy study:report number. 6:design,methods, and baseline results; report number 7:a modification of the Airlie House classification of diabetic retinopathy[J]. Invest Ophthalmol Vis Sci,1981,21(1 Pt 2):1-226.
9. Avitabile T, Bonfiglio V, Castiglione F, et al. Severe proliferative diabetic retinopathy treated with vitrectomy or panretinal photocoagulation:a monocenter randomized controlled clinical trial[J]. Can J Ophthalmol, 2011,46:345-351.
10. Miller JW, Adamis AP, Aiello LP. Vascular endothelial growth factor in ocular neovascularization and proliferative diabetic retinopathy[J]. Diabete Metab Rev,1997,13:37-50.
11. Adamis AP, Berman AJ. Immunological mechanisms in the pathogenesis of diabetic retinopathy[J].Semin Immunopathol,2008,30:65-84.
12. Lu M, Perez VL, Ma N, et al. VEGF increases retinal vascular ICAM-1 expression in vivo[J]. Invest Ophthalmol Vis Sci,1999,40:1808-1812.
13. Ishida S, Usui T, Yamashiro K, et al. VEGF164(165) as the pathological isoform:differential leukocyte and endothelial responses through VEGFR1 and VEGFR2[J]. Invest Ophthalmol Vis Sci,2004,45:368-374.
14. Ip MS, Domalpally A, Hopkins JJ,et al. Long-term effects of ranibizumab on diabetic retinopathy severity and progression[J]. Arch Ophthalmol,2012,130:1145-1152.
15. Yan SF, Tritto I, Pinsky D,et al. Induction of interleukin-6 (IL-6) by hypoxia in vascular cells. Central role of the binding site for nuclear factor-IL-6[J]. J Biol Chem,1995,270:11463-11471.
16. Cohen T, Nahari D, Cerem LW, et al. Interleukin 6 induces the expression of vascular endothelial growth factor[J].J Biol Chem,1996,271:736-741.
17. Taub DD, Anver M, Oppenheim JJ,et al. T lymphocyte recruitment by interleukin-8 (IL-8). IL-8-induced degranulation of neutrophils releases potent chemoattractants for human T lymphocytes both in vitro and in vivo[J]. J Clin Invest,1996,97:1931-1941.
18. Luster AD, Greenberg SM, Leder P. The IP-10 chemokine binds to a specific cell surface heparan sulfate site shared with platelet factor 4 and inhibits endothelial cell proliferation[J]. J Exp Med,1995,182:219-231.
19. Jeon S, Lee WK. Intravitreal bevacizumab increases intraocular interleukin-6 levels at 1 day after injection in patients with proliferative diabetic retinopathy[J]. Cytokine, 2012,60:535-539.
20. Petrovi AčG MG, Korošec P, Košnik M,et al. Association of preoperative vitreous IL-8 and VEGF levels with visual acuity after vitrectomy in proliferative diabetic retinopathy[J]. Acta Ophthalmol, 2010,88:311-316.
21. Joussen AM, Poulaki V, Le ML,et al. A central role for inflammation in the pathogenesis of diabetic retinopathy[J]. FASEB J, 2004,18:1450-1452.
22. Limb GA, Hickman-Casey J, Hollifield RD, et al. Vascular adhesion molecules in vitreous from eyes with proliferative diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 1999,40:2453-2457.
23. Yuuki T, Kanda T, Kimura Y, et al. Inflammatory cytokines in vitreous fluid and serum of patients with diabetic vitreoretinopathy[J]. J Diabetes Complications, 2001,15:257-259.
24. Jonas JB, Jonas RA, Neumaier M, et al. Cytokine concentration in aqueous humor of eyes with diabetic macular edema[J]. Retina, 2012,32:2150-2157.
25. Hinton DR, He S, Jin ML, et al. Novel growth factors involved in the pathogenesis of proliferative vitreoretinopathy[J]. Eye (Lond), 2002,16:422-428.
26. Abu El-Asrar AM, van den Steen PE, Al-Amro SA,et al. Expression of angiogenic and fibrogenic factors in proliferative vitreoretinal disorders[J]. Int Ophthalmol, 2007,27:11-22.
27. Yang H, Huang Y, Chen X,et al.The role of CTGF in the diabetic rat retina and its relationship with VEGF and TGF-β(2), elucidated by treatment with CTGFsiRNA[J]. Acta Ophthalmol, 2010,88:652-659.
28. Arevalo JF, Maia M, Flynn HW Jr, et al. Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy[J]. Br J Ophthalmol, 2008,92:213-216.
29. Kuiper EJ, van Nieuwenhoven FA, de Smet MD, et al. The angio-fibrotic switch of VEGF and CTGF in proliferative diabetic retinopathy. PLoS One, 2008,3:2675.[2008-07-16]http://www.biomedsearch.com/nih/angio-fibrotic-switch-VEGF-CTGF/18628999.html.

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Concentration of the inflammatory cytokines in vitreous of severe proliferative diabetic retinopathy after intravitreal ranibizumab injection

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