Quercetin and respiratory health -
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Crit Rev Food Sci Nutr. Keywords: SARS-Cov-2, COVID, vitamin C, quercetin, flavonoids, antiviral, Coronavirus, immunonutrition. Citation: Colunga Biancatelli RML, Berrill M, Catravas JD and Marik PE Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease COVID Received: 09 April ; Accepted: 04 June ; Published: 19 June Copyright © Colunga Biancatelli, Berrill, Catravas and Marik.
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Breathe a sigh of relief while perusing our respiratory health supplements. Clear all. To determine differential cell counts, an aliquot of cell suspension equivalent to 1 x 10 6 cells was labeled with antimouse CD45 antibody conjugated with magnetic microbeads Miltenyi Biotec Inc, Auburn, CA to isolate CD45 positive cells.
Cytospins of CD45 positive cells were prepared, stained with DiffQucik and number of macrophages, neutrophils and T cells were determined. Appropriate isotype-matched controls and fluorescence minus one FMO were used in all experiments.
All antibodies were purchased from BioLegend San Diego, CA. Cells were fixed and analyzed in BD LSR II Flow cytometerI BD Biosciences and data was analyzed using FlowJO version 10 Tree Star, Ashland, OR. Lungs were inflation fixed at a constant pressure of 30 cm.
Zero on this scale indicated no inflammatory change, while 5 represented severe inflammation. Number of PAS-positive cells per μ of airway epithelium was counted to quantify goblet cells as described [ 21 , 23 ].
Chord length was determined as described previously [ 23 ]. Dynamic lung elastance and compliance, and pressure-volume relationship were measured as described previously using a miniature computerized flexivent ventilator Scireq, Canada [ 23 ]. Airway responsiveness to nebulized methacholine was measured as described previously using Buxco FinePointe operating system connected to mechanical ventillator Wilmington, NC.
Results are expressed as mean ± SEM or median with range of data. Data were analyzed by using SigmaStat statistical software Systat Software, San Jose, CA. If the data were not normally distributed, it was analyzed by non-parametric test, ANOVA on ranks with Kruskal-Wallis H test.
Previously, we demonstrated that compared to RV-infected normal mice, mice with COPD phenotype show increased lung inflammation up to 4 days following RV infection. To examine whether mice with COPD phenotype resolves lung inflammation induced by RV, we examined lung histology at 14 days post-RV infection.
Irrespective of infection, normal mice showed no histological changes S1 Fig. Mice with COPD phenotype infected with RV and maintained on control diet showed mild to moderate peribronchial and perivascular inflammation that is somewhat exaggerated compared to sham-infected mice Fig 2A and 2B.
Additionally, these mice also showed enhanced emphysematous changes with more inflammatory cells Fig 2C to 2F. In contrast, COPD mice maintained on quercetin-containing diet and then infected with RV showed substantially less lung inflammation and emphysematous changes Fig 3A to 3F than mice fed with normal diet Fig 2A to 2F.
Semi-quantitation of lung inflammation revealed the scores in the range of 3—4 in RV-infected COPD mice maintained on control diet and 1—2 for mice maintained on quercetin diet Table 1. E and F , represent higher magnification of parenchyma showing macrophages in the air space represented by black arrow.
Insets in A and B represent magnified area marked in rectangle showing predominantly mononuclear inflammatory cells. Images are representative of 6 mice per group from two independent experiments.
E and F , represent higher magnifcation of parenchyma showing macrophages in the air space represented by black arrow. Images are representative of 6 mice per group. To determine whether the sustained lung inflammation in RV-infected mice with COPD phenotype parallels with viral persistence, we determined viral load by measuring viral RNA.
We used this method because it is more sensitive than plaque assay that detects infectious virus. Additionally, persistence of viral RNA in the absence of infectious virus may be sufficient to induce lung inflammation.
At 2 and 4 days post-infection both normal and mice with COPD phenotype showed viral RNA S2 Fig. At 7 days post-infection while only 2 out of 6 normal mice had detectable levels of viral RNA, 5 out of 6 mice with COPD phenotype showed viral RNA albeit at very low levels.
At 10 days post-infection neither normal nor mice with COPD phenotype had detectable levels of viral RNA in their lungs data not shown. Mice with COPD phenotype on quercetin diet showed 1 to 2 logs less viral RNA than mice on control diet at all time points.
These results indicate that lung inflammation persists even in the absence of detectable viral RNA and that quercetin enhances viral clearance in addition to ameliorating lung inflammation in mice with COPD phenotype.
The mRNA expression of selected cytokines that are involved in antiviral responses, IFN-α, IFN-β, IFN- λ 2 , neutrophil and macrophage chemoattractants, CXCL-1, CCL2, macrophage-derived inflammatory mediator, CCL3, T cell chemoattractant, CXCL and T cell derived cytokines, TNF-α, IFN-γ and ILA was determined at 2, 7, and 14 days post RV-infection.
Both normal mice and mice with COPD phenotype showed increase in the expression of all the cytokines at 2 days post-infection compared to respective sham-infected animals, which returned to basal levels in normal mice by day 7 post-infection Fig 4A to 4J.
Although mRNA levels of all these cytokines reduced in RV-infected mice with COPD phenotype, the levels of CXCL-1, CXCL, CCL3, TNF-α, ILA and IFN-γ remained high up to 14 days post-infection.
However at protein level, only CCL3, CXCL, IL, TNF-α and IFN-γ were found to be higher in RV-infected mice with COPD phenotype compared to respective sham Fig 5A to 5F. On the other hand, mice maintained on quercetin diet did not show increase in the protein or mRNA levels of CXCL-1, CXCL, IL, CCL3, TNF-α and IFN-γ Fig 5A to 5F and S3 Fig.
Total RNA isolated from the lungs of normal mice and mice with COPD phenotype at 2, 7 and 14 days post-infection was used to determine the mRNA expression of cytokines by qPCR.
Data was normalized to house keeping gene, β-actin and expressed as fold expression over respective sham-infected animals. Supernatants from lung homogenates of sham or RV infected normal and COPD mice were used for detection of cytokines by ELISA.
In order to determine what type of inflammatory cells accumulate in the lungs of mice with COPD phenotype following RV infection we assessed differential cell counts in lung homogenates obtained at 14 days post-RV infection.
Mice with COPD phenotype showed more neutrophils, macrophages and T cells as previously observed Fig 6A—6C. Following RV infection normal mice showed slightly increased T cells, but not neutrophils or macrophages.
In contrast, RV-infected mice with COPD phenotype, showed further increases in neutrophils, T cells and macrophages correlating with persistent increase in cytokine levels.
Mice maintained on quercetin diet showed reduction in all three cell types corroborating with reduced levels of chemokines. Experiment was performed twice with 3 mice per group.
Next, we conducted flow cytometry to determine subpopulation of accumulated macrophages and T cells. No significant differences were observed in any of the macrophage population between sham- and RV-infected normal mice Fig 7B to 7D. Compared to normal, COPD mice showed small increases in alveolar and intermediate macrophage population.
Intermediate, but not alveolar macrophage population significantly increased following RV infection in mice with COPD phenotype. Lung monocyte population also increased following RV infection in mice with COPD phenotype, but to a smaller extent. Quercetin treatment significantly reduced both alveolar and intermediate macrophage population, and also lung monocyte population in RV-infected mice with COPD phenotype.
Gating strategy for subtypes of T cells is shown in Fig 8A. Single cell suspensions from lung digest were stained with antibodies to CD45, CD3, CD8 and CD4 to detect subtypes of T cells.
Assessment of PAS-stained sections indicated that compared to normal, mice with COPD phenotype show more goblet cells in small airways as observed previously Fig 9A and 9C [ 21 ].
Fourteen days after RV infection, while mice with COPD mice maintained on control diet showed further increase in goblet cells Fig 9B and 9D , mice maintained on quercetin diet showed no goblet cells irrespective of infection and looked similar to normal mice Fig 9E and 9F.
Quantitation of goblet cells indicated significant increase in the number of goblet cells in COPD mice compared to normal mice, which further increased following RV infection and treatment with quercetin completely reduced the number of goblet cells in these mice Fig 9G.
Increase in goblet cells in mice with COPD phenotype prior to and after RV infection was accompanied with increased mRNA expression of goblet cell markers Gob5 and mucin gene Muc5AC Fig 9H and 9I. Mice maintained on quercetin diet inhibited not only RV-induced expression of Gob5 and mucin genes, but also at basal levels in mice with COPD phenotype.
Five micron thick paraffin sections were deparaffinized and stained with PAS to visualize goblet cells arrows. A and B normal mice C and D mice with COPD phenotype maintained on control diet, E and F mice with COPD phenotype maintained quercetin diet.
F quantitation indicate significantly more goblet cells RV-infected mice with COPD phenotype. G and H expression of Gob5 and Muc5ac was determined by qPCR using total lung RNA isolated from RV- or sham-infected normal and mice with COPD phenotype and data normalized to β-actin and expressed as fold change over respective sham-infected animals.
Histological evaluation suggested that RV further enhances emphysematous changes in mice with COPD phenotype Fig 2D. To quantify emphysematous changes we determined chord length, elastance, compliance and pressure volume loops. As previously observed mice with COPD phenotype showed increase in chord length Fig 10A.
This was accompanied by increase in dynamic compliance and decrease in elastance compared to normal mice Fig 10B and 10C.
Mice with COPD phenotype also showed left and upward shift in pressure-volume loops than normal mice, indicative of reduced elastic recoiling of the lungs as previously observed Fig 10D. After RV infection, mice with COPD phenotype showed further increase in chord length and compliance, and decrease in elastance and elastic recoiling.
These results corroborated with histological evaluation. Mice maintained on quercetin diet showed no change in either chord length, compliance or elastance, and elastic recoiling as indicated by pressure-volume loops Fig 10E following RV infection indicating quercetin blocks RV-induced progression of emphysematous changes in mice with COPD phenotype.
B to D anesthetized mice intubated and connected to mechanical ventilator were used to measure dynamic compliance and elastance, and pressure-volume relationship.
Data in D and E are representative of 6 mice per group. Airway cholinergic responsiveness was measured 14 days after RV infection. Normal mice infected with RV and sham showed very similar responsiveness to methacholine challenge Fig 11A.
In contrast, compared to sham-, RV-infected mice with COPD phenotype showed significantly higher response to methacholine challenge Fig 11B. Mice on quercetin diet did not show such increase in airway responsiveness to methacholine challenge following RV infection Fig 11C.
Interestingly, we found that mice with COPD phenotype had higher basal airway resistance compared to normal mice Fig 11D and this may indicate airway constriction in these mice.
A and B After relevant treatment, mice were anesthetized, intubated and connected to mechanical ventilator and airways responsiveness to nebulized increasing dose of methacholine was determined.
D mice with COPD phenotype show higher airway resistance at baseline. Taken together these results indicate that RV infection further increases lung inflammation and causes progression of lung disease including goblet cell metaplasia in the airways causing enhanced mucin gene expression, emphysema and airway function.
Quercetin inhibits these RV-induced effects in mice with COPD phenotype. This study provides first experimental evidence that RV causes persistent lung inflammation, mucus metaplasia and emphysematous changes up to 14 days in a relevant smoke exposed mouse model of COPD.
Interestingly, this appears to be dependent on sustained host responses rather than viral persistence. Some of the pathologic features observed in this mouse model of COPD recapitulates RV-induced pathologic changes in experimentally-infected COPD patients with mild disease. These pathological features include a persistent lung inflammation with accumulation of inflammatory cells including neutrophils, macrophages and T cells, and b enhanced mucus production, airway resistance and progression of emphysema, which together may cause airflow obstruction [ 8 ].
Quercetin, a natural flavonoid with potent anti-inflammatory and antioxidant properties, abrogated RV-induced pathological changes in this mouse model of COPD.
In our previous study, we demonstrated that RV induces acute lung inflammation in both normal and mice with COPD phenotype [ 21 ]. While normal mice infected with RV resolved lung inflammation by 4 days, mice with COPD phenotype showed sustained lung inflammation.
In the present study, we extended the time course up to 14 days to assess RV-induced lung inflammation and viral persistence. While RV-infected normal mice completely resolved lung inflammation at 14 days post-infection, mice with COPD phenotype showed enhanced peribronchiolar and perivascular inflammation.
The observed persistent lung inflammation was not due to defective viral clearance, because there was no detectable viral RNA beyond 7 days post-infection in these mice. Similar increase in T cells and neutrophils have been reported in COPD subjects who were experimentally infected with RV [ 8 , 9 ] indicating that this mouse model may be useful in obtaining mechanistic insight into RV-induced prolonged lung inflammation in COPD.
Additionally, this experimental mouse model of COPD may also be useful for testing new therapeutic strategies to treat COPD exacerbations. Persistent lung inflammation induced by RV in mice with COPD phenotype was associated with progression of lung disease encompassing both conductive airways and alveolar compartment.
In the conductive airways, RV induced goblet cell metaplasia and mucin gene expression, one of the features of airway epithelial remodeling. This was not associated with increase in IL expression data not shown indicating that pathways other than IL may contribute to RV-induced goblet cell metaplasia.
Our on-going studies indicate a role for NOTCH-dependent mechanism in RV-induced goblet cell metaplasia in COPD airway epithelial cells and this is yet to be confirmed in this mouse model of COPD. In alveolar compartment, RV causes enlargement of air spaces indicative of degradation of alveoli leading to progression of emphysema.
This may be due to expression of MMP12 by lung macrophages, accumulation of which is increased in RV-infected mice with COPD phenotype. Moreover, previously we have demonstrated that RV induces MMP12 expression particularly in airway epithelial cells isolated from COPD patients [ 26 ].
Additionally, RV has also been shown to induce MMP9 expression in airway epithelial cells [ 27 ]. Furthermore, expression of MMP12 is increased in the lungs of COPD patients and has been implicated in pathogenesis of emphysema [ 28 , 29 ].
Consistent with this notion, MMP12 knockout mice are protected from developing emphysema [ 30 ]. Prolonged lung inflammation in RV-infected mice with COPD phenotype was associated with sustained expression of chemoattractants, CCL3 and CXCL, Th1 cytokines, TNF-α and IFN-γ, and Th17 cytokine ILA.
Nieman Preventing peptic ulcers Appalachian State University. Upper Qercetin tract infections Quercefin are the hea,th common of Quercetin and respiratory health human illnesses. Such infections occur in the nose, sinuses, Qercetin, larynx, trachea, and bronchi, and are epitomized by the common cold. According to the National Institute of Allergy and Infectious Diseases, the average adult suffers from between two and four colds every year, whilst children can catch between six and Quercetin is an antioxidant flavonoid found in fruits and vegetables.Quercetin and respiratory health -
Another substantial finding of this study was that quercetin remarkably abated RV-induced inflammatory changes and progression of pulmonary disease in COPD mice, demonstrated by a decrease in goblet cell number and expression of goblet cell markers Gob5 and mucin gene.
These effects were due to the powerful antioxidant and anti-inflammatory of quercetin, which reduces the prolonged activation of epithelial cells generated by RV, hence reducing immune cell buildup and activation.
It is conceivable that quercetin may mitigate RV-induced pathogenic effects not only by suppressing the host inflammatory responses to RV but also by reinforcing the viral clearance [ 9 ]. Another study regarding the effect of quercetin against RV infection was explored by Ganesan et al.
The concentration required to inhibit viral replication was higher than in vivo, suggesting that quercetin achieves better absorption in vivo, thus rendering better stability and bioavailability. Another possibility is that quercetin metabolites generated in vivo act stronger than those in vitro.
The result showed that quercetin pretreatment suppressed RV-induced Akt phosphorylation. When quercetin was given after viral endocytosis, it reduced RV-stimulated IL-8 and IFN responses, which was consistent with downstream effects. Quercetin hindered RV replication by inhibiting RV genome transcription.
Quercetin, on the other hand, inhibited RV-induced cleavage of eIF4GI while increasing the phosphorylation of eIF2a [ 10 ]. Because quercetin promotes eIF2a phosphorylation beyond that triggered by RV infection, there is a possibility that quercetin restricts viral replication by boosting host innate immune responses.
Recently, it is shown that replication of enterovirus, a Picornaviridae family member, takes place in specialized organelles rich in phospho-inositidephosphate PI4P lipids produced by PIkinase IIIβ. If PI4P-enriched organelles are necessary for RV reproduction, quercetin, which inhibits PIkinases, may interfere with the development of these organelles, and ultimately, the viral replication is inhibited.
The results further showed that cleavage of eIFG4II and viral capsid protein levels were significantly lowered by quercetin, thus eventually decreasing positive- and negative-strand viral RNA. This mechanism implies that quercetin may inhibit initial polypeptide processing, which is required for both viral RNA polymerase processing and cleavage of eIFG4II, thereby blocking all downstream effects.
Another probability is that quercetin inhibits viral RNA polymerase directly, preventing genome translation and the manufacture of new offspring viruses [ 10 ].
Inhibition of rhinovirus replication at various stages by quercetin. Likewise, quercetin enhances viral clearance via mitochondrial antiviral response [ 10 ].
Typical influenza lesions including interstitial pneumonia and necrotizing bronchiolitis were also noticed. Q3R administration on influenza-infected mice showed moderate inflammation including pulmonary edema and elevated numbers of inflammatory cells and necrosis.
Particularly, a dose of 6. Moreover, the result of the CPE 50 assay to determine the viral titer in the mice lung demonstrated the average titer for Q3R-treated mice was approximately lower than that of the placebo group and two times lower than that of the oseltamivir-treated group. Intriguingly, Q3R and oseltamivir treatment given for influenza uninfected mice displayed similar histopathological results to placebo-controlled mice [ 11 ].
The influenza virus envelope protein hemagglutinin has been targeted to block the viral entry by pretreatment and co-treatment with quercetin [ 12 ]. It revealed that quercetin generated an obvious inhibitory action against H3N2 and H1N1 virus strain infections in a dose-dependent manner.
The inhibitory effect was pronounced when the virus was preincubated with quercetin or when quercetin was added to the virus-infected cells MDCK and A cells. Based on the time of additional assay, quercetin effectively acts during the viral entry stage, while inhibitory effects during or after infection were less clear.
Furthermore, the results confirm that quercetin generated a strong binding affinity to the HA2 subunit of influenza A virus Fig. Illustration of influenza virus life cycle and the pathways modulated by quercetin.
Influenza virus utilizes hemagglutinin HA receptor for binding and entry. Moreover, membrane-2 M2 ion channel promotes fusion and uncoating, and neuraminidase NA facilitates the progeny virus release.
Collectively, quercetin interferes at different steps including viral binding, uncoating, mRNA synthesis, negative-strand synthesis, assembly, and release [ 12 ].
There has been some evidence during acute influenza virus infection that oxidative stress plays a crucial role in the living cells affected [ 13 ].
This process eventually promotes lung injury, apoptosis, inflammation, or allergy and further alters cellular metabolism, particularly mitochondrial function resulting in mitochondrial ROS production [ 13 , 14 ]. However, quercetin supplementation failed to increase the vitamin E level significantly in both normal and infected-H3N2 mice models.
The study concluded that quercetin proved to raise the antioxidant concentration in the lung and bring them nearly to normal levels. These findings consistently supported that quercetin demonstrated the ability to block ROS production by neutrophils, particularly by blocking protein kinase C PKC , an enzyme that activates NADPH oxidase and respiratory burst [ 15 ].
A previous in vitro study by Wan et al. showed that quercetin has the ability to reduce the mRNA and protein overexpression of cyclin-dependent kinase-4 CDK4 in A lung epithelial tumor cells infected with H1N1 [ 16 ].
The expression of CDK4 mRNA and protein in H1N1-infected cells treated with quercetin and ribavirin was significantly lower than in untreated infected cells. Albeit the direct antiviral action of quercetin on H1N1 was not as strong as ribavirin, the result showed quercetin was less toxic and able to inhibit CDK4 mRNA and protein overexpression in H1N1-infected A cells.
These findings are presumably due to the ability of quercetin to induce DNA repair, thus promoting host cell proliferation [ 16 ]. Another study by Gansukh et al. Likewise, virus-induced ROS and autophagy formation were also evaluated.
Human respiratory syncytial virus hRSV , a member of the family Pneumoviridae, is an important pathogen in the development of acute lower respiratory infection ALRI and a major cause of hospitalization in the pediatric population worldwide.
To date, the existing treatment and management of hRSV infections like the use of palivizumab and ribavirin encounter challenges. For instance, difficulty in administration, the generation of drug escape mutants, substantial side effects, long-term administration, low efficacy against the virus, and expensive cost are entailed in prophylaxis.
Hence, some researchers have been done to discover alternative compounds or design new strategies against hRSV to suppress its spread and halt the infection [ 18 ].
Quercetin is a bioactive flavonoid that confers several biological effects, including anti-hRSV [ 19 ]. Notwithstanding, the issue still exists pertaining to low solubility and low stability of quercetin in the lipophilic media of a membrane owing to the presence of hydroxyl groups [ 20 ].
A previous study done by Lopes et al. used quercetin as a parent compound Q0 and acetylation of quercetin; quercetin pentaacetate Q1 was tested on Hep-2 cells infected with hRSV to evaluate its capability in halting the viral entry and replication [ 21 ].
Initially, cytotoxicity of Q0 and Q1 was done in incubated Hep-2 cells in the selected range of concentration 0. The results revealed that the Q1 had lower cytotoxicity than the Q0. As compared to Q0, Q1 showed relevant cell protection 2. Likewise, in a dose-dependent manner, the infected cells treated with Q1 revealed a reduction of syncytia formation, no cell detachment in post-treatment at the lowest MOI, and a great reduction of syncytia formation in the virucidal assay at MOI 0.
Concerning cytotoxicity, it has been shown that Q1 is more hydrophobic than Q0. Hence, Q1 would penetrate cells by which it is protected by degradation of extracellular space [ 22 ]. To further understand, in silico analysis was done in the same study to prove that the compound may interact with the F-protein of hRSV [ 21 ].
Similar to G, the F-protein has been established to interact with cellular heparan sulfate or immobilized heparin, facilitating attachment to and infection of immortalized cells [ 18 ]. The study verified the effect of Q1 on the stability of the hRSV-F modeled hRSVmF -Q1 complex and used the hRSVmF-JNJ as reference control.
Q0 demonstrated an escaping trend from the hRSVmF central cavity, which did not happen with the reference ligand. Intriguingly, Q1 exhibited a closer interaction with the cavity when compared to Q0 and towards the end of the trajectory demonstrated a similar pattern to the reference ligand.
There were no hydrogen bonds observed between Q1 and hRSVmF cavity residues, showing the occurrence of hydrophobic interactions. Albeit Q1 exhibited lower electrostatic contributions and did not exert hydrogen bonds with hRSVmF cavity residues, the interaction energy of Q1 is higher than that observed for Q0, indicating the structural differences between the two molecules.
The chemical modification from Q0 to Q1 implies the replacement of the hydroxyl group for acetyl, hence resulting in greater affinity for the cavity hRSVmF [ 21 ]. The hRSV cycle entails adsorption, internalization, transcription, translation, assembling, and budding.
Previous studies revealed that the hRSV infection cycle is complete in about 24—48 h postinfection hpi [ 23 ]. According to the same study, the effect of Q1 in the hRSV cycle was tested in adsorption, internalization, and time addition protocols with MOI 0.
The result showed that Q1 exhibits great protection on adsorption assay in all tested concentrations 1. Notwithstanding, in internalization protocol, Q1 did not exhibit any effect on hRSV infection. Moreover, Q1 at 6 μM only exhibited significant protection in time addition protocol in 0 and 36 hpi [ 21 ].
Another important target protein possessed by hRSV is the M protein. It is an essential anti-termination factor for the transcription process that averts the premature dissociation of the polymerase complex.
Hence, it becomes a potential target for the development of viral replication inhibitors [ 24 ]. A study done by Guimaraes et al. evaluated the interaction of Q1 and tetraacetylated Q2 quercetin derivatives with the M tetramer. The acetylation was done to generate a stronger bioactive compound against the oxidation process.
To further understand the formed interaction, molecular docking was done, and it demonstrated that the possible binding site takes place between the globular domain α-helix 6 from one monomer with the zinc finger domain from other monomers of the tetramer.
Persistent lung inflammation induced by RV in mice with COPD phenotype was associated with progression of lung disease encompassing both conductive airways and alveolar compartment.
In the conductive airways, RV induced goblet cell metaplasia and mucin gene expression, one of the features of airway epithelial remodeling. This was not associated with increase in IL expression data not shown indicating that pathways other than IL may contribute to RV-induced goblet cell metaplasia.
Our on-going studies indicate a role for NOTCH-dependent mechanism in RV-induced goblet cell metaplasia in COPD airway epithelial cells and this is yet to be confirmed in this mouse model of COPD.
In alveolar compartment, RV causes enlargement of air spaces indicative of degradation of alveoli leading to progression of emphysema.
This may be due to expression of MMP12 by lung macrophages, accumulation of which is increased in RV-infected mice with COPD phenotype. Moreover, previously we have demonstrated that RV induces MMP12 expression particularly in airway epithelial cells isolated from COPD patients [ 26 ].
Additionally, RV has also been shown to induce MMP9 expression in airway epithelial cells [ 27 ]. Furthermore, expression of MMP12 is increased in the lungs of COPD patients and has been implicated in pathogenesis of emphysema [ 28 , 29 ].
Consistent with this notion, MMP12 knockout mice are protected from developing emphysema [ 30 ]. Prolonged lung inflammation in RV-infected mice with COPD phenotype was associated with sustained expression of chemoattractants, CCL3 and CXCL, Th1 cytokines, TNF-α and IFN-γ, and Th17 cytokine ILA.
Both CCL3 and CXCL are potent chemoattractant for T cells and recruits T cells into tissues, which in turn may increase expression of TNF-α, IFN-γ and ILA.
This is consistent with earlier report in which enhanced Th1 responses was observed in mice exposed to cigarette smoke and infected with influenza virus [ 31 ]. However, one cannot rule out the possibility of pulmonary macrophages contributing to the observed increases in CXCL and TNF-α, because macrophages have been shown to express CXCL and TNF-α in response to rhinovirus infection in vitro [ 32 , 33 ].
Mice with COPD phenotype also showed increased airway responsiveness to cholinergic challenge following RV infection and this may be due to increase in the expression of TNF-α and CXCL Both these cytokines have been shown to increase airways hyper responsiveness in mice [ 34 , 35 ].
However it remains to be confirmed whether these cytokines contribute to RV-induced airways hyper responsiveness to methacholine challenge in a mouse model of COPD.
Another important finding of this study is marked attenuation of RV-induced inflammatory changes and progression of lung disease in a mouse model of COPD by quercetin.
Being a potent anti-oxidant and anti-inflammatory agent, quercetin may suppress persistent activation of epithelial cells induced by RV thus attenuating accumulation and activation of immune cells. Consistent with this notion, quercetin was recently shown to universally suppress accumulation and activation of immune cells and to improve mitochondrial function in the adipose tissue of diet-induced obese mice [ 36 ].
Mitochondrial dysfunction is one of the features of COPD [ 37 ]. Previously, we and others have shown that quercetin inhibits respiratory viral replication both in vitro and in vivo by interfering at various stages of replication including viral endocytosis, viral genome transcription and translation [ 17 , 38 ].
In the present study, quercetin supplemented mice with COPD phenotype showed lower viral load than mice on control diet. Therefore, it is conceivable that quercetin may alleviate RV-induced pathogenic effects not only by limiting the host inflammatory responses to RV, but also by enhancing the viral clearance.
Based on these facts we speculate that quercetin may mitigate RV-induced pathological changes and progression of lung disease in COPD following viral associated exacerbations.
However, further experimental evidence is required prior to using quercetin as a new therapeutic strategy to prevent virus-induced exacerbations in COPD patients. In conclusion, our findings demonstrate that RV induces lung inflammation with accumulation of neutrophils, T cells and macrophages in a mouse model of COPD.
Mice with COPD phenotype also show progression of lung disease following RV infection and this was mitigated effectively by quercetin supplementation in the diet. In some aspects, this mouse model recapitulated the clinical outcome observed in COPD subjects, who were experimentally-infected with RV.
Based on these observations, we conclude that the mouse model of COPD described here may be useful in providing mechanistic insights into RV-induced pathogenesis in COPD, and also for testing new therapeutic strategies.
Secondly, quercetin supplementation with or without conventional steroid therapy may prevent severity of COPD exacerbations and progression of lung disease. Normal mice infected with RV do not show inflammation at 14 days post-infection. Normal mice were infected with sham or RV by intranasal route and sacrificed 14 days after infection.
Lungs were perfused with PBS, fixed and embedded in paraffin. Lung Viral RNA load in normal and mice with COPD phenotype. Mice with COPD phenotype were shifted to control or quercetin diet. One week later mice with COPD phenotype and normal mice were infected with sham or RV and sacrificed at 2, 4, 7 and 10 days.
Experiment was conducted 2 times with 3 mice per group. Quercetin attenuates RV-induced cytokine responses. Mice with COPD phenotype either maintained on control or quercetin diet were infected with sham or RV. Mice were sacrificed after 14 days, total lung RNA isolated and expression of cytokines were measured by qPCR.
We thank Nathaniel Xander for technical assistance. This study was funded by National Center for Comprehensive and Integrative Health of National Institutes of Health, AT and AT to US.
Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Article Authors Metrics Comments Media Coverage Reader Comments Figures. Abstract Acute exacerbations are the major cause of morbidity and mortality in patients with chronic obstructive pulmonary disease COPD.
Introduction Chronic obstructive pulmonary disease COPD , a relatively prevalent lung disease is also one of the leading causes of morbidity and mortality worldwide [ 1 ].
Download: PPT. Fig 1. Scheme showing exposure of mice to cigarette smoke and heat-killed NTHi, treatment with RV infection and maintenance of mice on quercetin diet. Rhinovirus and infection Both RV1B and H1 HeLa cells were purchased from American Type Culture Collection, Manassas, VA.
Quercetin supplementation Mice with COPD phenotype were shifted to control or 0. RNA isolation and qPCR After relevant treatment, lungs were collected under aseptic conditions and homogenized in 2 ml PBS.
ELISA Supernatants from lung homogenates were used for ELISA to quantify protein levels of cytokines. Histology Lungs were inflation fixed at a constant pressure of 30 cm.
Analysis of lung mechanics and airway resistance Dynamic lung elastance and compliance, and pressure-volume relationship were measured as described previously using a miniature computerized flexivent ventilator Scireq, Canada [ 23 ]. Statistical analysis Results are expressed as mean ± SEM or median with range of data.
Results Quercetin reduces rhinovirus-induced persistent lung inflammation in mice with COPD phenotype Previously, we demonstrated that compared to RV-infected normal mice, mice with COPD phenotype show increased lung inflammation up to 4 days following RV infection.
Fig 2. Mice with COPD phenotype show persistent inflammation after RV infection. Fig 3. Quercetin blocks RV-induced inflammation in mice with COPD phenotype. Table 1. Histopathological scores of RV-infected COPD mice maintained on control or quercetin diet.
RV causes sustained increase in the expression of inflammatory cytokines The mRNA expression of selected cytokines that are involved in antiviral responses, IFN-α, IFN-β, IFN- λ 2 , neutrophil and macrophage chemoattractants, CXCL-1, CCL2, macrophage-derived inflammatory mediator, CCL3, T cell chemoattractant, CXCL and T cell derived cytokines, TNF-α, IFN-γ and ILA was determined at 2, 7, and 14 days post RV-infection.
Fig 4. Mice with COPD phenotype show sustained expression of cytokines following RV infection. Fig 5. Querecetin blocks RV-induced sustained increase in cytokines at protein level. RV promotes accumulation of neutrophils, macrophages and T cells in the lungs of mice with COPD phenotype In order to determine what type of inflammatory cells accumulate in the lungs of mice with COPD phenotype following RV infection we assessed differential cell counts in lung homogenates obtained at 14 days post-RV infection.
Fig 6. Quercetin reduces accumulation of inflammatory cells in RV-infected mice with COPD phenotype. Fig 7. RV-infected COPD mice show accumulation of intermediate macrophages. Fig 8. Quercetin inhibits RV-induced mucus metaplasia in mice with COPD phenotype Assessment of PAS-stained sections indicated that compared to normal, mice with COPD phenotype show more goblet cells in small airways as observed previously Fig 9A and 9C [ 21 ].
Fig 9. RV-infected mice with COPD phenotype show enhanced goblet cells metaplasia. Quercetin prevents progression of RV-induced emphysematous changes in mice with COPD phenotype Histological evaluation suggested that RV further enhances emphysematous changes in mice with COPD phenotype Fig 2D.
Fig Quercetin abrogates progression of emphysematous changes in RV-infected mice with COPD phenotype. RV-induced airway resistance is attenuated in quercetin-fed mice with COPD phenotype Airway cholinergic responsiveness was measured 14 days after RV infection.
Quercetin inhibits RV-induced airway hyperreactivity in mice with COPD phenotype. Discussion This study provides first experimental evidence that RV causes persistent lung inflammation, mucus metaplasia and emphysematous changes up to 14 days in a relevant smoke exposed mouse model of COPD. Supporting information.
S1 Fig. s PDF. S2 Fig. S3 Fig. Acknowledgments We thank Nathaniel Xander for technical assistance. References 1. Adeloye D, Chua S, Lee C, Basquill C, Papana A, Theodoratou E, et al. Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease.
Thorax — Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease.
Am J Respir Crit Care Med — Langsetmo L, Platt RW, Ernst P, Bourbeau J Underreporting exacerbation of chronic obstructive pulmonary disease in a longitudinal cohort.
Wilkinson TMA, Aris E, Bourne S, Clarke SC, Peeters M, Pascal TG, et al. Koul PA, Mir H, Akram S, Potdar V, Chadha MS Respiratory viruses in acute exacerbations of chronic obstructive pulmonary disease.
Lung India 29— George SN, Garcha DS, Mackay AJ, Patel AR, Singh R, Sapsford RJ, et al. Eur Respir J. View Article Google Scholar 8. Mallia P, Message SD, Gielen V, Contoli M, Gray K, Kebadze T, et al. Mallia P, Message SD, Contoli M, Gray K, Telcian A, Laza-Stanca V, et al. Respir Med 78— Breathe a sigh of relief while perusing our respiratory health supplements.
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Collection Respiratory Health. Clear all Apply Apply. Bioactive Quercetin EMIQ 50 mg Highly bioavailable form of the antioxidant nutrient quercetin. Black Elderberry Standardized Extract mg Helps relieve symptoms of cold and flu and provides antioxidants. N-Acetyl-L-Cysteine Amino Acid mg Protects against free radical damage.
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