Proteomics of Vitreous Humor of Patients with Exudative Age-Related Macular Degeneration

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Abstract

Background

There is absence of specific biomarkers and an incomplete understanding of the pathophysiology of exudative age-related macular degeneration (AMD).

Methods and Findings

Eighty-eight vitreous samples (73 from patients with treatment naïve AMD and 15 control samples from patients with idiopathic floaters) were analyzed with capillary electrophoresis coupled to mass spectrometry in this retrospective case series to define potential candidate protein markers of AMD. Nineteen proteins were found to be upregulated in vitreous of AMD patients. Most of the proteins were plasma derived and involved in biological (ion) transport, acute phase inflammatory reaction, and blood coagulation. A number of proteins have not been previously associated to AMD including alpha-1-antitrypsin, fibrinogen alpha chain and prostaglandin H2-D isomerase. Alpha-1-antitrypsin was validated in vitreous of an independent set of AMD patients using Western blot analysis. Further systems biology analysis of the data indicated that the observed proteomic changes may reflect upregulation of immune response and complement activity.

Conclusions

Proteome analysis of vitreous samples from patients with AMD, which underwent an intravitreal combination therapy including a core vitrectomy, steroids and bevacizumab, revealed apparent AMD-specific proteomic changes. The identified AMD-associated proteins provide some insight into the pathophysiological changes associated with AMD.

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Most cited references 28

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Aqueous humour levels of cytokines are correlated to vitreous levels and severity of macular oedema in branch retinal vein occlusion.

H Tsukamoto, Hideharu Funatsu, H. Yamashita … (2007)

To investigate whether the aqueous levels of vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) are correlated to the vitreous levels of these substances and to the severity of macular oedema in branch retinal vein occlusion (BRVO). Aqueous and vitreous samples were obtained during cataract and vitreous surgery from 24 patients (24 eyes) with macular oedema in BRVO. The VEGF and IL-6 levels in aqueous humour, vitreous fluid, and plasma were determined by enzyme-linked immunosorbent assay. The degree of retinal ischaemia was evaluated in terms of the area of capillary nonperfusion using the Scion Image. The severity of macular oedema was evaluated using the OCT. The aqueous level of VEGF was significantly correlated with the vitreous level of VEGF (P<0.0001). Vitreous levels of VEGF and IL-6 were significantly correlated with the nonperfusion area of BRVO (P<0.0001, P=0.0061, respectively), as were the aqueous levels of VEGF and IL-6 (P<0.0001, P=0.0267, respectively). Furthermore, the vitreous levels of VEGF and IL-6 and the aqueous level of VEGF were significantly correlated with the severity of macular oedema of BRVO (P=0.0001, P=0.0331, P=0.0272, respectively). Our results suggest that the aqueous level of VEGF may reflect its vitreous level. Measurement of the aqueous level of VEGF may be clinically useful to indicate the severity of macular oedema with BRVO.

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Physiology of vitreous surgery.

Einar Stefánsson (2009)

Vitreous surgery has various physiological and clinical consequences, both beneficial and harmful. Vitrectomy reduces the risk of retinal neovascularization, while increasing the risk of iris neovascularization, reduces macular edema and stimulates cataract formation. These clinical consequences may be understood with the help of classical laws of physics and physiology. The laws of Fick, Stokes-Einstein and Hagen-Poiseuille state that molecular transport by diffusion or convection is inversely related to the viscosity of the medium. When the vitreous gel is replaced with less viscous saline, the transport of all molecules, including oxygen and cytokines, is facilitated. Oxygen transport to ischemic retinal areas is improved, as is clearance of VEGF and other cytokines from these areas, thus reducing edema and neovascularization. At the same time, oxygen is transported faster down a concentration gradient from the anterior to the posterior segment, while VEGF moves in the opposite direction, making the anterior segment less oxygenated and with more VEGF, stimulating iris neovascularization. Silicone oil is the exception that proves the rule: it is more viscous than vitreous humour, re-establishes the transport barrier to oxygen and VEGF, and reduces the risk for iris neovascularization in the vitrectomized-lentectomized eye. Modern vitreous surgery involves a variety of treatment options in addition to vitrectomy itself, such as photocoagulation, anti-VEGF drugs, intravitreal steroids and release of vitreoretinal traction. A full understanding of these treatment modalities allows sensible combination of treatment options. Retinal photocoagulation has repeatedly been shown to improve retinal oxygenation, as does vitrectomy. Oxygen naturally reduces VEGF production and improves retinal hemodynamics. The VEGF-lowering effect of photocoagulation and vitrectomy can be augmented with anti-VEGF drugs and the permeability effect of VEGF reduced with corticosteroids. Starling's law explains vasogenic edema, which is controlled by osmotic and hydrostatic gradients between vessel and tissue. It explains the effect of VEGF-induced vascular permeability changes on plasma protein leakage and the osmotic gradient between vessel and tissue. At the same time, it takes into account hemodynamic changes that affect the hydrostatic gradient. This includes the influence of arterial blood pressure, and the effect oxygen (laser treatment) has in constricting retinal arterioles, increasing their resistance, and thus reducing the hydrostatic pressure in the microcirculation. Reduced capillary hydrostatic pressure and increased osmotic gradient reduce water fluxes from vessel to tissue and reduce edema. Finally, Newton's third law explains that vitreoretinal traction decreases hydrostatic tissue pressure in the retina, increases the pressure gradient between vessel and tissue, and stimulates water fluxes from vessel into tissue, leading to edema.

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Risk factors for age-related macular degeneration.

Jennifer Evans (2001)

There is an increasing body of evidence as to the risk factors for age-related macular degeneration. Age and genetic make-up are the most important risk factors identified to date. Over the next decade, the different genes that are involved in the development of age-related macular degeneration will be identified. There is reasonably consistent evidence that smoking cigarettes results in increased risk of the disease. The question as to whether antioxidant vitamin and mineral supplementation prevents or delays the development of the disease will be resolved as the results of large ongoing trials become available in the next few years. Currently, there is conflicting evidence as to their benefits and some indication as to possible harm. Other risk factors such as alcohol consumption, oestrogen replacement and lifetime light exposure require further study. The study of the epidemiology of age-related macular degeneration would be facilitated by a greater standardization of methods. Studies with large numbers of late stage disease are needed in order to provide the power to investigate moderate risks. This may either be achieved by adding on macular degeneration studies to large cohort studies already in place, or by pooling data from smaller studies.

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Author and article information

Contributors

Sanjoy Bhattacharya: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 14 May 2014

Volume: 9

Issue: 5

Electronic Location Identifier: e96895

Affiliations

[1 ]Department of Ophthalmology, Goethe University, Frankfurt am Main, Germany

[2 ]Doheny Eye Institute, Los Angeles, California, United States of America

[3 ]Department of Ophthalmology, Ruprecht Karls University, Heidelberg, Germany

[4 ]Mosaiques Diagnostics, Hannover, Germany

[5 ]BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom

[6 ]Department of General Ophthalmology, Lublin University, Poland

[7 ]Department of Nephrology, Endocrinology, and Transplantation Medicine Charité-Universitaetsmedizin, Berlin, Germany

[8 ]Department of Ophthalmology, Philipps University, Marburg, Germany

[9 ]Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France

[10 ]Université Toulouse III Paul-Sabatier, Toulouse, France

Bascom Palmer Eye Institute, University of Miami School of Medicine, United States of America

Author notes

* E-mail: Michael.koss@ 123456me.com

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: MK HM JH JPS FK. Performed the experiments: MK JH NN HM HH JJ FK. Analyzed the data: MK JH RR WM JK JS WM JPS. Contributed reagents/materials/analysis tools: JH MK NN JS KK HM JJ. Wrote the paper: MK JH TB JS MP JPS.

Article

Publisher ID: PONE-D-13-36225

DOI: 10.1371/journal.pone.0096895

PMC ID: 4020801

PubMed ID: 24828575

SO-VID: cd283e2e-1a7e-4d3e-aa1c-dd124c826f87

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 20 August 2013

Date accepted : 11 April 2014

Page count

Pages: 11

Funding

The study was financed in part by the Adolf Messer Stiftung in Königstein, Hessen, Germany; No additional external funding was received for this study. http://www.adolf-messer-stiftung.de/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Proteomics of Vitreous Humor of Patients with Exudative Age-Related Macular Degeneration

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Abstract

Background

Methods and Findings

Conclusions

Related collections

PLOS Climate

Most cited references 28

Aqueous humour levels of cytokines are correlated to vitreous levels and severity of macular oedema in branch retinal vein occlusion.

Physiology of vitreous surgery.

Risk factors for age-related macular degeneration.

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