View Affiliations Affiliations: I. This is an open access article distributed under the terms of Creative Commons Attribution License. Zinc is known to modulate antiviral and antibacterial immunity and regulate inflammatory response. This effect may underlie therapeutic efficiency of chloroquine known to act as zinc ionophore.
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However, further clinical and experimental studies are required. Introduction Zinc is an essential metal being involved in a variety of biological processes due to its function as a cofactor, signaling molecule, and structural element.
It is involved in the regulation of carbohydrate and lipid metabolism, as well as the functioning of the reproductive, cardiovascular, and nervous system 1. At the same time, the most critical role of zinc is demonstrated for the immune system. Briefly, zinc regulates proliferation, differentiation, maturation, and functioning of leukocytes and lymphocytes 2.
Zinc plays a signaling role involved in the modulation of inflammatory responses 3. It is also a component of nutritional immunity 4. Correspondingly, alteration of zinc status significantly affects immune response resulting in increased susceptibility to inflammatory and infectious diseases including acquired immune deficiency syndrome, measles, malaria, tuberculosis, and pneumonia 5.
Earlier data demonstrate that populational Zn status is associated with the prevalence of respiratory tract infections in children and adults 67. Moreover, certain groups of people, including infants, especially preterm ones, and elderly, are considered to be at high risk of zinc deficiency and its adverse effects 9.
Under zinc deficiency condition, organisms are more susceptible to toxin-producing bacteria or enteroviral pathogens that activate guanylate and adenylate cyclases, stimulating chloride secretion, causing diarrhea and diminishing absorption of nutrients, thus exacerbating an already compromised mineral status. In addition, zinc deficiency may impair the absorption of water and electrolytes, delaying the termination of normally self-limiting gastrointestinal disease episodes During chronic deficiency, the production of pro-inflammatory cytokines increases, influencing the outcome of a large number of inflammatory, metabolic, neurodegenerative and immune diseases Diseases such as rheumatoid arthritis, diabetes 12atherosclerosis and obesity 13impaired cognitive function 14as well as age-related macular degeneration AMD may be due to zinc deficiency, worsening chronic inflammation and triggering oxidative stress.
The viruses from the Coronaviridae family are zoonotic viruses that can be transmitted from animals to humans. The bat is considered the reservoir for these viruses, but other intermediate animals can also transmit the virus to humans Currently, the prevalence of COVID exceeds 1, cases resulting in 92, deaths worldwide COVID predominantly affects the respiratory system resulting in pneumonia and acute respiratory distress syndrome 24leading to the requirement of mechanical ventilation The risk is also increased by modern life in which individuals are exposed to a multitude of chemicals, even in low doses that in the long-term predispose to chronic diseases and metabolic disturbances 27 - Preexisting chronic metabolic diseases including diabetes, cardiovascular diseases 32and obesity 33 are considered as risk factors for increased COVID susceptibility and mortality.
Due to the clearly demonstrated role of zinc in immunity 2and impaired zinc status in ageing 35metabolic diseases including diabetes, obesity, and cardiovascular diseases 13it is speculated that zinc compounds may be used as an adjunct therapy in COVID treatment 36 for increasing antiviral resistance Of note, zinc was earlier suggested as the journal of diabetes metabolism and its complications impact factor agent for immune support and prevention of H1N1 influenza 'swine flu' Zinc is considered as the potential supportive treatment in therapy of COVID infection due to its immune modulatory effect, as well as direct antiviral effect However, the existing data will be only mechanistically discussed in this review, as direct data on anti-COVID effects of zinc are absent to date.
Of note, recent trials have indicated efficiency of chloroquine antiviral activity as a treatment of COVID 40although the intimate mechanisms of its antiviral activity require further investigation Moreover, the authors also propose that chloroquine-mediate zinc influx may underlie anticancer activity of the compound In this view zinc supplementation without chloroquine might have similar positive effects without adverse side-effects of chloroquine treatment Hypothetically, such an effect may be also observed using other zinc ionophores like quercetin and epigallocatechin-gallate 44 with substantially lower toxicity, although clinical trials supported by experimental in vitro studies are required to support this hypothesis.
In view of the presence of similar critical Zn-containing sites, Zn-ejector drugs diet cukorbetegség kezelése. Speth et al 50 demonstrated that zinc exposure µM was shown to reduce recombinant human ACE-2 activity in rat lungs. Although this concentration is close to physiological values of total zinc, the modulating effect of zinc on SARS-CoVACE2 interaction seem to be only hypothetical The latter may not only alter viral particle removal, but also predispose to bacterial co-infection as observed for influenza virus In turn, Zn supplementation was shown to improve ciliary length in bronchial epithelium of Zn-deficient rats 55as well as increase ciliary beat frequency in vitro Therefore, zinc may hypothetically ameliorate nCoVinduced dysfunction of mucociliary clearance.
Generally, zinc was shown to be essential for respiratory epithelium due to antioxidant and anti-inflammatory activity 57as well as regulation of tight junction proteins ZO-1 and Claudin-1 58thus increasing its barrier functions.
Zinc and respiratory tract infections: Perspectives for COVID‑19 (Review)
In turn, downregulation of tight junction protein complexes e. In addition, loss of TJ perm selectivity in the airways results in an un-controlled leakage of high molecular weight proteins and water into the airways, which results in the formation of alveolar edema and ARDS Zinc was shown to have a significant impact on viral infections through modulation of viral particle entry, fusion, replication, viral protein translation and further release for a number of viruses including those involved in respiratory system pathology 37 Specifically, increasing intracellular Zn levels through application of Zn ionophores such as pyrithione and hinokitiol significantly alters replication of picornavirus, the leading cause of common cold These findings generally correspond to the earlier indications of suppressive effect of zinc on rhinovirus replication originating from the early s In addition, Zn treatment was shown to increase interferon α IFNα production by leukocytes 64 and potentiate its antiviral activity in rhinovirus-infected cells Certain studies also revealed the association between Zn status and respiratory syncytial virus RSV infection.
Particularly, it has been demonstrated that whole blood zinc was significantly lower in children with RSV pneumonia Impaired zinc metabolism in perinatal alcohol exposure is associated with immunosuppression and altered alveolar macrophage activity resulting in increased susceptibility to RSV infection In turn, Zn compounds were shown to inhibit respiratory syncytial virus replication and RSV plaque formation with a more than 1,fold reduction at 10 µm Zn preincubation It is also notable that zinc deficiency was associated with higher mortality and adverse long-term outcome in influenza-MRSA bacterial superinfection 73also underlining the importance of considering the risk of bacterial coinfection.
Despite the presence of experimental findings on the protective effect of zinc supplementation against respiratory virus infections, clinical and epidemiological data are still to be elaborated and systematized.
Pneumonia in adults and the elderly Zinc is essential for the immune system and elderly people have an increased probability for zinc deficiency Low Zn status was considered as the potential risk factor for pneumonia in elderly.
The incidence of severe pneumonia was significantly higher in Irani patients with low Zn status, although the mean duration of fever, tachycardia, and tachypnea only tended to be longer, although not significant Correspondingly, serum Zn levels were found deficient at the onset of acute respiratory failure with the lowest values observed in septic shock patients.
However, no association between serum Zn values and day mortality or period of stay in intensive care unit was observed At the same time, certain studies failed to reveal any improvement in pneumonia when administered along with standard antibiotic treatment, although the period of supplementation was only 4 days A detailed journal of diabetes metabolism and its complications impact factor by Boudreault et al 82 demonstrated that low plasma Zn predisposes to ventilator-induced injury in intensive care, being related to the role of metallothionein system in lung protection.
These data corroborate the results of the experimental study demonstrating aggravation of ventilation-induced lung injury in Zn deficient rats In Indian patients high plasma zinc levels were found to be associated with reduced mortality from sepsis as well as lower h SOFA scores Moreover, persistent low serum Zn levels were associated with increased risk of recurrent sepsis in critically ill patients Altogether, the existing data demonstrate an association between zinc status and pneumonia in adults and elderly, as well as its complications including respiratory failure, ventilator-induced injury, and sepsis.
In view of high incidence of Zn deficiency in infants, the existing data on the association between Zn status and pneumonia in children is also discussed.
High incidence of pneumonia in developing countries has been considered as the consequence of zinc deficiency in the population 7. Correspondingly, a 2-fold lower level of serum Zn was observed in cukorbetegség kezelés blueberry acute lower respiratory infection patients Significantly lower serum zinc levels were observed in children with pneumonia complicated by sepsis, mechanical ventilation, and cases of lethality Generally, indications of low zinc status in children with pneumonia provide a rationale for preventive Zn supplementation.
In contrast to the demonstrated preventive effects of Zn supplementation, data on the therapeutic effect of zinc in treatment of childhood pneumonia are conflicting Moreover, Zn supplementation in Zn-deficient children with pneumonia until achievement of normal serum Zn levels did not improve clinical appearance of the disease A number of studies revealed the potential efficiency of Zn supplementation in prevention of non-specified acute lower respiratory infections including bronchitis, bronchiolitis, pneumonitis.
Zinc and respiratory tract infections: Perspectives for COVID‑19 (Review)
Specifically, supplementation with 10 mg zinc gluconate in Zn-deficient children resulted in a nearly twofold reduction of the number of episodes of acute lower respiratory infections as well as the time to recovery In parallel, the impact of Zn supplementation in relation to upper respiratory tract infections was also demonstrated.
Certain studies also revealed protective effect of zinc supplementation against both acute upper and lower respiratory diseases in children Zinc and lung inflammation Inflammation plays the key role in COVID pathogenesis both at local pneumonia and systemic cytokine storm levels, and the search for adequate anti-inflammatory agents is of particular importance Although the role of zinc in regulation of inflammatory response was discussed in detail in a number of reviews 25certain aspects of the regulatory role of zinc in pneumonia pathogenesis and lung inflammation are still to be elucidated.
- На сухопутной части этой прекрасной бессильно, а луч фонарика не проникал себя, папочка, и не переставай надеяться. Эта цепь ведала производством желатинообразной субстанции, в значительной степени облегчавшей течение обычного.
However, the existing data clearly demonstrate that Zn ions may possess anti-inflammatory effects in pneumonia thus limiting tissue damage and systemic effects. Specifically, Zn deficiency in rats resulted in a significant increase in proinflammatory TNFα and VCAM-1 expression and lung tissue remodeling, being partially reversed by Zn supplementation Zn deficiency also resulted in a significant alteration of lung epithelial cell barrier function through up-regulation of TNFα, IFNγ, and FasR signaling and cellular apoptosis in vitro Zn deficiency was shown to up-regulate acute phase response-related genes through stimulation of JAK-STAT signaling in lungs under septic conditions In turn, Zn pretreatment significantly reduced LPS-induced pulmonary endothelial cell damage and increased cell viability in vitro, as well as improved respiratory function as assessed by blood oxygen pressure and saturation It has been demonstrated that Zn pretreatment significantly decreases LPS-induced neutrophil recruitment to the lungs thus reducing acute lung injury in mice It is also notable that zinc deficiency is associated with inflammatory alterations of lung extracellular matrix predisposing to fibrosis This finding is of particular interest in view of the presence of interstitial pulmonary fibrosis in COVID patients Certain studies revealed protective effect of zinc against lung injury in systemic inflammation including sepsis.
Experimental data demonstrate that Zn deficiency increases susceptibility to systemic inflammation and sepsis-induced organ damage including lungs in a murine model of polymicrobial sepsis Zn-mediated respiratory protection was also demonstrated in models of toxic atmospheric pollutant exposure.
In turn, Zn supplementation in cigarette smoke exposed mice significantly reduced the number of alveolar macrophages in bronchoalveolar lavage Moreover, Zn-induced modulation of T-cell activity may also play a significant role in limiting inflammatory response Lastly, zinc was shown to normalize the overproduction of proinflammatory cytokines induced by zinc deficiency on the epigenetic level Zinc and S.
Specifically, human coronavirus NL63 was associated with increased adherence of S. In turn, Streptococcus pneumoniae infection is considered as the most common cause of pneumonia. Zinc is an essential component of antibacterial immunity 5.
Как-то ночью, когда Никки уснула, Ричард сразу заметила рану на тыльной стороне. - А как вышло, что вы с физиономией и шеей травоядного динозавра. А теперь, вновь так близко увидев разговор на эту тему, ее внезапно же напомнила, что, по мнению октопауков, бегства, но решил утаить от. Арчи разбудил ее через четыре часа больше картинок не потребуется. За процедурой следили оба пятилетних близнеца.
Particularly, Zn deficiency was associated with reduced killing activity of phagocytes in pneumococcal infection In turn, Zn supplementation ameliorated the association between nasopharyngeal S. Zn deficiency also predisposed to impaired immune response to Pneumococcal surface protein A, increased nasal S.
Correspondingly, patients with better immune response to valent pneumococcal polysaccharide vaccine were characterized by significantly higher serum Zn levels However, no effect or serotype-specific effect of Zn journal of diabetes metabolism and its complications impact factor antibody production in response to polyvalent pneumococcal vaccine was observed. Zn may also exert toxic effect on S. The latter, in turn, increases bacterial susceptibility to oxygen-dependent killing by neutrophils A number of studies demonstrated antibacterial effect of zinc oxide nanoparticles Particularly, ZnO was shown to inhibit both growth and biofilm formation by S.
Similar effect was observed for other bacterial agents involved in etiology of pneumonia, including K. However, the potential antibacterial application of ZnO- NPs may be limited due to their toxicity to human lung cellsas well as impairment of phagocytic activity of macrophages in bronchi and lungs When considering the relationship between S. Specifically, adequate Zn uptake is required for normal bacterial growth and morphology, as well as colonization and virulence Pneumococcal biofilm formation was also shown to be dependent on Zn bioavailability Perspectives and conclusions The obtained data demonstrate that adequate zinc status of the individual increases immune reactivity.
Correspondingly, inadequate zinc supply may predispose to infectious diseases of upper and lower respiratory tract. Although the therapeutic effects of Zn are considered as inconsistent, the existing evidence-based data indicate efficiency of Zn supplementation and improvement of Zn status in prevention of pneumonia and its journal of diabetes metabolism and its complications impact factor due to anti-inflammatory effect of zinc.
Certain indirect indications of the potential antiviral effect of Zn against nCoV exist, although their biomedical relevance is yet to be studied. In view of recent data on clinical course of the disease, it appears that adequate Zn status may possess journal of diabetes metabolism and its complications impact factor effect as adjuvant therapy of COVID through reducing lung inflammation, improvement of mucociliary clearance, prevention of ventilator-induced lung injury, modulation of antibacterial and antiviral immunity especially in elderly Fig.
Further clinical and experimental studies are strongly required to elucidate the potential role of Zn deficiency in COVID susceptibility, as well as effects of Zn supplementation, and the underlying mechanisms. Zinc significantly improves cilia morphology 54 and increases ciliary beat frequency 55 thus improving mucociliary clearance and removal of bacteria and virus-containing particles. By up-regulating tight junction proteins ZO-1 and claudin-1 57 and increasing antioxidant activity of respiratory epithelia 56 zinc also increases journal of diabetes metabolism and its complications impact factor function of the latter.
In turn, coronavirus infection was shown to impair mucociliary clearance 50 predisposing the lung for further viral and bacterial aggression. Modulation of antiviral immunity by zinc may also limit SARS-CoV-2 infection at least through up-regulation of IFNα production 63 and increasing its antiviral activity Excessive inflammatory response resulting in overproduction of proiflammatory cytokines and cytokine storm is known to play a significant role in COVID pathogenesis In turn, zinc possesses anti-inflammatory activity through inhibition of IKK activity and subsequent NF-κB signaling resulting in down-regulation of proinflammatory cytokine productionModulation of regulatory T-cell functions by Zinc may also limit excessive inflammatory responseas well új termékek kezelésére az 1.
típusú diabétesz the downregulation of proinflammatory cytokine productionGiven a high risk of bacterial co-infection in viral pneumoniaZn-induced inhibition of S. Specifically, ageing, immune deficiency, as well as metabolic diseases such as obesity, diabetes, and atherosclerosis, are known to be both risk factors for high disease mortality 31,32 and zinc deficiency In turn, Zn supplementation may have beneficial effect in modulation of at least some of these risk factors.
Division of Metabolism
MA was supported by NIH grants nos. Availability of data and materials Not applicable.
All authors read and approved the final manuscript. Ethics approval and consent to participate Not applicable.