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Zinc supplementation inhibits complement activation in age-related macular degeneration.

Smailhodzic D, van Asten F, Blom AM, Mohlin FC, den Hollander AI, van de Ven JP, van Huet RA, Groenewoud JM, Tian Y, Berendschot TT, Lechanteur YT, Fauser S, de Bruijn C, Daha MR, van der Wilt GJ, Hoyng CB, Klevering BJ - PLoS ONE (2014)

Bottom Line: Oral zinc supplementation can reduce the progression of AMD but the precise mechanism of this protective effect is as yet unclear.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.This could explain part of the mechanism by which zinc slows AMD progression.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Radboud university medical center, Nijmegen, the Netherlands.

ABSTRACT

Unlabelled: 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<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.

Trial registration: The Netherlands National Trial Register NTR2605.

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Related in: MedlinePlus

The effect of zinc on the hemolytic activity of human serum and on the membrane attack complex (MAC) deposition on retinal pigment epithelial (RPE) cells.(A) Zinc sulphate inhibits the lysis of rabbit erythrocytes in a dose-dependent manner. (B–C) the amount of MAC deposited on RPE cells exposed to oxidative stress can be reduced in a dose dependent manner by zinc. *p<0.05 and ***p<0.001.
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pone-0112682-g005: The effect of zinc on the hemolytic activity of human serum and on the membrane attack complex (MAC) deposition on retinal pigment epithelial (RPE) cells.(A) Zinc sulphate inhibits the lysis of rabbit erythrocytes in a dose-dependent manner. (B–C) the amount of MAC deposited on RPE cells exposed to oxidative stress can be reduced in a dose dependent manner by zinc. *p<0.05 and ***p<0.001.

Mentions: To demonstrate the in vitro effect of zinc on the complement activity of human serum and to better understand the effect observed in vivo in the patients, we performed an alternative pathway hemolytic assay. Results showed that zinc sulphate inhibits the lysis of rabbit erythrocytes in a dose-dependent manner (Figure 5A). Retina is exposed to high levels of oxidative stress from light exposure and metabolic processes [44]. We tested in vitro whether zinc could also protect the RPE from a oxidative stress related damage from the complement system. The test results show that the amount of MAC deposited on RPE cells exposed to oxidative stress can be reduced in a dose dependent manner by zinc sulphate (Figure 5B–C). In the negative controls, zinc and serum were omitted.


Zinc supplementation inhibits complement activation in age-related macular degeneration.

Smailhodzic D, van Asten F, Blom AM, Mohlin FC, den Hollander AI, van de Ven JP, van Huet RA, Groenewoud JM, Tian Y, Berendschot TT, Lechanteur YT, Fauser S, de Bruijn C, Daha MR, van der Wilt GJ, Hoyng CB, Klevering BJ - PLoS ONE (2014)

The effect of zinc on the hemolytic activity of human serum and on the membrane attack complex (MAC) deposition on retinal pigment epithelial (RPE) cells.(A) Zinc sulphate inhibits the lysis of rabbit erythrocytes in a dose-dependent manner. (B–C) the amount of MAC deposited on RPE cells exposed to oxidative stress can be reduced in a dose dependent manner by zinc. *p<0.05 and ***p<0.001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4231060&req=5

pone-0112682-g005: The effect of zinc on the hemolytic activity of human serum and on the membrane attack complex (MAC) deposition on retinal pigment epithelial (RPE) cells.(A) Zinc sulphate inhibits the lysis of rabbit erythrocytes in a dose-dependent manner. (B–C) the amount of MAC deposited on RPE cells exposed to oxidative stress can be reduced in a dose dependent manner by zinc. *p<0.05 and ***p<0.001.
Mentions: To demonstrate the in vitro effect of zinc on the complement activity of human serum and to better understand the effect observed in vivo in the patients, we performed an alternative pathway hemolytic assay. Results showed that zinc sulphate inhibits the lysis of rabbit erythrocytes in a dose-dependent manner (Figure 5A). Retina is exposed to high levels of oxidative stress from light exposure and metabolic processes [44]. We tested in vitro whether zinc could also protect the RPE from a oxidative stress related damage from the complement system. The test results show that the amount of MAC deposited on RPE cells exposed to oxidative stress can be reduced in a dose dependent manner by zinc sulphate (Figure 5B–C). In the negative controls, zinc and serum were omitted.

Bottom Line: Oral zinc supplementation can reduce the progression of AMD but the precise mechanism of this protective effect is as yet unclear.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.This could explain part of the mechanism by which zinc slows AMD progression.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Radboud university medical center, Nijmegen, the Netherlands.

ABSTRACT

Unlabelled: 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<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.

Trial registration: The Netherlands National Trial Register NTR2605.

Show MeSH
Related in: MedlinePlus