Differential association of elevated inflammatory cytokines with postoperative fibrous proliferation and neovascularization after unsuccessful vitrectomy in eyes with proliferative diabetic retinopathy

Kobayashi, Yoshiyuki; Nakao, Shintaro; Sassa, Yukio; Hisatomi, Toshio; Ikeda, Yasuhiro; Oshima, Yuji; Kono, Toshihiro; Ishibashi, Tatsuro; Sonoda, Koh Hei

doi:10.2147/opth.s141821

Cited by 26 publications

(15 citation statements)

References 29 publications

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“…Such unspecific upregulation of many cytokines may result from a damage to the retinovascular barrier following retinal detachment. Therefore, the cytokine milieu changes may represent a timely response to the tissue trauma which cannot be attributed to one single biological process [16,33,34,35]. The significant upregulation of pro-fibrotic and pro-inflammatory cytokines in eyes with RD compared to MH found in our study is in good agreement with previous studies that have found similar upregulations compared to eyes with either macular hole, epiretinal membrane or retinal vein occlusion, notably for cytokines as IL-6 and IL-8 [1,16,19,20,36,37], MCP1, MIP-1beta and IP10 [36,38], and in RD with PVR for IL-6, IL-8, IL-10, TNF, INF-gamma, CCL2, CCL3, CCL4, CCL5, CCL11, CCL17, CCL18, CCL19, CXCL9, CXCL19, G-CSF and FGF [2,12,39].…”

Section: Discussionmentioning

confidence: 99%

Biomarkers for PVR in rhegmatogenous retinal detachment

et al. 2019

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Purpose Various profibrotic and proinflammatory cytokines have been found upregulated in uncomplicated primary retinal detachment (pRD), but without providing a uniform picture. Here, we compare the cyto- and chemokine profiles in pRD with and without proliferative vitreoretinopathy (PVR) in an attempt to unravel relevant differences not in single cytokines, but in the cytokine profiles at diagnosis. Methods Undiluted vitreous fluid (VF) was obtained at the beginning of surgery from 174 eyes with pRD without relevant PVR (maximally grade B; group 1; n = 81) and with moderate or advanced PVR requiring a gas tamponade (group 2; n = 49) or silicon oil filling (group 3; n = 44). VF of eyes undergoing macular hole (MH) surgery served as controls (group 4; n = 26). Forty-three cytokines were quantified in parallel using a multiplex cytokine analysis system (Bioplex). For all comparisons we applied Holm’s correction to control for multiple comparisons. Results 44.9% of group 2 eyes presented grade C1 and 55.1% C2-C3, whereas 86.4% of group 3 eyes exhibited a PVR grade of C2-D. CCL19 was the only cytokine that displayed higher concentrations in the vitreous of eyes with PVR C1 compared to lower PVR grades. Eyes with PVR C2-D showed higher levels of CCL27, CXCL6, IL4, IL16, CXCL10, CCL8, CCL22, MIG/CXCL9, CCL15, CCL19, CCL 23 and CXCL12 compared to controls. Interestingly, no difference of cytokine levels was detected between C1 and C2-D PVR. Conclusions CCL19 may represent a potential biomarker for early PVR progression that holds promise for future diagnostic and therapeutic applications.

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Section: Discussionmentioning

confidence: 99%

Biomarkers for PVR in rhegmatogenous retinal detachment

et al. 2019

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“…Intraocular neovascularization is an important clinical manifestation which is the pathological basis for numerous ocular disorders, such as proliferative diabetic retinopathy, ischemic central retinal vein occlusion and retinopathy of prematurity ( 1 – 3 ). No effective treatment for retinal neovascularization (RNV) is available to date.…”

Section: Introductionmentioning

confidence: 99%

β‑elemene inhibits oxygen‑induced retinal neovascularization via promoting miR‑27a and reducing VEGF expression

et al. 2019

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The present study aimed to investigate the significant role of β-elemene in mouse models of oxygen-induced retinopathy (OIR). C57BL/6J neonatal mice were used to establish OIR models. They were divided into four groups: Normoxia, OIR, OIR control and OIR-treated. Mice in the OIR group were exposed to 75±5% oxygen for 5 days and returned to a normal oxygen environment on postnatal day 12 (P12). The OIR treated group was intravitreally injected with 1 µl β-elemene on P12 and subsequently returned to a normal oxygen environment for 5 days (P12-P17). Retinas were obtained on P17. Retinal neovascularization (RNV) was detected using adenosine diphosphatase staining and analyzed by counting the nuclei of neovascular endothelial cells. Vascular endothelial growth factor (VEGF) expression was determined by reverse transcription-quantitative polymerase chain reaction, immunohistochemistry and western blot analysis. MicroRNA (miRNA/miR) microarrays were used to screen out differentially expressed miRNAs between the OIR and β-elemene-treated groups. Binding the 3′-untranslated region (UTR) of VEGF and miR-27a was confirmed using luciferase assays. It was found that high oxygen concentrations accelerated RNV and increased the number of preretinal neovascular cells; β-elemene treatment reduced these effects. VEGF mRNA and protein expression was higher in the OIR and OIR control groups, compared with the normoxia and OIR-treated groups. Further, it was shown that miR-22, miR-181a-1, miR-335-5p, miR-669n, miR-190b, miR-27a and miR-93 were upregulated in the OIR-treated group, and downregulated in the OIR group. The prediction websites TargetScan and miRanda revealed that VEGF contained a potential miR-27a binding site in its 3′-untranslated region (UTR). Luciferase assays demonstrated that miR-27a directly bound to the 3′-UTR of VEGF. In vitro experiments demonstrated that miR-27a inhibited VEGF expression. In addition, β-elemene treatment upregulate miR-27a expression in vivo and in vitro . When miR-27a expression was depleted by miR-27a inhibitor, the protective effect of β-elemene on RNV was eliminated. The present study demonstrated that β-elemene reduced RNV in mouse OIR models via miR-27a upregulation, leading to reduced VEGF expression. This finding may contribute to the development of novel therapeutic strategies for human retinopathy.

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“…The dominant finding from the current study was the inflammation. There are several pathways involved in the development of PVR; however, ocular inflammation is the hallmark of PVR formation (Yoshida et al., 2017 ). Inflammation can cause the blood-retina barrier to breakdown.…”

Section: Discussionmentioning

confidence: 99%

New model of proliferative vitreoretinopathy in rabbit for drug delivery and pharmacodynamic studies

et al. 2018

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Blinding retinal diseases become more epidemic as the population ages. These diseases, such as diabetic retinopathy and macular edema, are of chronic nature and require protracted drug presence at the disease site. A sustained intravitreal porous silicon delivery system with dexamethasone (pSiO2-COO-DEX) was evaluated in a new rabbit model of proliferative vitreoretinopathy (PVR) in a real treatment design. In contrast to the pretreatment design model, pSiO2-COO-DEX was intravitreally injected into the eyes with active inflammation. Subretinal injection of vascular endothelial growth factor (VEGF) and Matrigel induced a late-onset vitreoretinal inflammation that gradually developed into PVR. This method mimics the human disease better than PVR induced by either intravitreal cell injection or trauma. The pSiO2-COO-DEX intervened eyes had minimal PVR, while balanced saline solution or free dexamethasone intervened eyes had significantly more PVR formation. In addition, adding VEGF to the Matrigel for subretinal injection induced greater inflammation and retinal neovascularization in comparison to only Matrigel injected under the medullary ray. Clinical and pathological examinations, including fundus fluorescein angiography and optical coherence tomography, confirmed these changes. In the current study, neither subretinal injection of Matrigel or subretinal injection of VEGF and Matrigel induced choroidal neovascularization. However, the current PVR model demonstrates a chronic course with moderate severity, which may be useful for drug screening studies.

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Differential association of elevated inflammatory cytokines with postoperative fibrous proliferation and neovascularization after unsuccessful vitrectomy in eyes with proliferative diabetic retinopathy

Cited by 26 publications

References 29 publications

Biomarkers for PVR in rhegmatogenous retinal detachment

Biomarkers for PVR in rhegmatogenous retinal detachment

β‑elemene inhibits oxygen‑induced retinal neovascularization via promoting miR‑27a and reducing VEGF expression

New model of proliferative vitreoretinopathy in rabbit for drug delivery and pharmacodynamic studies

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