You are here

  • Home
  • Archive
  • Volume 99, Issue 10
  • Six-month changes in cytokine levels after intravitreal bevacizumab injection for diabetic macular oedema and macular oedema due to central retinal vein occlusion

Article Text

Article menu

Download PDFPDF

Clinical science
Six-month changes in cytokine levels after intravitreal bevacizumab injection for diabetic macular oedema and macular oedema due to central retinal vein occlusion
  1. Jing Wen1,2,3,
  2. Yanrong Jiang1,2,3,
  3. Xiaoxue Zheng1,2,3,
  4. Ying Zhou1,2,3
  1. 1Department of Ophthalmology, Peking University People's Hospital, Beijing, China
  2. 2Key Laboratory of Vision Loss and Restoration (Peking University), Ministry of Education, Beijing, China
  3. 3Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, Beijing, China
  1. Correspondence to Dr Yanrong Jiang, Department of Ophthalmology, Peking University People's Hospital, 11 Xizhimen South Street, Xicheng District, Beijing 100044, China; drjiangyr{at}gmail.com

Abstract

Background/aims This study evaluated the impact of intravitreal injection of bevacizumab (IVB) on the microenvironment of the eyes of diabetic macular oedema (DMO) and macular oedema due to central retinal vein occlusion (CRVO-MO) patients.

Methods This study comprised 136 patients, including 51 patients in the DMO group, 70 in the CRVO-MO group and 15 in the control group, who were followed for 6 months after IVB. Angiogenic cytokines, inflammatory cytokines and growth factors concentrations in the aqueous humour were measured before and after IVB using suspension array technology. We compared the levels of cytokines among DMO patients, CRVO-MO patients and control patients. We compared the levels of cytokines among groups according to the interval between the first and second injections of bevacizumab and according to the number of injections received during the 6-month follow-up period.

Results Significantly higher concentrations of vascular endothelial growth factor (VEGF), transforming growth factor β (TGF-β), hepatocyte growth factor (HGF), interleukin 6 (IL-6), serum amyloid A (SAA) and monocyte chemoattractant protein-1 (MCP-1) were found in the aqueous humour of DMO and CRVO-MO patients compared with cataract patients. One month after IVB, the intraocular concentrations of VEGF were significantly decreased in the eyes of DMO (p=0.045) and CRVO-MO (p=0.002) patients compared with baseline. No other cytokine was significantly altered by bevacizumab therapy.

Conclusions Angiogenic, inflammatory and growth factors are involved in the development of DMO and CRVO-MO. In addition to VEGF, IVB did not cause significant differences in other inflammatory cytokines and growth factors in DMO and CRVO-MO patients.

  • Retina
  • Treatment Medical

https://doi.org/10.1136/bjophthalmol-2014-306341

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Introduction

    Macular oedema (MO) is a retinal complication of diabetic retinopathy (DR) and central retinal vein occlusion (CRVO) that is the predominant contributor to vision loss.1 The breakdown of the blood–retina barrier and the consequent vascular leakage and thickening of the retina are the primary events involved in disease pathogenesis. VEGF is a potent angiogenic factor associated with retinal neovascularisation and the increased vascular permeability leading to MO.

    Numerous other chemical mediators and cytokines have been identified in the ocular fluid of patients with DR and CRVO, such as transforming growth factor β (TGF-β),2 hepatocyte growth factor (HGF),3 ,4 basic fibroblast growth factor (bFGF),5 monocyte chemoattractant protein-1 (MCP-1),6 serum amyloid A (SAA)7 and interleukin 6 (IL-6),6 enhancing our understanding of the ocular biochemical milieu of this condition. Furthermore, SAA and IL-6 have been shown to associate with central macular thickness (CMT) in CRVO patients.5

    Several studies have demonstrated the utility of the intravitreal injection of anti-VEGF agents such as bevacizumab for the management of diabetic macular oedema (DMO) and CRVO-MO. However, the effects of this treatment differ for each disease, and the results have varied between studies.8–11 In addition, several studies have shown that the angio-fibrotic switch has been observed in diabetic fibrovascular proliferative membranes after bevacizumab treatment12 and that intravitreal injection of bevacizumab (IVB) increases the intraocular levels of inflammatory cytokines in patients with proliferative diabetic retinopathy (PDR).2 ,13 The aetiology of these changes after IVB remains unclear.

    Therefore, in this study, we measured and compared the concentrations of angiogenic factors, inflammatory cytokines and growth factors in the aqueous humour from the eyes of DMO and CRVO-MO patients before and after IVB. We investigated how anti-VEGF treatment affected intraocular cytokine levels in DR and CRVO patients based on a 6-month observation.

    Materials and methods

    The samples were collected after receiving approval from the Institutional Review Board of the People's Hospital affiliated with Peking University and in accordance with the Declaration of Helsinki. Written informed consent for all examinations and procedures was obtained from each participant.

    Study subjects

    We included patients who were treated with IVB from May 2012 to August 2013. The inclusion criteria for MO secondary to DR or CRVO were as follows: (1) a decrease in visual acuity, (2) diffuse MO based on fundus fluorescein angiography (FFA), (3) a CMT greater than 250 μm based on optical coherence tomography (OCT) and (4) a follow-up visit at least 6 months after IVB. The exclusion criteria were as follows: (1) vitreous haemorrhaging, tractional retinal detachment (TRD) or glaucoma before IVB; (2) previous ocular surgery; (3) intravitreal injection of corticosteroids or bevacizumab or pan-retinal photocoagulation within 6 months prior to the study and (4) MO caused by any retinal condition other than DR or CRVO.

    All patients received an intravitreal injection of 1.25 mg of bevacizumab per 0.05 mL of saline solution (Avastin; Genentech, San Francisco, California, USA). Reference samples were obtained from patients undergoing cataract surgery. Ophthalmic examinations were performed before and after IVB, including a best corrected visual acuity (BCVA) test using manifest refraction and the logarithm of the minimum angle of resolution (logMAR) visual acuity chart, non-contact tonometry, slit-lamp examination, fundus examination and FFA, which was performed using a fundus camera (TRC-50EX; Tokyo Optical, Tokyo, Japan). CMT was defined as the value of a 1 mm central area based on OCT (Zeiss-Humphrey, Dublin, California, USA).

    The patients were categorised into four groups according to the interval between the first and second injections: the baseline group, patients from whom the aqueous humour was collected before the first injection; the Month 1 group, patients who received a second treatment at 1 month; the Month 3 group, patients who received a second treatment at 3 months and the Month 6 group, patients who received a second treatment at 6 months. For the last three groups, we collected aqueous humour samples just before the second IVB.

    The patients were also separated into three groups according to the number of injections received during the 6-month follow-up period. In the 1-injection group, patients received one injection during the study period. The sample was taken before the second injection, which was 6 months after the first injection. In the 2-injections group, patients received two injections during the study period. The sample was taken before the third injection, which was at least 1 month after the second injection. In the 3-injections group, patients received three injections during the study period. The sample was taken before the fourth injection, which was at least 1 month after the third injection.

    Sample collection

    All injections and cataract surgeries were performed by the same surgeon (YJ) at the People's Hospital affiliated with Peking University. Undiluted aqueous humour samples were collected during intravitreal injection or cataract surgery. Approximately 200 μl of aqueous humour samples were obtained via anterior chamber paracentesis. These samples were stored in a sterilised plastic tube (2 mL; Corning, Troy, Michigan, USA) and were immediately frozen at −80°C until analysis. The samples were assayed within 6 months of collection.

    Measurement of cytokines

    Procarta Cytokine Assay Kits (Panomics, Fremont, California, USA) were used to measure the concentrations of TGF-β, HGF, bFGF, MCP-1, SAA, IL-6 and VEGF in the aqueous humour samples. These assays employed suspension array technology (xMAP; Luminex, Austin, Texas, USA) using multi-analyte profiling beads to detect and quantify multiple protein targets simultaneously, the detailed process of which was reported in a similar study.14

    Statistical analysis

    All statistical analyses were performed using SPSS V.21.0 for Windows (SPSS, Chicago, Illinois, USA). The levels of TGF-β, HGF, bFGF, MCP-1, SAA, IL-6 and VEGF in the aqueous humour were expressed as the means±SD. A one-sample Kolmogorov–Smirnov test was performed to examine whether the samples were normally distributed. Differences in the clinical characteristics between the DMO and CRVO-MO groups at baseline and after IVB were estimated using the Mann–Whitney U test. When appropriate, the Mann–Whitney U test and the t test were used to compare the levels of cytokines between the controls and DMO patients, between the controls and CRVO-MO patients and between the CRVO-MO and DMO patients. Between-group comparisons were performed using the Kruskal–Wallis H test and analysis of variance (ANOVA). p Values <0.05 were considered to indicate significant differences. For statistical analysis, the data (the levels of TGF-β, HGF, bFGF, MCP-1, SAA, IL-6 and VEGF) were transformed into a logarithmic scale.

    Results

    This study consisted of 136 patients, including 51 patients in the DMO group, 70 patients in the CRVO-MO group and 15 non-retinal disease patients with cataracts (the control group). As shown in table 1, the general clinical characteristics, including age, gender, hypertension proportion and duration of symptoms, did not vary significantly between the three groups (p>0.05).

    View this table:
    Table 1

    Demographic characteristics of the patients in the DMO, CRVO-MO and control groups

    Influence of anti-angiogenic therapy on clinical parameters

    As shown in table 2, intraocular pressure (IOP), outer CMT and complete CMT did not vary significantly between, before (ie, baseline) and after IVB among the DMO and CRVO-MO groups. In the CRVO-MO group, BCVA was significantly improved following IVB compared with baseline (p=0.027). In the DMO group, BCVA was slightly improved following IVB compared with baseline, although this difference was not significant (p=0.415). In the DMO group, no patients in the control or IVB group were found to experience vitreous haemorrhage, rubeosis iridis, fibroneovascular membranes or TRD. None of the patients in the CRVO-MO group exhibited proliferative vitreoretinopathy before or after treatment.

    View this table:
    Table 2

    Clinical characteristics of the patients in the DMO and CRVO-MO groups

    Concentrations of cytokines in patients compared with controls

    The concentrations of cytokines in the aqueous humour from the DMO, CRVO-MO and control groups are listed in table 3. The levels of all measured cytokines, except for bFGF, were significantly higher in the aqueous humour of patients with DMO than control subjects. The levels of all measured cytokines were significantly higher in the eyes of patients with CRVO-MO compared with control subjects. Furthermore, analysis of the cytokine levels in the aqueous humour revealed that the level of MCP-1 was significantly higher in DMO patients compared with CRVO-MO patients.

    View this table:
    Table 3

    Cytokine levels (log concentration pg/mL) in the aqueous humour from the eyes of DMO and CRVO-MO patients before IVB

    Influence of anti-angiogenic therapy on the cytokine levels

    One month after the first IVB treatment, the intraocular concentrations of VEGF were significantly decreased in DMO eyes compared with baseline (p=0.045). The levels of VEGF were slightly lower 3 months after IVB compared with baseline (p=0.44), although these levels were nearly identical between 6 months after IVB and baseline. All other cytokines were not affected by bevacizumab therapy, and the levels were similar between the DMO groups (figure 1). A similar result was observed for the CRVO-MO groups (figure 1). Only VEGF displayed a significant decrease between the baseline group and the Month 1 group (p=0.002). None of the other examined cytokines, including TGF-β, HGF, bFGF, MCP-1, SAA and IL-6, displayed any significant difference after IVB compared with baseline in the CRVO-MO groups (p=0.155, 0.614, 0.078, 0.585, 0.066 and 0.15, respectively).

    Figure 1
    Figure 1
    Figure 1

    Changes in the cytokine levels (log concentration pg/mL) in the aqueous humour before and after IVB treatment in the diabetic macular oedema (DMO) and macular oedema due to central retinal vein occlusion (CRVO-MO) groups according to the interval between the first and second injections. (A) One month after IVB, the VEGF levels were decreased in the DMO and CRVO-MO groups (p=0.045 for the DMO group and 0.002 for the CRVO-MO group). (B) The concentrations of transforming growth factor β (TGF-β), hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), monocyte chemoattractant protein-1 (MCP-1), serum amyloid A (SAA) and interleukin 6 (IL-6) in DMO eyes were not significantly different between the IVB treatment intervals (p=0.178, 0.32, 0.335, 0.899, 0.089 and 0.745, respectively). (C) None of the other measured cytokines, including TGF-β, HGF, bFGF, MCP-1, SAA and IL-6, displayed any significant difference after IVB compared with baseline in the CRVO-MO group (p=0.155, 0.614, 0.078, 0.585, 0.066 and 0.15, respectively). Analysis of variance (ANOVA) (labelled ‘1’) or the Kruskal–Wallis H test (labelled ‘2’) was performed. *Indicates p<0.05.

    Figure 2 shows the changes in various intraocular cytokines in different injection groups during the 6-month follow-up period. No significant difference in VEGF, TGF-β, HGF, bFGF, MCP-1, SAA or IL-6 was detected among DMO patients in the different injection groups (p=0.395, 0.071, 0.819, 0.879, 0.899, 0.051 and 0.551, respectively). In the CRVO-MO group, the VEGF concentration was significantly decreased in the 2-injections group and the 3-injections group compared with the baseline group, whereas no significant difference was detected between the 1-injection group and the baseline group. Other cytokines, including TGF-β, HGF, bFGF, MCP-1, SAA and IL-6, did not vary significantly between the different injection groups (p=0.955, 0.275, 0.33, 0.713, 0.302 and 0.156, respectively).

    Figure 2
    Figure 2
    Figure 2

    Changes in the cytokine levels (log concentration pg/mL) in the aqueous humour before and after IVB in the diabetic macular oedema (DMO) and macular oedema due to central retinal vein occlusion (CRVO-MO) groups according to the number of injections during the follow-up period. (A) No significant difference in the level of VEGF, transforming growth factor β (TGF-β), hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), monocyte chemoattractant protein-1 (MCP-1), serum amyloid A (SAA) or interleukin 6 (IL-6) was detected between the different injection groups of DMO patients (p=0.395, 0.071, 0.819, 0.879, 0.899, 0.051 and 0.551, respectively). (B) In the CRVO-MO group, the VEGF concentration was significantly decreased in the 2-injections group (p=0.007) and the 3-injections group (p=0.038) compared with the baseline group. Other cytokines, including TGF-β, HGF, bFGF, MCP-1, SAA and IL-6, did not significantly differ between the different injection groups (p=0.955, 0.275, 0.33, 0.713, 0.302 and 0.156, respectively). Analysis of variance (ANOVA) (labelled ‘1’) or the Kruskal–Wallis H test (labelled ‘2’) was performed. *Indicates p<0.05.

    Discussion

    Our study showed that the intraocular VEGF levels were strikingly higher in patients with MO as a result of DR or CRVO compared with control patients. The results also indicated that significantly higher concentrations of TGF-β, HGF, MCP-1, SAA and IL-6 were found in the eyes of DR and CRVO patients than in the control eyes. Angiogenic, inflammatory and growth factors were therefore involved in the development of MO secondary to DR and CRVO. These results are consistent with those of previous studies.15 ,16

    As shown in previous studies, intravitreal injection of the anti-VEGF agent, bevacizumab, was beneficial to eyes with MO secondary to DR and CRVO. In our study, we found that VEGF levels were significantly decreased 1 month after IVB. The decreased VEGF levels were sustained for 3 months after IVB. VEGF levels were decreased in multiple-injection group in DMO and CRVO-MO patients.

    Previous reports of vitreous levels in the eyes of patients with PDR who received pretreatment IVB have suggested that IVB influences intraocular mediators in addition to VEGF. We observed no significant difference in the level of MCP-1, SAA or IL-6 in the aqueous humour during the 6-month bevacizumab treatment period. MCP-1 is a specific and potent chemoattractant for monocytes that has been implicated in a variety of inflammatory processes. SAA is a classical acute phase protein that responds to injury, infection, inflammation and neoplasia.7 IL-6 is a multifunctional cytokine that is essential for the regulation of immune processes and the induction of acute inflammatory responses.17 Together, MCP-1, SAA and IL-6 act as acute mediators of inflammatory changes. A previous study showed that the levels of IL-6 significantly increased 1 day after IVB and then significantly decreased 7 days after IVB, suggesting that IVB exacerbated intraocular inflammatory cytokine production in PDR.13 Based on the data from our study, the concentrations of inflammatory cytokines at 1, 3 and 6 months after IVB were not different from those measured at baseline. Furthermore, we did not detect any significant differences in the levels of MCP-1, SAA or IL-6 between DMO and CRVO-MO patients, regardless of the number of injections. We speculate that IVB may mediate acute inflammatory changes and that this effect may not persist in DMO and CRVO-MO patients, which may not significantly alter the intraocular environment.

    TGF-β is one of the most potent regulators of the production and deposition of the extracellular matrix, and this factor is also involved in the control of endothelial cell proliferation and adhesion.18 The elevated expression of TGF-β has been observed in the vitreous body in PDR patients and has been investigated in relation to proliferative membranes in this disease.19 Furthermore, research has suggested that TGF-β might act as the primary inducer of myofibroblastic differentiation in fibrous epiretinal membranes in PDR. Previous studies have described the elevation of TGF-β after IVB in PDR patients. Forooghian et al2 reported that TGF-β2 increased significantly at a mean of 10 days after IVB. Jeon and Lee13 also found a significant increase in TGF-β2 at 7 days. These authors suggested that a reduction in VEGF levels might lead to an increase in TGF-β2. However, our data showed that TGF-β did not vary significantly during bevacizumab therapy both in DMO and CRVO-MO patients. We suggest that the reduction of VEGF might have more of an effect in PDR patients than in DMO or CRVO-MO patients.

    The limitations of our study should be mentioned. First, this was a retrospective comparative study. Second, due to the small sample size, significant differences in cytokine levels may have been obscured. In addition, the significant results reported may represent tendencies and must be confirmed in further prospective studies that include a randomised design.

    In conclusion, in addition to VEGF, IVB did not cause significant differences in other inflammatory cytokines or growth factors in DMO and CRVO-MO patients. This finding may present evidence of the safety of using anti-VEGF treatment in DMO and CRVO-MO patients.

    References

    1. ↵
      1. Cheung N,
      2. Mitchell P,
      3. Wong TY
      . Diabetic retinopathy. Lancet 2010;376:124–36. doi:10.1016/S0140-6736(09)62124-3
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      1. Forooghian F,
      2. Kertes PJ,
      3. Eng KT, et al
      . Alterations in the intraocular cytokine milieu after intravitreal bevacizumab. Invest Ophthalmol Vis Sci 2010;51:2388–92. doi:10.1167/iovs.09-4065
      OpenUrlAbstract/FREE Full Text
    3. ↵
      1. McAuley AK,
      2. Sanfilippo PG,
      3. Hewitt AW, et al
      . Vitreous biomarkers in diabetic retinopathy: a systematic review and meta-analysis. J Diabetes Complications 2014;28:419–25. doi:10.1016/j.jdiacomp.2013.09.010
      OpenUrlCrossRefPubMed
    4. ↵
      1. Simo R,
      2. Carrasco E,
      3. Garcia-Ramirez M, et al
      . Angiogenic and antiangiogenic factors in proliferative diabetic retinopathy. Curr Diabetes Rev 2006;2:71–98. doi:10.2174/157339906775473671
      OpenUrlCrossRefPubMed
    5. ↵
      1. Feng J,
      2. Zhao T,
      3. Zhang Y, et al
      . Differences in aqueous concentrations of cytokines in macular edema secondary to branch and central retinal vein occlusion. PLoS ONE 2013;8:e68149. doi:10.1371/journal.pone.0068149
      OpenUrlCrossRefPubMed
    6. ↵
      1. Funk M,
      2. Kriechbaum K,
      3. Prager F, et al
      . Intraocular concentrations of growth factors and cytokines in retinal vein occlusion and the effect of therapy with bevacizumab. Invest Ophthalmol Vis Sci 2009;50:1025–32. doi:10.1167/iovs.08-2510
      OpenUrlAbstract/FREE Full Text
    7. ↵
      1. Ma Y,
      2. Tao Y,
      3. Lu Q, et al
      . Intraocular expression of serum amyloid a and interleukin-6 in proliferative diabetic retinopathy. Am J Ophthalmol 2011;152:678–85.e2. doi:10.1016/j.ajo.2011.03.007
      OpenUrlCrossRefPubMed
    8. ↵
      1. Wolf-Schnurrbusch UE,
      2. Ghanem R,
      3. Rothenbuehler SP, et al
      . Predictors of short-term visual outcome after anti-VEGF therapy of macular edema due to central retinal vein occlusion. Invest Ophthalmol Vis Sci 2011;52:3334–7. doi:10.1167/iovs.10-6097
      OpenUrlAbstract/FREE Full Text
    9. ↵
      1. Rajendram R,
      2. Fraser-Bell S,
      3. Kaines A, et al
      . A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data: report 3. Arch Ophthalmol 2012;130:972–9. doi:10.1001/archophthalmol.2012.393
      OpenUrlCrossRefPubMed
    10. ↵
      1. Astam N,
      2. Batioglu F,
      3. Ozmert E
      . Short-term efficacy of intravitreal bevacizumab for the treatment of macular edema due to diabetic retinopathy and retinal vein occlusion. Int Ophthalmol 2009;29:343–8. doi:10.1007/s10792-008-9242-2
      OpenUrlCrossRefPubMed
    11. ↵
      1. Stahl A,
      2. Agostini H,
      3. Hansen LL, et al
      . Bevacizumab in retinal vein occlusion-results of a prospective case series. Graefes Arch Clin Exp Ophthalmol 2007;245:1429–36. doi:10.1007/s00417-007-0569-6
      OpenUrlCrossRefPubMedWeb of Science
    12. ↵
      1. El-Sabagh HA,
      2. Abdelghaffar W,
      3. Labib AM, et al
      . Preoperative intravitreal bevacizumab use as an adjuvant to diabetic vitrectomy: histopathologic findings and clinical implications. Ophthalmology 2011;118:636–41. doi:10.1016/j.ophtha.2010.08.038
      OpenUrlCrossRefPubMed
    13. ↵
      1. Jeon S,
      2. Lee WK
      . Intravitreal bevacizumab increases intraocular interleukin-6 levels at 1 day after injection in patients with proliferative diabetic retinopathy. Cytokine 2012;60:535–9. doi:10.1016/j.cyto.2012.07.005
      OpenUrlCrossRefPubMedWeb of Science
    14. ↵
      1. Jung SH,
      2. Kim KA,
      3. Sohn SW, et al
      . Association of aqueous humor cytokines with the development of retinal ischemia and recurrent macular edema in retinal vein occlusion. Invest Ophthalmol Vis Sci 2014;55:2290–6. doi:10.1167/iovs.13-13587
      OpenUrlAbstract/FREE Full Text
    15. ↵
      1. Koss MJ,
      2. Pfister M,
      3. Rothweiler F, et al
      . Comparison of cytokine levels from undiluted vitreous of untreated patients with retinal vein occlusion. Acta Ophthalmol 2012;90:e98–103. doi:10.1111/j.1755-3768.2011.02292.x
      OpenUrlCrossRefPubMed
    16. ↵
      1. Sohn HJ,
      2. Han DH,
      3. Kim IT, et al
      . Changes in aqueous concentrations of various cytokines after intravitreal triamcinolone versus bevacizumab for diabetic macular edema. Am J Ophthalmol 2011;152:686–94. doi:10.1016/j.ajo.2011.03.033
      OpenUrlCrossRefPubMed
    17. ↵
      1. Lee WJ,
      2. Kang MH,
      3. Seong M, et al
      . Comparison of aqueous concentrations of angiogenic and inflammatory cytokines in diabetic macular oedema and macular oedema due to branch retinal vein occlusion. Br J Ophthalmol 2012;96:1426–30. doi:10.1136/bjophthalmol-2012-301913
      OpenUrlAbstract/FREE Full Text
    18. ↵
      1. Harada C,
      2. Mitamura Y,
      3. Harada T
      . The role of cytokines and trophic factors in epiretinal membranes: involvement of signal transduction in glial cells. Prog Retin Eye Res 2006;25:149–64. doi:10.1016/j.preteyeres.2005.09.001
      OpenUrlCrossRefPubMedWeb of Science
    19. ↵
      1. Bochaton-Piallat ML,
      2. Kapetanios AD,
      3. Donati G, et al
      . TGF-beta 1, TGF-beta receptor II and ED-A fibronectin expression in myofibroblast of vitreoretinopathy. Invest Ophthalmol Vis Sci 2000;41:2336–42.
      OpenUrlAbstract/FREE Full Text
    View Abstract

    Footnotes

    • Correction notice This article has been corrected since it was published Online First. All instances of DME and CRVO-ME in figures 1 and 2 have been changed to DMO and CRVO-MO to match the text.

    • Contributors JW and YJ conceived and designed the research. XZ analysed and interpreted the data. JW, YJ and YZ conducted experiments resulting in the data. JW drafted the manuscript.

    • Funding This study was supported by the National Natural Science Foundation of China (No. 81271027), an EFSD/CDS/Lilly grant (2127000043), the Research Fund for the Doctoral Program of Higher Education of China (No. 20110001110042) and Peking University People's Hospital Research and Development Funds (RDC2012–21).

    • Competing interests The authors have no proprietary or commercial interest in any materials discussed in this article.

    • Patient consent Obtained.

    • Ethics approval The Institutional Review Board of the People’s Hospital affiliated with Peking University.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    Linked Articles

    • At a glance
      Highlights from this issue
      Keith Barton James Chodosh Jost Jonas
      British Journal of Ophthalmology 2015; 99 i-i Published Online First: 22 Sep 2015. doi: 10.1136/bjophthalmol-2015-307813