Molecular basis of the inner blood-retinal barrier and its breakdown in diabetic macular edema and other pathological conditions

Klaassen, Ingeborg; Noorden, C. J. F. Van; Schlingemann, Reinier O.

doi:10.1016/j.preteyeres.2013.02.001

Cited by 591 publications

(559 citation statements)

References 392 publications

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“…The common pathway that leads to macular oedema in DMO as well as other exudative retinal conditions is breakdown of the blood-retinal barrier (BRB) [8]. The BRB consists of the inner BRB and the outer BRB, which exist to maintain homeostasis in the neural tissue.…”

Section: Pathophysiologymentioning

confidence: 99%

“…Disruption of the BRB in diabetic retinopathy results from the release of inflammatory cytokines and growth factors in states of chronic hyperglycaemia. Important factors implicated include VEGF-A, placenta growth factor (PlGF), IL-8, IL-6, IL-1β, TNF-α and matrix metalloproteinases [8][9][10].…”

Section: Pathophysiologymentioning

confidence: 99%

“…AGEs also bind to AGE receptors in Müller cells, causing upregulation of nuclear factor-κB, which increases the transcription of inflammatory cytokines and VEGF [15]. BRB function may be affected directly by AGE-mediated alterations of transmembrane proteins, such as integrins [8].…”

Section: Pathophysiologymentioning

confidence: 99%

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Diabetic macular oedema: pathophysiology, management challenges and treatment resistance

Bahrami

Zhu

Hong³

et al. 2016

Diabetologia

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Diabetic macular oedema (DMO) is the leading cause of vision loss in patients living with diabetes. DMO results from hyperglycaemia-induced activation of pathways that lead to oxidative stress and release of cytokines, impairing the inner and outer blood-retinal barriers. Improved understanding of the pathophysiological mechanisms leading to DMO have led to the development of effective therapies, including vitreoretinal surgery, laser photocoagulation, intravitreal anti-vascular endothelial growth factor drugs and corticosteroids. Advances in imaging, including fluorescein angiography and optical coherence tomography, have also enhanced diagnosis and management of the condition. Despite these advances, there remain patients who do not respond completely to therapy, reflecting the complex pathophysiology of DMO. These patients may be considered treatment-resistant. In this review, we summarise the pathophysiology of DMO, as well as the available treatments and their mechanism of action. Additionally, we focus on treatment-resistant disease and review the literature on potential options for managing this complication of diabetes.

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Section: Pathophysiologymentioning

confidence: 99%

Section: Pathophysiologymentioning

confidence: 99%

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Diabetic macular oedema: pathophysiology, management challenges and treatment resistance

Bahrami

Zhu

Hong³

et al. 2016

Diabetologia

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“…At the most advanced stage, the new vessels can lead to retinal traction with subsequent retinal detachment. 9 Diabetic retinopathy is diagnosed through observation of the changes described above through direct and indirect fundoscopy, retinography, photographic records of the retina or angiofluoresceinography. 8,9 Early diagnosis is crucial for the best response to treatments, since more advanced degrees of retinopathy have worse prognoses.…”

Section: Introductionmentioning

confidence: 99%

What do Cochrane systematic reviews say about diabetic retinopathy?

et al. 2017

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CONTEXT AND OBJECTIVE: Diabetic retinopathy is a disease caused by increased permeability of retinal vessels. Its incidence and prevalence have been increasing due to urbanization, greater life expectancy and the habits of modern life. Its onset is insidious and it may lead to blindness in 75% of individuals who have been diabetic for more than 20 years. The aim here was to evaluate the evidence from Cochrane systematic reviews on interventions relating to diabetic retinopathy. DESIGN AND SETTING: Review of systematic reviews, conducted at Cochrane Brazil. METHODS:We included Cochrane systematic reviews on interventions relating to diabetic retinopathy. Two researchers evaluated the inclusion criteria, summarized the reviews and presented the results narratively. RESULTS: Ten reviews met the inclusion criteria. They showed some evidence of benefits from: (a) photocoagulation for diabetic retinopathy; (b) strict glucose and pressure control for postponing the onset of retinopathy; (c) antiangiogenic drugs for macular edema (high-quality evidence); (d) anti-vascular endothelial growth factor agents for proliferative diabetic retinopathy (very low to low-quality evidence); and (e) intravitreal injection or surgical implantation for treating persistent or refractory macular edema. However, blood pressure control seems to have no benefit after the onset of retinopathy. CONCLUSION: Only a few options are likely to be effective for treating diabetic retinopathy. These include photocoagulation and anti-vascular endothelial growth factor agents. Strict glucose and pressure control seem to postpone the onset of retinopathy. For macular edema, antiangiogenic drugs, intravitreal injection and surgical implantation seem to have some benefit. RESUMO CONTEXTO:A retinopatia diabética é uma doença causada pelo aumento da permeabilidade dos vasos da retina. Sua incidência e prevalência vêm aumentando devido à urbanização, maior expectativa de vida e hábitos de vida modernos. Seu início é insidioso e pode levar à cegueira em 75% dos pacientes diabéti-cos com mais de 20 anos de doença. O objetivo foi avaliar a evidência das revisões sistemáticas Cochrane sobre intervenções para retinopatia diabética.

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“…1,2,15,16 In the retina, leakage is due to increased permeability that occurs at the retinal 'neurovascular' unit, which consists of single layer of tightly adherent ECs, basal lamina, surrounding pericytes, astrocytes, and microglia leading to increased EC trans-or paracellular permeability, as summarised in the recent review by Klaassen et al 17 There are contributory anatomical and biochemical changes that are interlinked ( Figure 1). The anatomic changes include EC damage-death or dysfunction, pericyte loss or dysfunction, thickened basement membrane, loss or dysfunction of glial cells, and loss/change of EC Glycocalyx.…”

Section: Introductionmentioning

confidence: 99%

A review of therapies for diabetic macular oedema and rationale for combination therapy

Amoaku

Saker

Stewart

2015

Eye

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Diabetic macular oedema (DMO) is responsible for significant visual impairment in diabetic patients. The primary cause of DMO is fluid leakage resulting from increased vascular permeability through contributory anatomical and biochemical changes. These include endothelial cell (EC) death or dysfunction, pericyte loss or dysfunction, thickened basement membrane, loss or dysfunction of glial cells, and loss/change of EC Glycocalyx. The molecular changes include increased reactive oxygen species, pro-inflammatory changes: advanced glycation end products, intracellular adhesion molecule-1, Complement 5-9 deposition and cytokines, which result in increased paracellular permeability, tight junction disruption, and increased transcellular permeability. Laser photocoagulation has been the mainstay of treatment until recently when pharmacological treatments were introduced. The current treatments for DMO target reducing vascular leak in the macula once it has occurred, they do not attempt to treat the underlying pathology. These pharmacological treatments are aimed at antagonising vascular endothelial growth factor (VEGF) or non-VEGF inflammatory pathways, and include intravitreal injections of anti-VEGFs (ranibizumab, aflibercept or bevacizumab) or steroids (fluocinolone, dexamethasone or triamcinolone) as single therapies. The available evidence suggests that each individual treatment modality in DMO does not result in a completely dry macula in most cases. The ideal treatment for DMO should improve vision and improve morphological changes in the macular (eg, reduce macular oedema) for a significant duration, reduced adverse events, reduced treatment burden and costs, and be well tolerated by patients. This review evaluates the individual treatments available as monotherapies, and discusses the rationale and potential for combination therapy in DMO.

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Molecular basis of the inner blood-retinal barrier and its breakdown in diabetic macular edema and other pathological conditions

Cited by 591 publications

References 392 publications

Diabetic macular oedema: pathophysiology, management challenges and treatment resistance

Diabetic macular oedema: pathophysiology, management challenges and treatment resistance

What do Cochrane systematic reviews say about diabetic retinopathy?

A review of therapies for diabetic macular oedema and rationale for combination therapy

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