Airway Epithelial Barrier Dysfunction Research Articles

Chrysene contribution to bronchial asthma: Activation of TRPA1 disrupts bronchial epithelial barrier via ERK pathway

BackgroundElevated polycyclic aromatic hydrocarbon (PAH) levels are associated with exacerbation of asthma. Chrysene is one of the most prevalent unsubstituted PAHs in the environment. Transient receptor potential ankyrin 1 (TRPA1) can be used as a chemoreceptor to detect inhaled stimuli and plays an important role in the occurrence and deterioration of asthma. Whether exposure to a high concentration of chrysene in the environment can activate TRPA1 and contribute to the development of asthma, potentially through the dysfunction of the bronchial epithelial barrier, remains unclear. MethodsA cell-based assay was performed to verify the downregulation of the expression of E-cadherin and tight junction (TJ) proteins by chrysene in bronchial epithelial cells to explore the role of chrysene-mediated TRPA1 activation in the regulation of TJ protein expression through the extracellular signal-regulated protein kinase (ERK) pathway. Animal tests were conducted to determine whether chrysene could enhance airway hyperresponsiveness (AHR) induced by house dust mites (HDMs) and disrupt barrier function, thereby contributing to asthma. ResultsThe cell-based assay revealed that chrysene could disrupt the function of the bronchial epithelial barrier and decrease the expression levels of E-cadherin, zonula occludens-1 (ZO-1), occludin, and claudin-5 through the ERK pathway. Chrysene induced airway epithelial barrier dysfunction primarily through TRPA1 instead of transient receptor potential vanilloid 1. TRPA1 knockdown was able to attenuate chrysene-induced downregulation of TJ protein expression and downregulate ERK activation (p-ERK). Compared with exposure to HDM alone, coexposure to chrysene and HDM resulted in an increased incidence of AHR, disruption of barrier function, and eosinophilic inflammatory responses in a mouse model of asthma. Coexposure to chrysene and HDM increased TRPA1 expression. The animal test verified that the TRPA1 inhibitor HC030031 could suppress chrysene and HDM-induced asthma in mice. ConclusionsOur findings showed that chrysene contributed to the breakdown of the function of the bronchial epithelial barrier through the TRPA1–ERK axis and therefore acted as an adjuvant to contribute to asthma.

Lentinan attenuates allergic airway inflammation and epithelial barrier dysfunction in asthma via inhibition of the PI3K/AKT/NF-κB pathway

BackgroundAllergic asthma has been regarded as an inflammatory disease mediated by type 2 immunity. The treatment of progressive forms of asthma remains unsatisfactory despite substantial progress in drug development. Lentinan (LTN), a specific polysaccharide derived from Lentinus edodes, exhibits anti-inflammatory and immunomodulatory functions. Nevertheless, the effect and underlying mechanisms of Lentinan on asthma remain unclear. PurposeThis research investigated the regulatory role of Lentinan on allergic airway inflammation and epithelial barrier dysfunction in HDM (house dust mite)-induced asthma. Study designHDM-induced C57BL/6 mice received different dosages of Lentinan through intraperitoneal injections, to observe the effect of Lentinan against allergic airway inflammation and epithelial barrier dysfunction in asthma. MethodsMice were intranasally administered HDM extract solution on days 0, 1, 2 and on days 8 to 12, establishing the allergic asthma model. On days 8 to 12, mice were intraperitoneally administered varying doses of Lentinan (5/10/20mg/kg) 1h before HDM challenge. On day 14, samples were harvested for analysis. Cell counting, flow cytometry, ELISA, HE and PAS staining, IF staining, western blotting, RT-PCR, and bioinformatic analysis were conducted to delve into the underlying functions and mechanisms of Lentinan in asthma. ResultsOur study revealed that the treatment of Lentinan significantly ameliorated allergic airway inflammation and improved epithelial barrier dysfunction in experimental mice. Following Lentinan treatment, there was a significant reduction in eosinophil counts, accompanied by a diminished presence of type 2 cytokines. Reversal of epithelial barrier dysfunction after treatment was also observed. The therapeutic mechanism involved suppression of the PI3K/AKT/ NF-κB pathway. ConclusionOur research illuminated the protective role of Lentinan in allergic airway inflammation and impaired epithelial barrier, suggesting LTN could be an innovative and promising candidate for asthma treatment.

IL-37 protects against house dust mite-induced airway inflammation and airway epithelial barrier dysfunction via inhibiting store-operated calcium entry

BackgroundAirway epithelial barrier dysfunction has been proved to contribute to the development of type 2 inflammation of asthma. Interleukin (IL)-37 is a negative regulator of immune responses and allergic airway inflammation. However, whether IL-37 has any effect on airway epithelial barrier has been unknown. MethodsWe evaluated the role of IL-37 in both mouse model and cultured 16HBE cells. Histology and ELISA assays were used to evaluate airway inflammation. FITC-dextran permeability assay was used to evaluate the airway epithelial barrier function. Immunofluorescence, western blot and quantitative Real-Time PCR (RT-PCR) were used to evaluate the distribution and expression of tight junction proteins. RT-PCR and Ca2+ fluorescence measurement were used to evaluate the mRNA expression and activity of store-operated calcium entry (SOCE). ResultsIL-37 inhibited house dust mite (HDM)-induced airway inflammation and decreased the levels of IgE in serum and type 2 cytokines in bronchoalveolar lavage fluid (BALF) compared to asthmatic mice. IL-37 protected against HDM-induced airway epithelial barrier dysfunction, including reduced leakage of FITC-dextran, enhanced expression of TJ proteins, and restored the membrane distribution of TJ proteins. Moreover, IL-37 decreased the level of IL-33 in the BALF of asthmatic mice and the supernatants of HDM-treated 16HBE cells. IL-37 decreased the peak level of Ca2+ fluorescence induced by thapsigargin and HDM, and inhibited the mRNA expression of Orai1, suggesting an inhibiting effect of IL-37 on SOCE in airway epithelial cells. ConclusionIL-37 plays a protective role in airway inflammation and HDM-induced airway epithelial barrier dysfunction by inhibiting SOCE.

Nicotinamide mononucleotide attenuates airway epithelial barrier dysfunction via inhibiting SIRT3 SUMOylation in asthma

Nicotinamide adenine dinucleotide (NAD+) is an essential element in cellular metabolism that regulates fundamental biological processes. Growing evidence suggests that a decline in NAD+ is a common pathological factor in various diseases and aging. However, its role in airway epithelial barrier function in response to asthma remains underexplored. The current study aims to explore the efficacy of restoring cellular NAD+ concentration through supplementation with the NAD+ precursor, nicotinamide mononucleotide (NMN), in the treatment of allergic asthma and to investigate the role of SIRT3 in mediating the effects of NAD+ precursors. In this research, NMN alleviated airway inflammation and reduced mucus secretion in house dust mite (HDM)-induced asthmatic mice. It also mitigated airway epithelial barrier disruption in HDM-induced asthma in vitro and in vivo. But inhibition of SIRT3 expression abolished the effects of NMN. Mechanistically, HDM induced SIRT3 SUMOylation and proteasomal degradation. Mutation of these two SIRT3 SUMO modification sites enhanced the stability of SIRT3. Additionally, SIRT3 was targeted by SENP1 which acted to de-conjugate SUMO. And down-regulation of SENP1 expression in HDM-induced models was reversed by NMN. Collectively, these findings suggest that NMN attenuates airway epithelial barrier dysfunction via inhibiting SIRT3 SUMOylation in asthma. Blockage of SIRT3 SUMOylation emerges as for the treatment of allergic asthma.

Novel nasal formulation of xylometazoline with hyaluronic acid: In vitro ciliary beat frequency study

Acute viral rhinosinusitis (viral ARS), or commonly referred to as the “common cold”, is caused by respiratory viruses that cause disruption of the airway epithelial barrier and mucociliary dysfunction. Treatment of ARS is mainly symptomatic, with xylometazoline, a direct-acting α-adrenoceptor agonist, commonly used as a nasal decongestant. Unfortunately, this treatment does not resolve the epithelial dysfunction observed in ARS, and its use might negatively impact the nasal mucosa causing issues such as dryness, stinging, burning, rebound congestion, as well as atrophy. In light of this, a novel nasal spray formulation containing both xylometazoline and hyaluronic acid (HA) was developed to provide a more effective and safer treatment for viral ARS. HA is a natural polysaccharide known to hydrate and moisturise the upper respiratory tract, maintain the integrity of the nasal mucosa, and promote mucociliary clearance and wound healing. To investigate the potential of this combination, this study was conducted using the nasal MucilAirTMin vitro model and high-speed phase-contrast microscopy to examine the effect of xylometazoline and HA on ciliary function by measuring ciliary beat frequency and their cytotoxicity by morphological, histological and ultrastructural analysis. This research is the first to assess the effects of a specific dose and molecular weight of HA as an active pharmaceutical ingredient in nasal spray formulations. The combination of a fast-acting decongestant and an additional active agent targeting nasal epithelial dysfunction has the potential to provide an improved, reliable and safe treatment for viral ARS, and may serve as the basis for future clinical studies.

SARS-CoV-2 infection of polarized human airway epithelium induces necroptosis that causes airway epithelial barrier dysfunction.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause the ongoing pandemic of coronavirus disease 2019 (COVID19). One key feature associated with COVID-19 is excessive pro-inflammatory cytokine production that leads to severe acute respiratory distress syndrome. Although the cytokine storm induces inflammatory cell death in the host, which type of programmed cell death mechanism that occurs in various organs and cells remains elusive. Using an in vitro culture model of polarized human airway epithelium (HAE), we observed that necroptosis, but not apoptosis or pyroptosis, plays an essential role in the damage of the epithelial barrier of polarized HAE infected with SARS-CoV-2. Pharmacological inhibitors of necroptosis, necrostatin-2 and necrosulfonamide, efficiently prevented cell death and epithelial barrier dysfunction caused by SARS-CoV-2 infection. Moreover, the silencing of genes that are involved in necroptosis, RIPK1, RIPK3, and MLKL, ameliorated airway epithelial damage of the polarized HAE infected with SARS-CoV-2. This study, for the first time, confirms that SARS-CoV-2 infection triggers necroptosis that disrupts the barrier function of human airway epithelia in vitro.

Ethanol-exposed lung fibroblasts cause airway epithelial barrier dysfunction.

Chronic alcohol ingestion predisposes to lung injury and disrepair during sepsis. Our previous studies outlined roles for transforming growth factor-beta 1 (TGFβ1) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in epithelial barrier homeostasis and how alcohol perturbs their expression and signaling. Here we hypothesize that ethanol-exposed lung fibroblasts (LF) are a source of dysregulated TGFβ1 and GM-CSF and thereby alter airway epithelial barrier function. Human or rat LF were cultured ± ethanol for 2 weeks and then co-cultured with human or rat airway epithelial cells (AEC) seeded on Transwell permeable supports. In selected groups, a TGFβ1 receptor type 1 (TGFβR1) inhibitor (SB431542) or a TGFβ1 neutralizing antibody was applied. Transepithelial electrical resistance (TER) was measured prior to co-culture and on day 5 of co-culture. AEC were then analyzed for the expression of selected tight junction and mesenchymal proteins, and transwell membranes were analyzed by immunofluorescence microscopy for ZO-1 expression and localization. TGFβ1 and GM-CSF levels in conditioned media from the co-cultures were quantified by ELISA. AEC co-cultured with ethanol-exposed LF (ELF) showed a significant reduction in TER and corresponding decreases in ZO-1 expression, whereas collagen type 1A1 and α-smooth muscle actin protein expression were increased. In parallel, in conditioned media from the ELF + AEC co-cultures, activated TGFβ1 levels increased and GM-CSF levels decreased. Notably, all the effects of ELF on the AEC were prevented by blocking TGFβ1 activity. Prior ethanol exposure to LF induces barrier dysfunction in naive AEC in a paracrine fashion through activation of TGFβ1 signaling and suppression of GM-CSF. These experimental findings provide a potential mechanism by which chronic alcohol ingestion impairs airway epithelial integrity and renders individuals susceptible to lung injury.

Dopamine D1 receptor agonist alleviates acute lung injury via modulating inflammatory responses in macrophages and barrier function in airway epithelial cells

Acute lung injury (ALI) or its severe form, acute respiratory distress syndrome (ARDS) is a life-threatening illness without effective therapeutic interventions currently. Multiple lines of evidence indicated that overwhelming inflammatory responses and impaired epithelial barrier contributed to the pathogenesis of ALI/ARDS. Recently, dopamine (DA) system was identified to participate in various pulmonary diseases. Here, we discovered that dopamine D1-like receptors mainly expressed in macrophages and airway epithelial cells (AECs), which were downregulated by lipopolysaccharide (LPS) challenge in ALI mouse lung. SKF38393 (SKF) is a selective agonist for D1-like receptors and was demonstrated to inhibit excessive inflammatory responses and oxidative stress in THP-1 cell-derived macrophages and Beas-2B cells, as well as improve airway epithelial barrier dysfunction induced by LPS stimulation. Moreover, SKF administration could effectively decrease pulmonary inflammation, ameliorate tissue damage in the LPS-triggered ALI mice. The broad protective actions of SKF might be attributed to the activation of Nrf2 antioxidative system by use of the specific inhibitor, ML385. This study offers evidence of potent immunoregulatory activity of SKF in macrophages, AECs as well as ALI mouse model, which opens novel therapeutic avenues for the intervention of ALI/ARDS.

Secreted S100A4 causes asthmatic airway epithelial barrier dysfunction induced by house dust mite extracts via activating VEGFA/VEGFR2 pathway

The airway epithelial barrier dysfunction plays a crucial role in pathogenesis of asthma and causes the amplification of downstream inflammatory signal pathway. S100 calcium binding protein A4 (S100A4), which promotes metastasis, have recently been discovered as an effective inflammatory factor and elevated in bronchoalveolar lavage fluid in asthmatic mice. Vascular endothelial growth factor-A (VEGFA), is considered as vital regulator in vascular physiological activities. Here, we explored the probably function of S100A4 and VEGFA in asthma model dealt with house dust mite (HDM) extracts. Our results showed that secreted S100A4 caused epithelial barrier dysfunction, airway inflammation and the release of T-helper 2 cytokines through the activation of VEGFA/VEGFR2 signaling pathway, which could be partial reversed by S100A4 polyclonal antibody, niclosamide and S100A4 knockdown, representinga potential therapeutic target for airway epithelial barrier dysfunction in asthma.

Azithromycin ameliorated cigarette smoke-induced airway epithelial barrier dysfunction by activating Nrf2/GCL/GSH signaling pathway

BackgroundAirway epithelium is the first barrier against environmental insults, and epithelial barrier dysfunction caused by cigarette smoke (CS) is particularly relevant to chronic obstructive pulmonary disease (COPD) progression. Our study was to determine whether Azithromycin (AZI) ameliorates CS-induced airway epithelial barrier dysfunction and the underlying mechanisms.MethodsPrimary bronchial epithelial cells (PBECs), human bronchial epithelial cells (HBECs), Sprague Dawley rats and nuclear factor erythroid 2-related factor 2 (Nrf2)−/− mice were pretreated with AZI and subsequently exposed to CS. Transepithelial electronic resistance (TEER), junction proteins as well as pro-inflammatory cytokines and apoptosis markers were examined to assess epithelial barrier dysfunction. Metabolomics study was applied to explore the underlying mechanism of AZI.ResultsCS-induced TEER decline and intercellular junction destruction, accompanied with inflammatory response and cell apoptosis in PBECs were restored by AZI dose-dependently, which were also observed in CS-exposed rats. Mechanistically, GSH metabolism pathway was identified as the top differentially impacted pathway and AZI treatment upregulated the activities of glutamate cysteine ligase (GCL) and the contents of metabolites in GSH metabolic pathway. Furthermore, AZI apparently reversed CS-induced Nrf2 suppression, and similar effects on airway epithelial barrier dysfunction were also found for Nrf2 agonist tert-butylhydroquinone and vitamin C. Finally, deletion of Nrf2 in both HBECs and C57BL/6N mice aggravated CS-induced GSH metabolism imbalance to disrupt airway epithelial barrier and partially deprived the effects of AZI.ConclusionThese findings suggest that the clinical benefits of AZI for COPD management are related with the protection of CS-induced airway epithelial barrier dysfunction via activating Nrf2/GCL/GSH pathway, providing potential therapeutic strategies for COPD.Graphical abstract

Blockade of CBX4-mediated β-catenin SUMOylation attenuates airway epithelial barrier dysfunction in asthma.

Epithelial barrier dysfunction is involved in the pathogenesis of asthma. Previous studies show that SUMOylation can regulate epithelial junction molecule localization. However, the role of SUMOylation in epithelial barrier dysfunction in asthma remains unclear. This study found that inhibition of SUMOylation attenuates house dust mite (HDM)-induced epithelial barrier dysfunction. The SUMOylation levels of junction molecules were determined by co-immunoprecipitation (CO-IP) and proximity ligation assay (PLA). HDM treatment significantly enhanced SUMOylation levels of β-catenin, while no effect was seen on ZO-1, Occludin, and E-cadherin SUMOylation levels. Inhibition of β-catenin SUMOylation through 2-D08 treatment or SUMOylation modification site mutant (K233A) promoted its membrane localization and repressed Wnt/β-catenin signaling. Further, we identified that CBX4, an E3 ligase, mediated SUMOylation of β-catenin. Knockdown of CBX4 promoted β-catenin membrane localization and improved epithelial barrier function. In vivo analysis showed that AAV6-shCBX4-mediated knockdown of CBX4 attenuated HDM-induced allergic airway inflammation and epithelial barrier dysfunction. The findings showed that inhibiting β-catenin SUMOylation by targeting CBX4 mitigated HDM-induced epithelial barrier dysfunction in asthma.

Cigarette Smoke Extract Disturbs Mitochondria-Regulated Airway Epithelial Cell Responses to Pneumococci.

Mitochondrial functionality is crucial for the execution of physiologic functions of metabolically active cells in the respiratory tract including airway epithelial cells (AECs). Cigarette smoke is known to impair mitochondrial function in AECs. However, the potential contribution of mitochondrial dysfunction in AECs to airway infection and airway epithelial barrier dysfunction is unknown. In this study, we used an in vitro model based on AECs exposed to cigarette smoke extract (CSE) followed by an infection with Streptococcus pneumoniae (Sp). The levels of oxidative stress as an indicator of mitochondrial stress were quantified upon CSE and Sp treatment. In addition, expression of proteins associated with mitophagy, mitochondrial content, and biogenesis as well as mitochondrial fission and fusion was quantified. Transcriptional AEC profiling was performed to identify the potential changes in innate immune pathways and correlate them with indices of mitochondrial function. We observed that CSE exposure substantially altered mitochondrial function in AECs by suppressing mitochondrial complex protein levels, reducing mitochondrial membrane potential and increasing mitochondrial stress and mitophagy. Moreover, CSE-induced mitochondrial dysfunction correlated with reduced enrichment of genes involved in apical junctions and innate immune responses to Sp, particularly type I interferon responses. Together, our results demonstrated that CSE-induced mitochondrial dysfunction may contribute to impaired innate immune responses to Sp.

Role of air pollutants in airway epithelial barrier dysfunction in asthma and COPD

Chronic exposure to environmental pollutants is a major contributor to the development and progression of obstructive airway diseases, including asthma and COPD. Understanding the mechanisms underlying the development of obstructive lung diseases upon exposure to inhaled pollutants will lead to novel insights into the pathogenesis, prevention and treatment of these diseases. The respiratory epithelial lining forms a robust physicochemical barrier protecting the body from inhaled toxic particles and pathogens. Inhalation of airborne particles and gases may impair airway epithelial barrier function and subsequently lead to exaggerated inflammatory responses and airway remodelling, which are key features of asthma and COPD. In addition, air pollutant-induced airway epithelial barrier dysfunction may increase susceptibility to respiratory infections, thereby increasing the risk of exacerbations and thus triggering further inflammation. In this review, we discuss the molecular and immunological mechanisms involved in physical barrier disruption induced by major airborne pollutants and outline their implications in the pathogenesis of asthma and COPD. We further discuss the link between these pollutants and changes in the lung microbiome as a potential factor for aggravating airway diseases. Understanding these mechanisms may lead to identification of novel targets for therapeutic intervention to restore airway epithelial integrity in asthma and COPD.

Galacto-oligosaccharides as an anti-bacterial and anti-invasive agent in lung infections

Emerging antimicrobial resistance in infections asks for novel intervention strategies. Galacto-oligosaccharides (GOS) might be attractive alternatives to antibiotics due to their anti-inflammatory and anti-adhesive properties. Mannheimia haemolytica is one of the major Pasteurellaceae associated with bovine lung infections. Using M. haemolytica, we demonstrated that GOS have the capacity to reduce bacterial viability and can be used as adjuvant to improve antibiotic efficacy. Using M. haemolytica-treated primary bronchial epithelial cells (PBECs) of calves, we identified the anti-adhesive and anti-invasive activities of GOS. The observed inhibition of cytokine/chemokine release and the prevention of airway epithelial barrier dysfunction in M. haemolytica-treated PBECs by GOS might be related to the downregulation of “toll-like receptor 4/nuclear factor-κB” pathway and the anti-invasive and anti-adhesive properties of GOS. Particularly, GOS lowered lipopolysaccharides- but not flagellin-induced cytokine/chemokine release in calf and human airway epithelial cells. Finally, we performed in vivo experiments in calves and demonstrated for the first time that intranasal application of GOS can relieve lung infections/inflammation and lower M. haemolytica positivity in the lungs without affecting clinical performance. These findings not only shed light on the anti-inflammatory mechanisms of GOS during lung infections, but GOS might also be a promising anti-bacterial agent for preventing (lung) infections.

The relation between age and airway epithelial barrier function

BackgroundThe prevalence of age-associated diseases, such as chronic obstructive pulmonary disease (COPD), is increasing as the average life expectancy increases around the world. We previously identified a gene signature for ageing in the human lung which included genes involved in apical and tight junction assembly, suggesting a role for airway epithelial barrier dysfunction with ageing.AimTo investigate the association between genes involved in epithelial barrier function and age both in silico and in vitro in the airway epithelium.MethodsWe curated a gene signature of 274 genes for epithelial barrier function and tested the association with age in two independent cohorts of bronchial brushings from healthy individuals with no respiratory disease, using linear regression analysis (FDR < 0.05). Protein–protein interactions were identified using STRING©. The barrier function of primary bronchial epithelial cells at air–liquid interface and CRISPR–Cas9-induced knock-down of target genes in human bronchial 16HBE14o-cells was assessed using Trans epithelial resistance (TER) measurement and Electric cell-surface impedance sensing (ECIS) respectively.ResultsIn bronchial brushings, we found 55 genes involved in barrier function to be significantly associated with age (FDR < 0.05). EPCAM was most significantly associated with increasing age and TRPV4 with decreasing age. Protein interaction analysis identified CDH1, that was negatively associated with higher age, as potential key regulator of age-related epithelial barrier function changes. In vitro, barrier function was lower in bronchial epithelial cells from subjects > 45 years of age and significantly reduced in CDH1-deficient 16HBE14o-cells.ConclusionThe significant association between genes involved in epithelial barrier function and age, supported by functional studies in vitro, suggest a role for epithelial barrier dysfunction in age-related airway disease.

Involvement and therapeutic implications of airway epithelial barrier dysfunction in type 2 inflammation of asthma.

Type 2 inflammation is a complex immune response and primary mechanism for several common allergic diseases including allergic rhinitis, allergic asthma, atopic dermatitis, and chronic rhinosinusitis with nasal polyps. It is the predominant type of immune response against helminths to prevent their tissue infiltration and induce their expulsion. Recent studies suggest that epithelial barrier dysfunction contributes to the development of type 2 inflammation in asthma, which may partly explain the increasing prevalence of asthma in China and around the globe. The epithelial barrier hypothesis has recently been proposed and has received great interest from the scientific community. The development of leaky epithelial barriers leads to microbial dysbiosis and the translocation of bacteria to inter- and sub-epithelial areas and the development of epithelial tissue inflammation. Accordingly, preventing the impairment and promoting the restoration of a deteriorated airway epithelial barrier represents a promising strategy for the treatment of asthma. This review introduces the interaction between type 2 inflammation and the airway epithelial barrier in asthma, the structure and molecular composition of the airway epithelial barrier, and the assessment of epithelial barrier integrity. The role of airway epithelial barrier disruption in the pathogenesis of asthma will be discussed. In addition, the possible mechanisms underlying the airway epithelial barrier dysfunction induced by allergens and environmental pollutants, and current treatments to restore the airway epithelial barrier are reviewed.

Is the epithelial barrier hypothesis the key to understanding the higher incidence and excess mortality during COVID-19 pandemic? The case of Northern Italy.

The high incidence and increased mortality of COVID‐19 make Italy among the most impacted countries by SARS‐CoV‐2 outbreak. In the beginning of the pandemic, Northern regions accounted for 40% of cases and 45% of deaths from COVID‐19 in Italy. Several factors have been suggested to explain the higher incidence and excess mortality from COVID‐19 in these regions. It is noticed that Northern Italian regions, and particularly the cities in Po Valley, are the areas with the highest air pollution due to commercial vehicle traffic, industry and a stagnant meteorological condition, with one of the highest levels in Italy and Europe of fine particulate matter 2.5 micron or smaller in size (PM2.5). PM2.5, the major environmental pollutant deriving mainly by factory and automobile exhaust emissions and coal combustion, increases the expression of angiotensin‐converting enzyme 2, the epithelial cell entry receptor for SARS‐CoV‐2, and thus increase the susceptibility to this virus. The epithelial barrier hypothesis proposes that many diverse diseases may rise from the disruption of epithelial barrier of skin, respiratory tract and gastrointestinal system, including allergic diseases, metabolic and autoimmune diseases, and chronic neuropsychiatric conditions. There is evidence of a close correlation between air pollution and airway epithelial barrier dysfunction. Air pollution, causing lung epithelial barrier dysfunction, may contribute to local chronic inflammation, microbiome dysbiosis and impaired antiviral immune response against SARS‐CoV‐2, all of which contribute to the high incidence and excess mortality from COVID‐19. In addition, air pollution and epithelial barrier dysfunction contribute also to the higher prevalence of several comorbidities of COVID‐19, such as diabetes, chronic obstructive pulmonary disease and obesity, which have been identified as risk factors for mortality of COVID‐19. In this article, on the basis of epidemiological and environmental monitoring data in Northern Italy, it is suggested that epithelial barrier hypothesis may help to understand the excess burden and mortality from COVID‐19.

Supplemental figures of "Blockade of β-catenin SUMOylation attenuates house dust mite-induced airway epithelial barrier dysfunction,"

Supplemental figures of "Blockade of β-catenin SUMOylation attenuates house dust mite-induced airway epithelial barrier dysfunction,"

Particulate matter induces airway epithelial barrier dysfunction in vivo and in vitro: from a more realistic inhalation scenario

Schematic diagram of particle matter induced airway epithelial barrier dysfunction.

Budesonide promotes airway epithelial barrier integrity following double-stranded RNA challenge.

Airway epithelial barrier dysfunction is increasingly recognized as a key feature of asthma and other lung diseases. Respiratory viruses are responsible for a large fraction of asthma exacerbations, and are particularly potent at disrupting epithelial barrier function through pattern recognition receptor engagement leading to tight junction dysfunction. Although different mechanisms of barrier dysfunction have been described, relatively little is known about whether barrier integrity can be promoted to limit disease. Here, we tested three classes of drugs commonly prescribed to treat asthma for their ability to promote barrier function using a cell culture model of virus-induced airway epithelial barrier disruption. Specifically, we studied the corticosteroid budesonide, the long acting beta-agonist formoterol, and the leukotriene receptor antagonist montelukast for their ability to promote barrier integrity of a monolayer of human bronchial epithelial cells (16HBE) before exposure to the viral mimetic double-stranded RNA. Of the three, only budesonide treatment limited transepithelial electrical resistance and small molecule permeability (4 kDa FITC-dextran flux). Next, we used a mouse model of acute dsRNA challenge that induces transient epithelial barrier disruption in vivo, and studied the effects budesonide when administered prophylactically or therapeutically. We found that budesonide similarly protected against dsRNA-induced airway barrier disruption in the lung, independently of its effects on airway inflammation. Taken together, these data suggest that an under-appreciated effect of inhaled budesonide is to maintain or promote airway epithelial barrier integrity during respiratory viral infections.