Abstract

To clarify the mechanisms and their temporal relationship in the development of proliferative vitreoretinopathy (PVR), we measured vitreous levels of pro-inflammatory cytokines and growth factors in a rabbit model of PVR. PVR was surgically induced in 11 rabbit eyes by vitrectomy, retinotomy, cryotherapy and injection of platelet-rich plasma at baseline. Severity of PVR was assessed on dilated fundal examination with indirect binocular ophthalmoscopy and graded based on the revised experimental PVR classification. Severe PVR was defined as stage 5 or worse. Vitreous concentrations of interleukin 6 (IL-6), interleukin 8 (IL-8), interleukin 1 beta (IL-1 β), tumor necrosis factor beta (TNF-β), granulocyte macrophage colony stimulating factor (GM-CSF), interferon gamma (IFN-γ), C reactive protein; (CRP), placental growth factor (PlGF), platelet derived growth factor BB (PDGF-BB), vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang-2) at weeks 2, 3 and 4 were compared to baseline and correlations between the cytokines with PVR severity were assessed. Four weeks after PVR induction, 5 eyes (45.5%) had developed severe PVR. IL-8 was raised at 2 weeks post PVR induction (1.46 ± 0.48 pg/ml vs 0.53 ± 0.25 pg/ml, p = 0.04) and remained significantly elevated at week 4 (2.6 ± 3.1 pg/ml, p = 0.03). CRP was significantly raised at week 4 (34.8 ± 12.0 pg/ml vs 13.0 ± 13.1 pg/ml, p < 0.001). Among the growth factors, PDGF-BB was the earliest to show significantly elevated levels, at 3 weeks (50.4 ± 19.0 pg/ml vs 6.2 ± 10.1 pg/ml) and remained elevated at week 4 (p = 0.002), while PlGF (11.2 ± 7.7 pg/ml vs 5.3 ± 3.8 pg/ml, p = 0.002) and Ang2 (13617.0 ± 8170.2 pg/ml vs 38593.8 ± 8313.4, p = 0.02) were significantly raised at week 4. IFN-γ (p = 0.03), PDGF-BB (p = 0.02) and VEGF (p = 0.02) were significantly associated with PVR severity. We demonstrated that inflammatory cytokines IL-6, -8, elevation post PVR induction is followed by elevated levels of fibroproliferative growth factors, Ang2, PlGF, VEGF and PDGF-BB in the development of PVR. These findings will guide future studies targeting appropriate therapeutic strategies for the treatment of PVR.

Highlights

  • To clarify the mechanisms and their temporal relationship in the development of proliferative vitreoretinopathy (PVR), we measured vitreous levels of pro-inflammatory cytokines and growth factors in a rabbit model of PVR

  • To more accurately model the emergence of human disease, we chose an experimental model that mimicked the development of PVR after surgery, by inducing retinal detachment, release of RPE cells into the vitreous cavity, simulating a pro-inflammatory environment with cryotherapy and the injection of platelet rich plasma, avoiding the injection of any non-native cells

  • We found that PVR began as early as 2 weeks after surgery, with about 50% of eyes developing severe PVR with retinal detachment at week 4

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Summary

Introduction

To clarify the mechanisms and their temporal relationship in the development of proliferative vitreoretinopathy (PVR), we measured vitreous levels of pro-inflammatory cytokines and growth factors in a rabbit model of PVR. We demonstrated that inflammatory cytokines IL-6, -8, elevation post PVR induction is followed by elevated levels of fibroproliferative growth factors, Ang[2], PlGF, VEGF and PDGF-BB in the development of PVR. These findings will guide future studies targeting appropriate therapeutic strategies for the treatment of PVR. To help clarify the mechanisms and their temporal relationship in the development of PVR, we conducted a study of changes in cytokine levels following surgically induced PVR in the rabbit This rabbit model is a surgical model based on human pathogenesis, i.e. PVR following retinal detachment and reflects clinically relevant disease. The aim of this study was to compare the levels of pro-inflammatory cytokines and growth factors involved in RPE cell proliferation and epithelial mesenchymal transition at various time points in the evolution of PVR, and to correlate these levels to the severity of PVR

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