Alterations in the aqueous humor proteome in patients with a glaucoma shunt device

Purpose To investigate whether implantation of a glaucoma shunt device leads to inappropriate accumulation of plasma derived proteins in the aqueous humor. Methods Aqueous humor samples were collected from 11 patients (study group) with a glaucoma shunt device undergoing either cataract surgery or a corneal transplant and 11 patients (control) with senile cataract undergoing routine cataract extraction. Of the study group, 9 had an Ahmed valve implant and 2 eyes had a Baerveldt implant. Tryptic digests of the mixture of proteins in aqueous humor (AH) were analyzed using Liquid Chromatography/Mass Spectrometry (LC-MS/MS). Proteins were identified with high confidence using stringent criteria and compared quantitatively using a label-free platform (IdentiQuantXLTM). Results We identified 135 proteins in the albumin-depleted fraction in both the study and control group AH. Using stringent criteria, 13 proteins were detected at a significantly higher level compared to controls. These proteins are known to play a role in oxidative stress, apoptosis, inflammation and/or immunity and include gelsolin (p=0.00005), plasminogen (p=0.00009), angiotensinogen (p=0.0001), apolipoprotein A-II (p=0.0002), beta-2-microglobulin (p=0.0002), dickkopf-3 (DKK-3; p=0.0002), pigment epithelium-derived factor (p=0.0002), RIG-like 7–1 (p=0.0002), afamin (p=0.0003), fibronectin 1 (FN1; p=0.0003), apolipoprotein A-I (p=0.0004), activated complement C4 protein (C4a; p=0.0004) and prothrombin (p=0.0004). Many of the identified proteins were novel proteins that have not been associated with glaucoma in prior studies. All but C4a (complement C4 is a plasma protein but not in an activated form) are known plasma proteins and the elevated levels of these proteins in the aqueous humor suggests a breach in the blood-aqueous barrier with passive influx into the anterior chamber of the eye. Conclusions The presence of these proteins in the aqueous humor suggests that glaucoma shunt device causes either a breach in blood-aqueous barrier or chronic trauma, increasing influx of oxidative, apoptotic and inflammatory proteins that could potentially cause corneal endothelial damage.

[1]  T. Bramsen,et al.  FIBRINOLYTIC FACTORS IN AQUEOUS HUMOUR AND SERUM FROM PATIENTS WITH FUCHS‘ DYSTROPHY AND PATIENTS WITH CATARACT , 1979, Acta ophthalmologica.

[2]  F. del Greco,et al.  Rationale and application of beta-2-microglobulin measurements to detect acute transplant rejection. , 1981, Nephron.

[3]  C. Kirkness.  Penetrating keratoplasty, glaucoma and silicone drainage tubing. , 1987, Developments in ophthalmology.

[4]  R. E. Smith,et al.  Molteno implant for control of glaucoma in eyes after penetrating keratoplasty. , 1988, Ophthalmology.

[5]  S. Wilson,et al.  Aqueous humor composition in Fuchs' dystrophy. , 1989, Investigative ophthalmology & visual science.

[6]  S. Wilson,et al.  Graft failure after penetrating keratoplasty. , 1990, Survey of ophthalmology.

[7]  S. Wilson,et al.  Epidermal growth factor, transforming growth factor alpha, transforming growth factor beta, acidic fibroblast growth factor, basic fibroblast growth factor, and interleukin-1 proteins in the cornea. , 1994, Experimental eye research.

[8]  T. Paunio,et al.  Toward understanding the pathogenic mechanisms in gelsolin-related amyloidosis: in vitro expression reveals an abnormal gelsolin fragment. , 1994, Human molecular genetics.

[9]  E. Rungger-Brändle,et al.  Expression and release of tumor necrosis factor-alpha by explants of mouse cornea. , 1996, Investigative ophthalmology & visual science.

[10]  C. O'brien,et al.  Activation of the coagulation cascade in untreated primary open-angle glaucoma. , 1997, Ophthalmology.

[11]  D Aravot,et al.  Beta-2 microglobulin in heart transplanted patients. , 1997, Transplantation proceedings.

[12]  A. Tarkkanen,et al.  Cellular and plasma fibronectin in the aqueous humour of primary open-angle glaucoma, exfoliative glaucoma and cataract patients , 1998, Eye.

[13]  A. Coleman,et al.  Follow-up of the original cohort with the Ahmed glaucoma valve implant. , 1999, American journal of ophthalmology.

[14]  R. Ayyala,et al.  Penetrating keratoplasty and glaucoma. , 2000, Survey of ophthalmology.

[15]  J. M. Taylor,et al.  Long-term results of eyes with penetrating keratoplasty and glaucoma drainage tube implant. , 2001, Ophthalmology.

[16]  J. Dayer,et al.  High-density lipoprotein-associated apolipoprotein A-I: the missing link between infection and chronic inflammation? , 2002, Autoimmunity reviews.

[17]  B. Seitz,et al.  Long-Term Follow-Up of Intraocular Pressure After Penetrating Keratoplasty for Keratoconus and Fuchs' Dystrophy: Comparison of Mechanical and Excimer Laser Trephination , 2002, Cornea.

[18]  Alexey I Nesvizhskii,et al.  Empirical statistical model to estimate the accuracy of peptide identifications made by MS/MS and database search. , 2002, Analytical chemistry.

[19]  M. Becker‐André,et al.  Vitamin E binding protein afamin protects neuronal cells in vitro. , 2002, Journal of neural transmission. Supplementum.

[20]  B. Harvey,et al.  Renin-angiotensin system expression and secretory function in cultured human ciliary body non-pigmented epithelium , 2002, The British journal of ophthalmology.

[21]  E. Duh,et al.  Retinal neuroprotection against ischemic injury mediated by intraocular gene transfer of pigment epithelium-derived factor. , 2003, Investigative ophthalmology & visual science.

[22]  R. Aebersold,et al.  A statistical model for identifying proteins by tandem mass spectrometry. , 2003, Analytical chemistry.

[23]  A. Al-Torbak.  Graft Survival and Glaucoma Outcome After Simultaneous Penetrating Keratoplasty and Ahmed Glaucoma Valve Implant , 2003, Cornea.

[24]  P. Evelson,et al.  Oxidative stress markers in aqueous humor of glaucoma patients. , 2004, American journal of ophthalmology.

[25]  M. Matsumura,et al.  Decrease of pigment epithelium-derived factor in aqueous humor with increasing age. , 2004, American journal of ophthalmology.

[26]  I. Schwab,et al.  The long-term results of keratoplasty in eyes with a glaucoma drainage device. , 2004, American journal of ophthalmology.

[27]  B. Honoré,et al.  Proteomic analysis of aqueous humour from patients with acute corneal rejection. , 2005, Acta ophthalmologica Scandinavica.

[28]  A. Izzotti,et al.  Oxidative DNA damage in the human trabecular meshwork: clinical correlation in patients with primary open-angle glaucoma. , 2005, Archives of ophthalmology.

[29]  R. Miskin,et al.  Plasminogen activator inhibitor-1 in the aqueous humor of patients with and without glaucoma. , 2005, Archives of ophthalmology.

[30]  J. Alvarado,et al.  Interactions between endothelia of the trabecular meshwork and of Schlemm's canal: a new insight into the regulation of aqueous outflow in the eye. , 2005, Transactions of the American Ophthalmological Society.

[31]  G. Tezel.  Oxidative stress in glaucomatous neurodegeneration: Mechanisms and consequences , 2006, Progress in Retinal and Eye Research.

[32]  R. Mott,et al.  Pigment epithelium‐derived factor (PEDF) is an endogenous antiinflammatory factor , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[33]  A. Hackam,et al.  Identification of two novel activities of the Wnt signaling regulator Dickkopf 3 and characterization of its expression in the mouse retina , 2007, BMC Cell Biology.

[34]  D. Coster,et al.  Risk Factors for Human Corneal Graft Failure Within the Australian Corneal Graft Registry , 2008, Transplantation.

[35]  Chang Sik Kim,et al.  Changes in corneal endothelial cell density and morphology after Ahmed glaucoma valve implantation during the first year of follow up , 2008, Clinical & experimental ophthalmology.

[36]  Young H. Kwon,et al.  Graft failure: III. Glaucoma escalation after penetrating keratoplasty , 2008, International Ophthalmology.

[37]  A. Chauhan,et al.  Anti-amyloidogenic, anti-oxidant and anti-apoptotic role of gelsolin in Alzheimer’s disease , 2008, Biogerontology.

[38]  N. Pfeiffer,et al.  Transthyretin and complex protein pattern in aqueous humor of patients with primary open-angle glaucoma , 2008, Molecular vision.

[39]  P. Janmey,et al.  Plasma gelsolin: function, prognostic value, and potential therapeutic use. , 2008, Current protein & peptide science.

[40]  Ningli Wang,et al.  Proteomic analysis of aqueous humor from patients with myopia , 2008, Molecular vision.

[41]  Mu Wang,et al.  Proteomic analysis of human aqueous humor using multidimensional protein identification technology , 2009, Molecular vision.

[42]  Xiaohong Zhou,et al.  Anti-inflammatory effect of pigment epithelium-derived factor in DBA/2J mice , 2009, Molecular vision.

[43]  E. Tamm,et al.  Modulation of extracellular matrix turnover in the trabecular meshwork. , 2009, Experimental eye research.

[44]  N. Suttorp,et al.  Role of Toll-like receptors, NOD-like receptors and RIG-I-like receptors in endothelial cells and systemic infections , 2009, Thrombosis and Haemostasis.

[45]  R. Beck,et al.  Recipient risk factors for graft failure in the cornea donor study. , 2009, Ophthalmology.

[46]  I. Kim,et al.  Knockdown of the Dickkopf 3 gene induces apoptosis in a lung adenocarcinoma. , 2010, International journal of molecular medicine.

[47]  Yehia Mechref,et al.  Alterations in the aqueous humor proteome in patients with Fuchs endothelial corneal dystrophy , 2010, Molecular vision.

[48]  Ningli Wang,et al.  Proteomic analysis of aqueous humor from patients with primary open angle glaucoma , 2010, Molecular vision.

[49]  H. Kaplan,et al.  Oxidative stress and the regulation of complement activation in human glaucoma. , 2010, Investigative ophthalmology & visual science.

[50]  C. Cartiglia,et al.  Proteome alterations in primary open angle glaucoma aqueous humor. , 2010, Journal of proteome research.

[51]  F. Alkuraya,et al.  Identification of differentially expressed proteins in the aqueous humor of primary congenital glaucoma. , 2011, Experimental eye research.

[52]  Sanjay V. Patel.  Graft survival after penetrating keratoplasty. , 2011, American journal of ophthalmology.

[53]  David A. Price,et al.  Descemet's stripping endothelial keratoplasty five-year graft survival and endothelial cell loss. , 2011, Ophthalmology.