Dataset Information

Modelling Macular Edema: The Effect of IL-6 and IL-6R Blockade on Human Blood-Retinal Barrier Integrity In Vitro.

ABSTRACT: Purpose:Macular edema (ME) is a leading cause of visual loss in a range of retinal diseases and despite the use of antivascular endothelial growth factor (anti-VEGF) agents, its successful treatment remains a major clinical challenge. Based on the indirect clinical evidence that interleukin-6 (IL-6) is a key additional candidate mediator of ME, we interrogated the effect of IL-6 on blood-retinal barrier (BRB) integrity in vitro. Methods:Human retinal pigment epithelial cell (ARPE-19) and human retinal microvascular endothelial cell (HRMEC) monolayers were used to mimic the outer and inner BRB, respectively. Their paracellular permeability was assessed by measuring the passive permeation of 40 kDa fluorescein isothiocyanate (FITC)-dextran across confluent cells in the presence of IL-6. Transendothelial/epithelial electrical resistance (TEER) then was measured and the distribution of the tight junction protein ZO-1 was assessed by immunofluorescence using confocal microscopy. Results:Treatment with IL-6 for 48 hours significantly increased the diffusion rate of FITC-dextran, decreased TEER, and disrupted the distribution of ZO-1 in ARPE-19 cells, which constitutively express the IL-6 transmembrane receptor, and this was reversed with IL-6R blockade. In contrast, IL-6 did not affect the paracellular permeability, TEER, or ZO-1 distribution in HRMECs. Conclusions:These in vitro data support the hypothesis that IL-6 reversibly disrupts the integrity of ARPE-19 cells, but it does not affect HRMECs. Translational Relevance:IL-6 is a candidate therapeutic target in the treatment of outer BRB driven ME.

SUBMITTER: Mesquida M

PROVIDER: S-EPMC6819001 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Modelling Macular Edema: The Effect of IL-6 and IL-6R Blockade on Human Blood-Retinal Barrier Integrity In Vitro.

Mesquida Marina M Drawnel Faye F Lait Philippa J PJ Copland David A DA Stimpson Madeleine L ML Llorenç Victor V Sainz de la Maza Maite M Adan Alfredo A Widmer Gabriella G Strassburger Pamela P Fauser Sascha S Dick Andrew D AD Lee Richard W J RWJ Molins Blanca B

Translational vision science & technology 20190901 5

<h4>Purpose</h4>Macular edema (ME) is a leading cause of visual loss in a range of retinal diseases and despite the use of antivascular endothelial growth factor (anti-VEGF) agents, its successful treatment remains a major clinical challenge. Based on the indirect clinical evidence that interleukin-6 (IL-6) is a key additional candidate mediator of ME, we interrogated the effect of IL-6 on blood-retinal barrier (BRB) integrity in vitro.<h4>Methods</h4>Human retinal pigment epithelial cell (ARPE- ...[more]

PMID: 31667008

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Project description:BackgroundPreterm birth preceded by spontaneous preterm labour often occurs in the clinical setting of sterile intra-amniotic inflammation (SIAI), a condition that currently lacks treatment.MethodsProteomic and scRNA-seq human data were analysed to evaluate the role of IL-6 and IL-1α in SIAI. A C57BL/6 murine model of SIAI-induced preterm birth was developed by the ultrasound-guided intra-amniotic injection of IL-1α. The blockade of IL-6R by using an aIL-6R was tested as prenatal treatment for preterm birth and adverse neonatal outcomes. QUEST-MRI evaluated brain oxidative stress in utero. Targeted transcriptomic profiling assessed maternal, foetal, and neonatal inflammation. Neonatal biometrics and neurodevelopment were tested. The neonatal gut immune-microbiome was evaluated using metagenomic sequencing and immunophenotyping.FindingsIL-6 plays a critical role in the human intra-amniotic inflammatory response, which is associated with elevated concentrations of the alarmin IL-1α. Intra-amniotic injection of IL-1α resembles SIAI, inducing preterm birth (7% vs. 50%, p = 0.03, Fisher's exact test) and neonatal mortality (18% vs. 56%, p = 0.02, Mann-Whitney U-test). QUEST-MRI revealed no foetal brain oxidative stress upon in utero IL-1α exposure (p > 0.05, mixed linear model). Prenatal treatment with aIL-6R abrogated IL-1α-induced preterm birth (50% vs. 7%, p = 0.03, Fisher's exact test) by dampening inflammatory processes associated with the common pathway of labour. Importantly, aIL-6R reduces neonatal mortality (56% vs. 22%, p = 0.03, Mann-Whitney U-test) by crossing from the mother to the amniotic cavity, dampening foetal organ inflammation and improving growth. Beneficial effects of prenatal IL-6R blockade carried over to neonatal life, improving survival, growth, neurodevelopment, and gut immune homeostasis.InterpretationIL-6R blockade can serve as a strategy to treat SIAI, preventing preterm birth and adverse neonatal outcomes.FundingNICHD/NIH/DHHS, Contract HHSN275201300006C. WSU Perinatal Initiative in Maternal, Perinatal and Child Health.

Project description:BackgroundThe comparative safety and efficacy of different doses of intravitreal triamcinolone acetonide (IVTA) for diabetic macular edema (DME) and macular edema (ME) secondary to retinal vein occlusion (RVO) is unclear.ObjectivesThis meta-analysis aimed to compare the safety and efficacy of different doses of IVTA in this setting.MethodsA systematic literature search for randomized clinical trials (RCTs) was conducted on Cochrane Library, Ovid MEDLINE, and EMBASE from January 2005 to May 2022. Studies that reported on patients with DME or ME secondary to RVO that received treatment with different doses of IVTA were included. A random-effects meta-analysis was performed. Cochrane's Risk of Bias Tool 2 was used to assess the risk of bias, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) guidelines were used to assess certainty of evidence.ResultsFive RCTs reporting on 1,041 eyes at baseline were included in this meta-analysis. In eyes with ME secondary to RVO, high-dose (4 mg) IVTA achieved a significantly better change in best-corrected visual acuity (WMD = -4.75 ETDRS letters, 95% CI = [-7.73, -1.78], p = 0.002) and reduction in retinal thickness (WMD = -93.02 μm, 95% CI = [-153.23, -32.82], p = 0.002) at months 4-6 compared to low-dose (1-2 mg) IVTA. However, high-dose IVTA had a higher risk of intraocular pressure-related adverse events (RR = 2.99, 95% CI = [1.05, 8.50], p = 0.04) and cataract surgery (RR = 5.67, 95% CI = [3.09, 10.41], p < 0.00001) than low-dose IVTA in eyes with ME secondary to RVO. These efficacy and safety differences in high-dose and low-dose IVTA were not observed in DME eyes.ConclusionsThe RCT evidence in this setting is limited. High-dose IVTA achieved greater improvements in visual acuity and reductions in retinal thickness than low-dose IVTA at months 4-6. However, high-dose IVTA had a less favorable safety profile than low-dose IVTA. The significance of these outcomes was based on patients with ME secondary to RVO, but not DME.

Project description:PurposeTo assess the relationship between best-corrected visual acuity (BCVA) and anatomic features in patients with macular edema (ME) related to retinal vein occlusion (RVO).DesignPost hoc analysis of 3 clinical trials, which included verified diagnoses, protocol refractions, and the assessment of OCT and fluorescein angiography (FA) images at a masked reading center.ParticipantsPatients diagnosed with RVO-ME.MethodsCorrelation analyses were performed to determine the correlation between BCVA and macular anatomy at baseline and at 12 and 24 weeks and between changes from baseline to 12 and 24 weeks.Main outcome measuresThe correlations between BCVA and central subfield thickness (CST), ellipsoid zone (EZ) integrity, intraretinal fluid (IRF), subretinal fluid, central leakage, and ischemia were assessed.ResultsIn a total of 828 eyes with RVO-ME, the mean age, BCVA, and CST at baseline was 64.7 years, 51.1 letters, and 656.9 μm, respectively. At baseline, a moderate negative correlation was observed between BCVA and CST (r = - 0.56, P < 0.001). At weeks 12 and 24, the mean BCVA of eyes with definitely abnormal (absent) EZ was statistically significantly worse than that of eyes with normal EZ. At week 12, a moderate negative correlation was observed between changes in BCVA and changes in CST (r = - 0.35, P < 0.001), with a similar degree of association noted at week 24 (r = - 0.35, P < 0.001). At weeks 12 and 24, eyes that showed any improvement in central IRF showed a greater improvement in BCVA than eyes that showed no improvement worsening (week 12: 463 eyes, 18.3 letters vs. 177 eyes, 13.0 letters, respectively, P < 0.001) and (week 24: 332 eyes, 20.2 letters vs. 131 eyes, 13.3 letters, respectively, P < 0.001). With respect to the correlation between baseline BCVA and fluorescein leakage or capillary nonperfusion, the Pearson correlation coefficients were - 0.41 (P < 0.001) and - 0.16 (P = 0.060), respectively.ConclusionsIn addition to CST, there are important clinically relevant relationships between BCVA and both OCT and FA anatomic features in patients with RVO-ME.

Project description:Importance:In diabetic macular edema (DME), identification of baseline markers on spectral-domain optical coherence tomography (SD-OCT) and their association with severity of diabetic retinopathy (DR) might aid in disease management and the design of future trials. Objective:To examine associations between DR severity, retinal morphology on SD-OCT, and visual acuity in participants with DME. Design, Setting, and Participants:This cross-sectional observational case series was conducted at a single tertiary care referral center. Demographics, visual acuity, SD-OCT, and color fundus photographs of 80 individuals with DME (102 eyes) seen between December 28, 2013, and April 30, 2014, were analyzed between May 1 and July 31, 2016. Main Outcomes and Measures:Features captured on SD-OCT and thickness metrics. On SD-OCT we graded type and shape of DME, shape and presence of septae within the intraretinal cystoid abnormalities, presence of hyperreflective dots and foci, integrity of the external limiting membrane and ellipsoid zone, presence and extent of disorganization of the inner retinal layers (DRIL), and the status of the vitreomacular interface and epiretinal membrane. We measured retinal thickness at the fovea and at the site of maximum pathology, choroidal thickness at the fovea, and 1000 ?m temporal and nasal to the fovea. Color photographs were graded to derive a DR severity stage. Results:The mean (SD) age was 63 (11) years, and 30 participants (37.5%) were women. The odds of having DRIL were greater in eyes with disrupted external limiting membrane (odds ratio [OR], 4.4; 95% CI, 1.6-12.0; P?=?.003), disrupted ellipsoid zone (OR, 2.7; 95% CI, 1.0-7.2; P?=?.03), presence of epiretinal membrane (OR, 2.8; 95% CI, 1.0-7.4; P?=?.03), and increase in retinal thickness at the fovea (OR, 1.6; 95% CI, 1.1-2.2; P?<?.001). Occurrence of DRIL was more likely in eyes with proliferative DR (OR, 7.3; 95% CI, 1.7-31.4; P?=?.007). Mean visual acuity decreased by approximately 4.7 letters for each 100-?m increase in the average global DRIL (95% CI, -7.9 to 1.4; P?=?.006). Conclusions and Relevance:An association was found between DRIL and disruption of the outer retina and increasing DR severity. Further longitudinal studies seem warranted to determine whether DRIL is a clinically relevant noninvasive morphological marker in eyes with DME.

Dataset Information

Modelling Macular Edema: The Effect of IL-6 and IL-6R Blockade on Human Blood-Retinal Barrier Integrity In Vitro.

Publications

Modelling Macular Edema: The Effect of IL-6 and IL-6R Blockade on Human Blood-Retinal Barrier Integrity In Vitro.

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