Zinc supplementation leads to immune modulation and improved survival in a juvenile model of murine sepsis

Abstract

Children with severe sepsis are known to have altered zinc homeostasis and decreased circulating zinc levels, suggesting a role for zinc supplementation to improve outcomes. We tested the hypothesis that zinc supplementation would improve survival in a juvenile model of polymicrobial sepsis. Juvenile (13-14-d-old) C57BL/6 mice were treated with 10 mg/kg of zinc via i.p. injections (or vehicle) for 3 d prior to induction of polymicrobial sepsis via i.p. cecal slurry injections. Survival after sepsis was followed for 3 d, and bacterial clearance, ex vivo phagocytosis, systemic inflammatory markers and neutrophil extracellular trap (NET) formation were quantified. We found a significant survival benefit and decreased bacterial burden among zinc supplemented mice when compared with the control group. Zinc supplementation also resulted in enhanced phagocytic activity, greater neutrophil recruitment in the peritoneal cavity and NET formation, suggesting a possible mechanism for improved bacterial clearance and survival. We also noted decreased serum cytokine levels and decreased myeloperoxidase activity in lung tissue following zinc supplementation, suggesting attenuation of the systemic inflammatory response. In conclusion, zinc supplementation improves bacterial clearance, and hence survival, in juvenile mice with polymicrobial sepsis.

Nutritional Modulation of Immune Function: Analysis of Evidence, Mechanisms, and Clinical Relevance

“…In human sepsis patients and in animal models, low zinc levels (probably due to internal redistribution of zinc) are associated with increased sensitivity to sepsis and fatality to infection (112), thus it is proposed that zinc supplementation might be a treatment option to improve the outcomes of sepsis. In some studies to address this issue, increasing blood zinc levels has been shown to be protective in animal sepsis models (113, 114), which is to certain degree echoed by a limited number of clinical trials, mainly in neonates (115, 116). However, no consensus is reached at present because the benefit of zinc supplementation in sepsis cannot be confirmed in other studies (62, 117).…”

The Potential Impact of Zinc Supplementation on COVID-19 Pathogenesis

“…As one example, exposure to organic dust increased lung damage, inflammation and macrophage hyper-activation in animals with zinc deficiency, predisposing these animals to pulmonary fibrosis, while zinc supplementation 24 h before induction of acute lung injury significantly attenuated the inflammatory reaction and tissue damage ( 17 , 67 ). Regarding systemic inflammatory diseases the number of studies showing benefits of especially preventive zinc supplementation is constantly increasing ( 17 , 18 , 58 , 65 , 68 ). Amongst the underlying mechanism, zinc's role as second messenger and importance in regulating intracellular signaling as detailed in Figure 1 were described as well as zinc's effects on the epigenome ( 56 , 57 , 69 – 74 ).…”

Zinc and Sepsis

“…The published animal studies mostly examined the effects of prophylactic zinc supplementation ( Table 2 ). In several of them the supplementation of zinc prior to induction of sepsis showed beneficial effects, such as improved survival, lower serum concentrations of pro-inflammatory cytokines, lower bacterial burden or improved pulmonary function compared to the control-group [ 50 , 83 , 84 , 85 ]. However, for the animal studies the results are also not consistent and a missing effect of zinc supplementation is reported [ 86 ] as well as a harmful outcome in a case where zinc was applied during the acute phase [ 87 ].…”