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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

C5a concentration throughout the study period.The C5a levels decreased significantly during the three months of zinc supplementation and returned to baseline level within 2 months after the cessation of zinc supplementation.
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pone-0112682-g004: C5a concentration throughout the study period.The C5a levels decreased significantly during the three months of zinc supplementation and returned to baseline level within 2 months after the cessation of zinc supplementation.

Mentions: We conducted further exploratory analyses whether zinc supplementation may have different effects within patients with different levels of baseline complement catabolism defined as C3d/C3 ratio. In this analysis, we observed a strong interaction between baseline C3d/C3 ratio and change in C3d/C3 ratio during zinc supplementation (p<0.001). The AMD patients with relatively high baseline levels of serum complement catabolism exhibited a more pronounced decline in their C3d/C3 ratio during the administration of zinc sulphate, compared to those AMD patients with lower baseline levels. After the zinc supplementation period, the decline in C3d/C3 ratio remained at this lower level for the following two months. Measurements performed at least nine months later (in months 14–22) showed that complement activation had returned to baseline levels. The AMD patients who already had a relatively low C3d/C3 ratio at baseline showed no decline in C3d/C3 ratio throughout the treatment period. Figure 3 illustrates the course of serum C3d/C3 ratio over time in three groups with different baseline C3d/C3 ratios. The statistical model was not based on these cut-off points. There was no significant association between C3d/C3 ratio and age or gender throughout the course of the study. C5a levels decreased significantly over the three-month supplementation period (p = 0.019) (Figure 4). We observed a similar baseline effect for the course of C5a levels, however, the interaction between baseline and time was not significant and therefore not included in the final model (p = 0.065).


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)

C5a concentration throughout the study period.The C5a levels decreased significantly during the three months of zinc supplementation and returned to baseline level within 2 months after the cessation of zinc supplementation.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0112682-g004: C5a concentration throughout the study period.The C5a levels decreased significantly during the three months of zinc supplementation and returned to baseline level within 2 months after the cessation of zinc supplementation.
Mentions: We conducted further exploratory analyses whether zinc supplementation may have different effects within patients with different levels of baseline complement catabolism defined as C3d/C3 ratio. In this analysis, we observed a strong interaction between baseline C3d/C3 ratio and change in C3d/C3 ratio during zinc supplementation (p<0.001). The AMD patients with relatively high baseline levels of serum complement catabolism exhibited a more pronounced decline in their C3d/C3 ratio during the administration of zinc sulphate, compared to those AMD patients with lower baseline levels. After the zinc supplementation period, the decline in C3d/C3 ratio remained at this lower level for the following two months. Measurements performed at least nine months later (in months 14–22) showed that complement activation had returned to baseline levels. The AMD patients who already had a relatively low C3d/C3 ratio at baseline showed no decline in C3d/C3 ratio throughout the treatment period. Figure 3 illustrates the course of serum C3d/C3 ratio over time in three groups with different baseline C3d/C3 ratios. The statistical model was not based on these cut-off points. There was no significant association between C3d/C3 ratio and age or gender throughout the course of the study. C5a levels decreased significantly over the three-month supplementation period (p = 0.019) (Figure 4). We observed a similar baseline effect for the course of C5a levels, however, the interaction between baseline and time was not significant and therefore not included in the final model (p = 0.065).

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