Zinc supplementation alters airway inflammation and airway hyperresponsiveness to a common allergen

Abstract

BackgroundZinc supplementation can modulate immunity through inhibition of NF-κB, a transcription factor that controls many immune response genes. Thus, we sought to examine the mechanism by which zinc supplementation tempers the response to a common allergen and determine its effect on allergic airway inflammation.MethodsMice were injected with zinc gluconate prior to German cockroach (GC) feces (frass) exposure and airway inflammation was assessed. Primary bone marrow-derived neutrophils and DMSO-differentiated HL-60 cells were used to assess the role of zinc gluconate on tumor necrosis factor (TNF)α expression. NF-κB:DNA binding and IKK activity were assessed by EMSA and in vitro kinase assay. Protein levels of A20, RIP1 and TRAF6 were assessed by Western blot analysis. Establishment of allergic airway inflammation with GC frass was followed by administration of zinc gluconate. Airway hyperresponsiveness, serum IgE levels, eosinophilia and Th2 cytokine production were assessed.ResultsAdministration of zinc gluconate prior to allergen exposure resulted in significantly decreased neutrophil infiltration and TNFα cytokine release into the airways. This correlated with decreased NF-κB activity in the whole lung. Treatment with zinc gluconate significantly decreased GC frass-mediated TNFα production from bone-marrow derived neutrophils and HL-60 cells. We confirmed zinc-mediated decreases in NF-κB:DNA binding and IKK activity in HL-60 cells. A20, a natural inhibitor of NF-κB and a zinc-fingered protein, is a potential target of zinc. Zinc treatment did not alter A20 levels in the short term, but resulted in the degradation of RIP1, an important upstream activator of IKK. TRAF6 protein levels were unaffected. To determine the application for zinc as a therapeutic for asthma, we administered zinc following the establishment of allergic airway inflammation in a murine model. Zinc supplementation decreased airway hyperresponsiveness and serum IgE levels, but had no effect on Th2 cytokine expression.ConclusionsThis report suggests that the mechanism by which zinc supplementation alters NF-κB activity is via the alteration of A20 activity. In addition, this study provides evidence that supplementation of zinc to asthmatics may alter airway reactivity and serum IgE levels, suggesting zinc supplementation as a potential treatment for asthmatics.

Effect of zinc supplementation in children with asthma: a randomized, placebo-controlled trial in northern Islamic Republic of Iran

“…El-Kholy et al reported that adequate dietary intake of zinc and zinc supplementation might decrease the severity of asthmatic attacks (26). Animal studies also demonstrated that zinc supplements reduced inflammatory and airway hyper-responsiveness (27). Prasad et al showed that zinc decreased oxidative stress and nuclear transcription factor NF-κB activation in isolated mononuclear cells via induction of zinc finger protein A20 (28).…”

Zinc in Infection and Inflammation

“…There are several studies that have examined the influence of zinc on A20-mediated NF-κB inhibition [39][40][41].Moreover, zinc inhibits NF-κB activation in the DNA nuclear binding levels by increasing the expression of peroxisome proliferator-activated receptor α (PPAR-α), which is a mediator for lipoprotein metabolism, inflammation, and glucose homeostasis. PPAR-α increase leads to the down-regulation of inflammatory cytokines and adhesion molecule [42].…”

Ranibizumab Pro Re nata versus Dexamethasone in the Management of Ischemic Retinal Vein Occlusion: Post-hoc Analysis from the COMRADE Trials

“…[26][27][28][29] It is therefore interesting to note that there was no major difference in the development of neovascularization between the treatment groups in our study. Further, it is known that patients with RVO have a unique array of vitreous proteins 30,31 , and that ischemic CRVO is associated with increased concentrations of a distinct set of these vitreous proteins. 26 It therefore may be possible that ranibizumab reduced the development of ischemia in our study by altering the angiogenic balance, however, further research is needed to confirm this.…”