Zinc supplementation inhibits complement activation in age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world. AMD is a multifactorial disorder but complement-mediated inflammation at the level of the retina plays a pivotal role. Oral zinc supplementation can reduce the progression of AMD but the precise mechanism...

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Veröffentlicht in:PloS one 2014-11, Vol.9 (11), p.e112682-e112682
Hauptverfasser: Smailhodzic, Dzenita, van Asten, Freekje, Blom, Anna M, Mohlin, Frida C, den Hollander, Anneke I, van de Ven, Johannes P H, van Huet, Ramon A C, Groenewoud, Joannes M M, Tian, Yuan, Berendschot, Tos T J M, Lechanteur, Yara T E, Fauser, Sascha, de Bruijn, Chris, Daha, Mohamed R, van der Wilt, Gert Jan, Hoyng, Carel B, Klevering, B Jeroen
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container_issue 11
container_start_page e112682
container_title PloS one
container_volume 9
creator Smailhodzic, Dzenita
van Asten, Freekje
Blom, Anna M
Mohlin, Frida C
den Hollander, Anneke I
van de Ven, Johannes P H
van Huet, Ramon A C
Groenewoud, Joannes M M
Tian, Yuan
Berendschot, Tos T J M
Lechanteur, Yara T E
Fauser, Sascha
de Bruijn, Chris
Daha, Mohamed R
van der Wilt, Gert Jan
Hoyng, Carel B
Klevering, B Jeroen
description Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world. AMD is a multifactorial disorder but complement-mediated inflammation at the level of the retina plays a pivotal role. Oral zinc supplementation can reduce the progression of AMD but the precise mechanism of this protective effect is as yet unclear. We investigated whether zinc supplementation directly affects the degree of complement activation in AMD and whether there is a relation between serum complement catabolism during zinc administration and the complement factor H (CFH) gene or the Age-Related Maculopathy susceptibility 2 (ARMS2) genotype. In this open-label clinical study, 72 randomly selected AMD patients in various stages of AMD received a daily supplement of 50 mg zinc sulphate and 1 mg cupric sulphate for three months. Serum complement catabolism-defined as the C3d/C3 ratio-was measured at baseline, throughout the three months of supplementation and after discontinuation of zinc administration. Additionally, downstream inhibition of complement catabolism was evaluated by measurement of anaphylatoxin C5a. Furthermore, we investigated the effect of zinc on complement activation in vitro. AMD patients with high levels of complement catabolism at baseline exhibited a steeper decline in serum complement activation (p
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AMD is a multifactorial disorder but complement-mediated inflammation at the level of the retina plays a pivotal role. Oral zinc supplementation can reduce the progression of AMD but the precise mechanism of this protective effect is as yet unclear. We investigated whether zinc supplementation directly affects the degree of complement activation in AMD and whether there is a relation between serum complement catabolism during zinc administration and the complement factor H (CFH) gene or the Age-Related Maculopathy susceptibility 2 (ARMS2) genotype. In this open-label clinical study, 72 randomly selected AMD patients in various stages of AMD received a daily supplement of 50 mg zinc sulphate and 1 mg cupric sulphate for three months. Serum complement catabolism-defined as the C3d/C3 ratio-was measured at baseline, throughout the three months of supplementation and after discontinuation of zinc administration. Additionally, downstream inhibition of complement catabolism was evaluated by measurement of anaphylatoxin C5a. Furthermore, we investigated the effect of zinc on complement activation in vitro. AMD patients with high levels of complement catabolism at baseline exhibited a steeper decline in serum complement activation (p&lt;0.001) during the three month zinc supplementation period compared to patients with low complement levels. There was no significant association of change in complement catabolism and CFH and ARMS2 genotype. In vitro zinc sulphate directly inhibits complement catabolism in hemolytic assays and membrane attack complex (MAC) deposition on RPE cells. This study provides evidence that daily administration of 50 mg zinc sulphate can inhibit complement catabolism in AMD patients with increased complement activation. This could explain part of the mechanism by which zinc slows AMD progression. 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AMD is a multifactorial disorder but complement-mediated inflammation at the level of the retina plays a pivotal role. Oral zinc supplementation can reduce the progression of AMD but the precise mechanism of this protective effect is as yet unclear. We investigated whether zinc supplementation directly affects the degree of complement activation in AMD and whether there is a relation between serum complement catabolism during zinc administration and the complement factor H (CFH) gene or the Age-Related Maculopathy susceptibility 2 (ARMS2) genotype. In this open-label clinical study, 72 randomly selected AMD patients in various stages of AMD received a daily supplement of 50 mg zinc sulphate and 1 mg cupric sulphate for three months. Serum complement catabolism-defined as the C3d/C3 ratio-was measured at baseline, throughout the three months of supplementation and after discontinuation of zinc administration. Additionally, downstream inhibition of complement catabolism was evaluated by measurement of anaphylatoxin C5a. Furthermore, we investigated the effect of zinc on complement activation in vitro. AMD patients with high levels of complement catabolism at baseline exhibited a steeper decline in serum complement activation (p&lt;0.001) during the three month zinc supplementation period compared to patients with low complement levels. There was no significant association of change in complement catabolism and CFH and ARMS2 genotype. In vitro zinc sulphate directly inhibits complement catabolism in hemolytic assays and membrane attack complex (MAC) deposition on RPE cells. This study provides evidence that daily administration of 50 mg zinc sulphate can inhibit complement catabolism in AMD patients with increased complement activation. This could explain part of the mechanism by which zinc slows AMD progression. 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AMD is a multifactorial disorder but complement-mediated inflammation at the level of the retina plays a pivotal role. Oral zinc supplementation can reduce the progression of AMD but the precise mechanism of this protective effect is as yet unclear. We investigated whether zinc supplementation directly affects the degree of complement activation in AMD and whether there is a relation between serum complement catabolism during zinc administration and the complement factor H (CFH) gene or the Age-Related Maculopathy susceptibility 2 (ARMS2) genotype. In this open-label clinical study, 72 randomly selected AMD patients in various stages of AMD received a daily supplement of 50 mg zinc sulphate and 1 mg cupric sulphate for three months. Serum complement catabolism-defined as the C3d/C3 ratio-was measured at baseline, throughout the three months of supplementation and after discontinuation of zinc administration. Additionally, downstream inhibition of complement catabolism was evaluated by measurement of anaphylatoxin C5a. Furthermore, we investigated the effect of zinc on complement activation in vitro. AMD patients with high levels of complement catabolism at baseline exhibited a steeper decline in serum complement activation (p&lt;0.001) during the three month zinc supplementation period compared to patients with low complement levels. There was no significant association of change in complement catabolism and CFH and ARMS2 genotype. In vitro zinc sulphate directly inhibits complement catabolism in hemolytic assays and membrane attack complex (MAC) deposition on RPE cells. This study provides evidence that daily administration of 50 mg zinc sulphate can inhibit complement catabolism in AMD patients with increased complement activation. This could explain part of the mechanism by which zinc slows AMD progression. The Netherlands National Trial Register NTR2605.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25393287</pmid><doi>10.1371/journal.pone.0112682</doi><oa>free_for_read</oa></addata></record>
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identifier ISSN: 1932-6203
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issn 1932-6203
1932-6203
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subjects Age
Age related diseases
Aged
Aged, 80 and over
Andra medicinska och farmaceutiska grundvetenskaper
Basic Medicine
Biology and Life Sciences
Blindness
Catabolism
Cells, Cultured
Complement
Complement activation
Complement Activation - drug effects
Complement C3 - immunology
Complement C3 - metabolism
Complement C3d - immunology
Complement C3d - metabolism
Complement C5a - immunology
Complement C5a - metabolism
Complement component C3
Complement component C5a
Complement Factor B - immunology
Complement Factor B - metabolism
Complement factor H
Complement Factor H - immunology
Complement Factor H - metabolism
Complement system
Copper Sulfate - administration & dosage
Dietary Supplements
Epithelial Cells - cytology
Epithelial Cells - drug effects
Epithelial Cells - immunology
Eye diseases
Fatty acids
Female
Gene Expression
Humans
Hypotheses
Inflammation
Laboratories
Macular degeneration
Macular Degeneration - blood
Macular Degeneration - diet therapy
Macular Degeneration - immunology
Macular Degeneration - pathology
Male
Medical and Health Sciences
Medicin och hälsovetenskap
Medicine and Health Sciences
Medicinska och farmaceutiska grundvetenskaper
Membrane attack complex
Mutation
Other Basic Medicine
Patients
Peritoneal dialysis
Proteins - genetics
Proteins - immunology
Retina
Retina - drug effects
Retina - immunology
Retina - pathology
Retinal Pigment Epithelium - cytology
Retinal Pigment Epithelium - drug effects
Retinal Pigment Epithelium - immunology
Sulfates
Systematic review
Zinc
Zinc Sulfate - administration & dosage
title Zinc supplementation inhibits complement activation in age-related macular degeneration
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