PMC:7408073 / 48938-53763 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7408073","sourcedb":"PMC","sourceid":"7408073","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7408073","text":"Zinc is considered a relatively nontoxic metal; however, several data report that excessive free extracellular zinc is toxic and induce apoptosis in different cell types [91,102]. Plasma excess of free Zn2+ is uptaken by ZIP transporters on the cell surface of each cells in contact with plasma (including immune cells, endothelial cells, neurons and cardiomyocytes), leading to increase of intracellular zinc that can modulate zinc associated cellular functions in both physiological and pathological conditions. Indeed, zinc is an important mediator/messenger involved in several cellular activities and the shift of zinc from plasma to cells may be significant for both normal physiological processes including energy metabolism, blood coagulation, and zinc signalling, and a range of disease states, including neurodegenerative and cardiovascular diseases, metabolic syndrome, inflammation, endothelial stress, diabetes and thrombosis [91]. For example, excess zinc intake has been shown to contribute to both amyloid beta-peptide plaque formation in Alzheimer’s disease and cardiac dysfunction, indicating that free zinc ion may be much more toxic than thought [91]. It has been reported that Alzheimer and other neurodegenerative disease patients show elevated levels not only of Zn2+ but also of other divalent metals such as Fe2+ and Cu2+ [112], suggesting a possible link between the increase metal ions and saturation of ZIP transporters. On the other hand, increased plasma ferritin levels (such as in COVID-19 [2,3,6]) might reduce free Fe2+ and its “competition” with Zn2+ for ZIP transporters, finally increasing cellular zinc uptake and functions. To this regard, EDTA metal chelator has been shown to protect from neural cell death and it was tested in neurodegenerative diseases [102]. Of interest, plasma albumin acts as a transport protein for both metal ions such as zinc and hydrophobic molecules such as free fatty acid (FFA) to allow their systemic distribution. Indeed, albumin is well beyond a mere carrier of metal ions and hydrophobic molecules, and by binding of these different molecules mediates their crosstalk and bioavailability [91]. To this regard, one particularly intriguing allosteric link exists between FFA and zinc binding to albumin [91]. When FFAs with ten or more carbon atoms bind to albumin causes the release of Zn2+, suggesting a possible link between dyslipidemia and toxic effects mediated by consequent increase of free zinc in plasma. For example, endothelial stress and activation and pro-inflammatory action of FFAs may be mediated by their effects on free zinc release from albumin and its consequent efflux from plasma. Different studies have suggested a role of albumin to inhibit interaction of free Zn2+ with amyloid beta-peptides and combat plaque formation in Alzheimer’s disease [91]. Zn2+ has also been shown to promote clot stability by binding to fibrinogen and inhibiting heparin activity [91]. An evidence that has suggested a possible positive correlation between increased levels of FFAs and thrombotic risk [91]. In addition, physiological conditions associated with elevated plasma FFAs, such as physical exercise, can also produce an increased plasma level of free zinc and its downstream physiological events (e.g., activation of the RAS). On the other hand, reduced concentrations of plasma albumin (such as IBD, ARDS and COVID-19) will induce elevated plasma levels of both free FFAs and bioavailable zinc. Intriguingly, ARDS is induced after inhalation exposure to ZnCl2/ZnO/hexachloroethane, the main ingredients in smoke bombs used for crowd dispersal [100,101,102]. To this regard, soldiers that breathed smoke-bomb fumes have been shown to quickly or slowly develope ARDS [100,101]. Interestingly, a patient who had the highest level of serum zinc rapidly developed ARDS that leads to death from multiorgan failure (including respiratory and hepatic failure) [100]. Instead, a slow progressive clinical course was associated with a significant increase of plasma zinc concentration that negatively correlated with pulmonary and liver function [100], finally leading to death for severe respiratory failure three to five weeks after inhalation [100,101]. At autopsy diffuse microvascular obliteration and marked endothelial cell injury was apparent [101]. Widespread occlusion of the pulmonary arteries may contribute to the development of acute pulmonary hypertension and extensive interstitial and intra-alveolar fibrosis was also observed [101]. Other soldiers wearing gas masks, immediately developed severe coughing and dyspnea, and slowly improved their lung function (only twelve months after exposure their lung function tests were nearly normal) [101]. All clinical conditions that strongly resemble those described in COVID-19 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