Role of zinc in the abatement of hepatocellular damage and mortality incidence in endotoxemic rats

Sobocinski, P Z; Powanda, Michael C.; Canterbury, W J; Machotka, S. V.; Walker, Richard I.; Snyder, Stephen L.

doi:10.1128/iai.15.3.950-957.1977

Cited by 20 publications

(8 citation statements)

References 9 publications

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“…Nevertheless, zinc significantly improved animal survival when administered before or coincident with the challenge. Intraperitoneal route of administration of zinc salt provided protection from mortality and necrotic lesions in the liver after a lethal quantity of intraperitoneally administered Salmonella typhimurium endotoxin (Sobocinski et al 1977a ). The authors perceive the reason for such protection in the ability of zinc to decrease the absorption of endotoxin from the peritoneal cavity with its subsequent hepatic uptake.…”

Section: Zinc and Immunitymentioning

confidence: 99%

Antioxidant and anti-inflammatory effects of zinc. Zinc-dependent NF-κB signaling

et al. 2017

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Zinc is a nutritionally fundamental trace element, essential to the structure and function of numerous macromolecules, including enzymes regulating cellular processes and cellular signaling pathways. The mineral modulates immune response and exhibits antioxidant and anti-inflammatory activity. Zinc retards oxidative processes on a long-term basis by inducing the expression of metallothioneins. These metal-binding cysteine-rich proteins are responsible for maintaining zinc-related cell homeostasis and act as potent electrophilic scavengers and cytoprotective agents. Furthermore, zinc increases the activation of antioxidant proteins and enzymes, such as glutathione and catalase. On the other hand, zinc exerts its antioxidant effect via two acute mechanisms, one of which is the stabilization of protein sulfhydryls against oxidation. The second mechanism consists in antagonizing transition metal-catalyzed reactions. Zinc can exchange redox active metals, such as copper and iron, in certain binding sites and attenuate cellular site-specific oxidative injury. Studies have demonstrated that physiological reconstitution of zinc restrains immune activation, whereas zinc deficiency, in the setting of severe infection, provokes a systemic increase in NF-κB activation. In vitro studies have shown that zinc decreases NF-κB activation and its target genes, such as TNF-α and IL-1β, and increases the gene expression of A20 and PPAR-α, the two zinc finger proteins with anti-inflammatory properties. Alternative NF-κB inhibitory mechanism is initiated by the inhibition of cyclic nucleotide phosphodiesterase, whereas another presumed mechanism consists in inhibition of IκB kinase in response to infection by zinc ions that have been imported into cells by ZIP8.

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Section: Zinc and Immunitymentioning

confidence: 99%

Antioxidant and anti-inflammatory effects of zinc. Zinc-dependent NF-κB signaling

et al. 2017

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“…The hepatoprotective dose for ZnCl 2 was selected based on the literature (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15), and a commonly used dose of Zn (100 mmol/kg) was injected s.c. to mice in a volume of 10 ml/kg, or to rats in a volume of 2 ml/kg, once per day in the morning for four consecutive days. Control animals were injected with the same volume of vehicle (saline).…”

Section: Animal Treatment and Sample Collectionmentioning

confidence: 99%

Changes in hepatic gene expression in response to hepatoprotective levels of zinc

Liu¹,

Zhou²,

Zhang³

et al. 2009

Liver International

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Background Zinc (Zn) administration at non-toxic doses protects against the hepatotoxicity produced by many agents, but the underlying mechanisms remain elusive. Aim To examine the basis of Zn-induced generalised hepato-protective effects. Methods Rats and mice were given Zn at known hepato-protective levels (100 μmol ZnCl2/kg/day, s.c., for 4 days) and molecular responses were assessed. Results Zn treatment produced changes in 5% of the genes on custom-designed mouse liver array and Rat Toxicology-II array. Changes in gene expression were further confirmed and extended by real-time reverse transcriptase-polymerase chain reaction. Zn treatment dramatically increased the expression of the metallothionein (Mt), and modestly increased the expression of acute-phase protein genes (ceruloplasmin, Stat3, egr1, Cxc chemokines and heat-shock proteins). For genes encoding for antioxidant enzymes, some were increased (Nrf2 and Nqo1), while others remained unaltered (Cu, Zn SOD and glutathione S-transferases). Expressions of cytokine and pro-inflammatory genes were not affected, while genes related to cell proliferation (cyclin D1) were modestly upregulated. Some metabolic enzyme genes, including cytochrome P450s and UDP-glucuronosyltransferase, were modestly suppressed, perhaps to switch cellular metabolic energy to acute-phase responses. Liver Zn content was increased between 1.6- and 2.1-fold, while hepatic MT protein was increased between 50 and 200-fold. Mice typically showed greater responses than rats. Conclusion Such gene expression changes, particularly the dramatic induction of MT and Nrf2 antioxidant pathway, occur in the absence of overt liver injury, and are probably important in the hepatoprotective effects of Zn against toxic insults.

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“…An association between altered zinc homeostasis and the severity of the inflammatory reactions has been suggested by several studies using various disease models and systems. These include studies of LPS-induced endotoxemia, acute stress, and sepsis in pigs (8,27), fowl (26,38), rodents (14,15,40), and human subjects (17).…”

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Zinc dyshomeostasis during polymicrobial sepsis in mice involves zinc transporter Zip14 and can be overcome by zinc supplementation

Weßels

Cousins

2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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Integrity of the immune system is particularly dependent on the availability of zinc. Recent data suggest that zinc is involved in the development of sepsis, a life-threatening systemic inflammation with high death rates, but with limited therapeutic options. Altered cell zinc transport mechanisms could contribute to the inflammatory effects of sepsis. Zip14, a zinc importer induced by proinflammatory stimuli, could influence zinc metabolism during sepsis and serve as a target for therapy. Using cecal ligation-and-puncture (CLP) to model polymicrobial sepsis, we narrowed the function of ZIP14 to regulation of zinc homeostasis in hepatocytes, while hepatic leukocytes were mostly responsible for driving inflammation, as shown by higher expression of IL-1β, TNFα, S100A8, and matrix metalloproteinase-8. Using Zip14 knockout (KO) mice as a novel approach, we found that ablation of Zip14 produced a delay in development of leukocytosis, prevented zinc accumulation in the liver, altered the kinetics of hypozincemia, and drastically increased serum IL-6, TNFα, and IL-10 concentrations following CLP. Hence, this model revealed that the zinc transporter ZIP14 is a component of the pathway for zinc redistribution that contributes to zinc dyshomeostasis during polymicrobial sepsis. In contrast, using the identical CLP model, we found that supplemental dietary zinc reduced the severity of sepsis, as shown by amelioration of cytokines, calprotectins, and blood bacterial loads. We conclude that the zinc transporter ZIP14 influences aspects of the pathophysiology of nonlethal polymicrobial murine sepsis induced by CLP through zinc delivery. The results are promising for the use of zinc and its transporters as targets for future sepsis therapy.

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Role of zinc in the abatement of hepatocellular damage and mortality incidence in endotoxemic rats

Cited by 20 publications

References 9 publications

Antioxidant and anti-inflammatory effects of zinc. Zinc-dependent NF-κB signaling

Antioxidant and anti-inflammatory effects of zinc. Zinc-dependent NF-κB signaling

Changes in hepatic gene expression in response to hepatoprotective levels of zinc

Zinc dyshomeostasis during polymicrobial sepsis in mice involves zinc transporter Zip14 and can be overcome by zinc supplementation

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