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Quercetin improves and protects Calu-3 airway epithelial barrier function.

ABSTRACT: Introduction: In light of the impact of airway barrier leaks in COVID-19 and the significance of vitamin D in COVID-19 outcomes, including airway barrier protection, we investigated whether the very common dietary flavonoid quercetin could also be efficacious in supporting airway barrier function. Methods: To address this question, we utilized the widely used airway epithelial cell culture model, Calu-3. Results: We observed that treating Calu-3 cell layers with quercetin increased transepithelial electrical resistance while simultaneously reducing transepithelial leaks of 14C-D-mannitol (Jm) and 14C-inulin. The effects of quercetin were concentration-dependent and exhibited a biphasic time course. These effects of quercetin occurred with changes in tight junctional protein composition as well as a partial inhibition of cell replication that resulted in decreased linear junctional density. Both of these effects potentially contribute to improved barrier function. Quercetin was equally effective in reducing the barrier compromise caused by the pro-inflammatory cytokine TNF-α, an action that seemed to derive, in part, from reducing the elevation of ERK 1/2 caused by TNF-α. Discussion: Quercetin improved Calu-3 barrier function and reduced TNF-α-induced barrier compromise, mediated in part by changes in the tight junctional complex.

SUBMITTER: DiGuilio KM

PROVIDER: S-EPMC10701405 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Quercetin improves and protects Calu-3 airway epithelial barrier function.

DiGuilio K M KM Rybakovsky E E Valenzano M C MC Nguyen H H HH Del Rio E A EA Newberry E E Spadea R R Mullin J M JM

Frontiers in cell and developmental biology 20231123

Introduction: In light of the impact of airway barrier leaks in COVID-19 and the significance of vitamin D in COVID-19 outcomes, including airway barrier protection, we investigated whether the very common dietary flavonoid quercetin could also be efficacious in supporting airway barrier function. Methods: To address this question, we utilized the widely used airway epithelial cell culture model, Calu-3. Results: We observed that treating Calu-3 cell layers with quercetin in ...[more]

PMID: 38078004

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Project description:BackgroundAirway basal cells from patients with chronic obstructive pulmonary disease (COPD) regenerate abnormal airway epithelium and this was associated with reduced expression of several genes involved in epithelial repair. Quercetin reduces goblet cell metaplasia and the expression of pro-inflammatory cytokines in COPD models. This study assessed whether quercetin improves epithelial regeneration from COPD airway basal cells.MethodsCOPD airway basal cells were treated with DMSO or 1 μM quercetin for three days. The cells were then cultured at air/liquid interface (ALI) for up to 4 weeks. Basal cells from healthy donors cultured at air/liquid interface were used as controls. Polarization of cells was determined at 8 days of ALI. The cell types and IL-8 expression in differentiated cell cultures were quantified by flow cytometry and ELISA. Microarray analysis was conducted on DMSO or quercetin-treated COPD basal cells to identify differentially regulated genes (DEG) and the enriched biological pathways. Bronchial brushings from COPD patients treated with either placebo or quercetin for 6 months were used to confirm the effects of quercetin on gene expression.ResultsCompared to DMSO, quercetin-treated COPD basal cells showed an increase in TER and regenerated the airway epithelium with more ciliated cells, and less goblet cells and IL-8. Comparison of DMSO- and quercetin-treated COPD basal cell transcriptomic profiles indicated that quercetin upregulated genes associated with tissue and epithelial development and differentiation. COPD patients treated with quercetin, but not placebo showed significantly increased expression of two developmental genes HOXB2 and ELF3, which were also increased in quercetin-treated COPD basal cells. Bronchial brushings from active smokers showed significantly increased mRNA expression of TGF-β and IL-8, and it was reduced after quercetin treatment.ConclusionsThese results indicate that quercetin may improve airway epithelial regeneration by increasing the expression of genes involved in epithelial development/differentiation in COPD.Trial registrationThis study was registered at ClinicalTrials.gov on 6-18-2019. The study number is NCT03989271.

Project description:BackgroundAirway basal cells (BC) from patients with chronic obstructive pulmonary disease (COPD) regenerate abnormal airway epithelium and this was associated with reduced expression of several genes involved in epithelial repair. Quercetin reduces airway epithelial remodeling and inflammation in COPD models, therefore we examined whether quercetin promotes normal epithelial regeneration from COPD BC by altering gene expression.MethodsCOPD BC treated with DMSO or 1 µM quercetin for three days were cultured at air/liquid interface (ALI) for up to 4 weeks. BC from healthy donors cultured at ALI were used as controls. Polarization of cells was determined at 8 days of ALI. The cell types and IL-8 expression in differentiated cell cultures were quantified by flow cytometry and ELISA respectively. Microarray analysis was conducted on DMSO or 1 µM quercetin-treated COPD BC for 3 days to identify differentially regulated genes (DEG). Bronchial brushings obtained from COPD patients with similar age and disease status treated with either placebo (4 subjects) or 2000 mg/day quercetin (7 subjects) for 6 months were used to confirm the effects of quercetin on gene expression.ResultsCompared to placebo-, quercetin-treated COPD BC showed significantly increased transepithelial resistance, more ciliated cells, fewer goblet cells, and lower IL-8. Quercetin upregulated genes associated with tissue and epithelial development and differentiation in COPD BC. COPD patients treated with quercetin, but not placebo showed increased expression of two developmental genes HOXB2 and ELF3, which were also increased in quercetin-treated COPD BC with FDR < 0.001. Active smokers showed increased mRNA expression of TGF-β (0.067) and IL-8 (22.0), which was reduced by 3.6 and 4.14 fold respectively after quercetin treatment.ConclusionsThese results indicate that quercetin may improve airway epithelial regeneration by increasing the expression of genes involved in epithelial development/differentiation in COPD.Trial registrationThis study was registered at ClinicalTrials.gov on 6-18-2019. The study number is NCT03989271.

Project description:Background and aimsThe impairment of intestinal epithelial barrier is the main etiologic factor of inflammatory bowel disease. The proper intestinal epithelial proliferation and differentiation is crucial for maintaining intestinal integrity. Metformin is a common anti-diabetic drug. The objective is to evaluate the protective effects of metformin on ileal epithelial barrier integrity using interleukin-10 deficient (IL10KO) mice.MethodsWild-type and IL10KO mice were fed with/without metformin for 6 weeks and then ileum was collected for analyses. The mediatory role of AMP-activated protein kinase (AMPK) was further examined by gain and loss of function study in vitro.ResultsCompared to wild-type mice, IL10KO mice had increased proliferation, reduced goblet cell and Paneth cell lineage differentiation in the ileum tissue, which was accompanied with increased crypt expansion. Metformin supplementation mitigated intestinal cell proliferation, restored villus/crypt ratio, increased goblet cell and Paneth cell differentiation and improved barrier function. In addition, metformin supplementation in IL10KO mice suppressed macrophage pro-inflammatory activity as indicated by reduced M1 macrophage abundance and decreased pro-inflammatory cytokine IL-1β, TNF-α and IFN-γ expressions. As a target of metformin, AMPK phosphorylation was enhanced in mice treated with metformin, regardless of mouse genotypes. In correlation, the mRNA level of differentiation regulator including bmp4, bmpr2 and math1 were also increased in IL10KO mice supplemented with metformin, which likely explains the enhanced epithelial differentiation in IL10KO mice with metformin. Consistently, in Caco-2 cells, metformin promoted claudin-3 and E-cadherin assembly and mitigated TNF-α-induced fragmentation of tight junction proteins. Gain and loss of function assay also demonstrated AMPK was correlated with epithelial differentiation and proliferation.ConclusionsMetformin supplementation promotes secretory cell lineage differentiation, suppresses inflammation and improves epithelial barrier function in IL10KO mice likely through activation of AMPK, showing its beneficial effects on gut epithelial.

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Quercetin improves and protects Calu-3 airway epithelial barrier function.

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Quercetin improves and protects Calu-3 airway epithelial barrier function.

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