Features Of Asthma Research Articles

Monensin inhibits mast cell mediated airway contractions in human and guinea pig asthma models

Asthma is a common respiratory disease associated with airway hyperresponsiveness (AHR), airway inflammation and mast cell (MC) accumulation in the lung. Monensin, an ionophoric antibiotic, has been shown to induce apoptosis of human MCs. The aim of this study was to define the effect of monensin on MC responses, e.g., antigen induced bronchoconstriction, and on asthmatic features in models of allergic asthma. Tracheal segments from house dust mite (HDM) extract sensitized guinea pigs were isolated and exposed to monensin, followed by histological staining to quantify MCs. Both guinea pig tracheal and human bronchi were used for pharmacological studies in tissue bath systems to investigate the monensin effect on tissue viability and antigen induced bronchoconstriction. Further, an HDM-induced guinea pig asthma model was utilized to investigate the effect of monensin on AHR and airway inflammation. Monensin decreased MC number, caused MC death, and blocked the HDM or anti-IgE induced bronchoconstriction in guinea pig and human airways. In the guinea pig asthma model, HDM-induced AHR, airway inflammation and MC hyperplasia could be inhibited by repeated administration of monensin. This study indicates that monensin is an effective tool to reduce MC number and MCs are crucial for the development of asthma-like features.

Macrophage migration inhibitory factor promotes glucocorticoid resistance of neutrophilic inflammation in a murine model of severe asthma

BackgroundSevere neutrophilic asthma is resistant to treatment with glucocorticoids. The immunomodulatory protein macrophage migration inhibitory factor (MIF) promotes neutrophil recruitment to the lung and antagonises responses to glucocorticoids. We hypothesised...

Alteration of glycosphingolipid metabolism by ozone is associated with exacerbation of allergic asthma characteristics in mice.

Asthma is a common chronic respiratory disease exacerbated by multiple environmental factors. Acute ozone exposure has previously been implicated in airway inflammation, airway hyperreactivity, and other characteristics of asthma, which may be attributable to altered sphingolipid metabolism. This study tested the hypothesis that acute ozone exposure alters sphingolipid metabolism within the lung, which contributes to exacerbations in characteristics of asthma in allergen-sensitized mice. Adult male and female BALB/c mice were sensitized intranasally to house dust mite (HDM) allergen on days 1, 3, and 5 and challenged on days 12-14. Mice were exposed to ozone following each HDM challenge for 6 h/day. Bronchoalveolar lavage, lung lobes, and microdissected lung airways were collected for metabolomics analysis (N = 8/sex/group). Another subset of mice underwent methacholine challenge using a forced oscillation technique to measure airway resistance (N = 6/sex/group). Combined HDM and ozone exposure in male mice synergistically increased airway hyperreactivity that was not observed in females and was accompanied by increased airway inflammation and eosinophilia relative to control mice. Importantly, glycosphingolipids were significantly increased following combined HDM and ozone exposure relative to controls in both male and female airways, which was also associated with both airway resistance and eosinophilia. However, 15 glycosphingolipid species were increased in females compared with only 6 in males, which was concomitant with significant associations between glycosphingolipids and airway resistance that ranged from R2 = 0.33-0.51 for females and R2 = 0.20-0.34 in male mice. These observed sex differences demonstrate that glycosphingolipids potentially serve to mitigate exacerbations in characteristics of allergic asthma.

Enhanced efficacy of formoterol-montelukast salt in relieving asthma features and in preserving β2-agonists rescue therapy

Adrenergic β2-agonists represent a mainstay in asthma management. Their chronic use has been associated with decreased bronchoprotection and rebound hyperresponsiveness. Here we investigate on the possible therapeutic advantage of a pharmacological association of β2-agonists with montelukast, a highly selective leukotriene receptor antagonist, in modulating bronchial reactivity and controlling asthma features. The study has been conducted in vitro and in vivo and also takes advantage of the synthesis of a salt that gave us the possibility to simultaneously administer in vivo formoterol and montelukast (MFS). In vitro studies demonstrate that montelukast (1) preserves β2-agonist response in isolated bronchi by preventing homologous β2-adrenoceptor desensitization; (2) reduces desensitization by modulating β2-receptor translocation in bronchial epithelial cells. In vivo studies demonstrate that sensitized mice receiving formoterol or montelukast display a significant reduction in airway hyperresponsiveness, but the β2-agonist relaxing response is still impaired. Allergen challenge causes β2 heterologous desensitization that is further increased by treatment in vivo with formoterol. Conversely MFS not only inhibits airway hyperresponsiveness but it rescues the β2-agonist response. Histological analysis confirms the functional data, demonstrating an enhanced therapeutic efficiency of MSF in controlling also pulmonary metaplasia and lung inflammation. MFS is efficacious also when sensitized mice received the drug by local administration. In conclusion, the data obtained evidenced a therapeutic advantage in the association of β2-agonists with montelukast in the control of asthma-like features and a better rescue bronchodilation response to β2-agonists.

Does the asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) exist? A narrative review from epidemiology and practice.

Asthma and chronic obstructive pulmonary disease (COPD) have traditionally been approached as separate entities that must be researched and treated separately. There is growing recognition, however, that a substantial proportion of patients with obstructive lung disease have characteristics of both asthma and COPD (termed the asthma-COPD overlap syndrome (ACOS)). Lung disease experts have difficulty defining ACOS, and many still resist accepting the possibility that asthma and COPD may be linked. It is likely that practicing clinicians may be equally confused about how to identify and treat ACOS. This narrative review aims to clarify concepts of ACOS definition, argues that the best way to understand ACOS is to view the chronic lung disease process longitudinally rather than cross-sectionally, and presents evidence that ACOS can be the end result of the natural history of severe asthma. The review also points out the serious gaps in knowledge regarding therapy for ACOS and presents emerging data supporting the intracellular respiratory pathogen Chlamydia pneumoniae as a possible common etiologic agent in severe asthma and ACOS.

High throughput virtual screening strategy to develop a potential treatment for bronchial asthma by targeting interleukin 13 cytokine signaling

Chronic inflammation in the airway passage leads to the clinical syndrome of pediatric asthma. Allergic reactions caused by bacterial, viral, and fungal infection lead to the immune dis-balance which primes T helper cells (Th2), a specific cluster of differentiation 4 (CD4) T cell differentiation. This favors the Th2-specific response by activating the inter-leukin 4/interleukin 13 (IL-4/IL-13) cytokine signaling and further activates the secretion of immunoglobulin E (IgE). IL-13 develops bronchial asthma by elevating bronchial hyperresponsiveness and enables production of immunoglobulin M (IgM) and IgE. The present study aims to target IL-13 signaling using molecular docking and understanding molecular dynamic simulation (MDS) to propose a compelling candidate to treat asthma. We developed a library of available allergic drugs (n=20) and checked the binding affinity against IL-13 protein (3BPN.pdb) through molecular docking and confirmed the best pose binding energy of -3.84 and -3.71 for epinephrine and guaifenesin, respectively. Studying the interaction of hydrogen bonds and Van der Walls, it is estimated that electrostatic energy is sufficient to interact with the active site of the IL-13 and has shown to inhibit inflammatory signaling. These computational results confirm epinephrine and guaifenesin as potential ligands showing potential inhibitory activity for IL-13 signaling. This study also suggests the designing of a new ligand and screening of a large cohort of drugs, in the future, to predict the exact mechanism to control the critical feature of asthma.

Computed tomography findings in bronchial asthma: quantification of air trapping and correlation with pulmonary function tests.

High-resolution computed tomography (HRCT) scans can help identify subsets of asthma patients who show rapid decline in lung function. To evaluate high-resolution computed tomography (HRCT) findings in adult patients with asthma, obtain quantitative measurements of air trapping on expiratory scans, and correlate the findings with pulmonary function tests (PFTs). Thirty adults with asthma with persistent-mild, persistent-moderate, and persistent-severe categories as per standard clinical guidelines were evaluated with inspiratory and expiratory HRCT for various imaging features of bronchial asthma. Expiratory HRCT scan were used to quantify degree of air-trapping, and their values quantified as "pixel index," using a special "density' mask" software. Complete spirometry and body plethysmography were performed on each patient within 0-2 days of HRCT scans. HRCT findings were correlated with the clinical severity groups and the CT pixel indices (PI) were correlated with the PFT results using correlation coefficients and linear regression analysis. The inspiratory CT findings did not correlate with increase in disease severity. Expiratory scans accurately quantified areas of air trapping. CT-PI correlated well with PFT values indicative of airway obstruction and airflow limitation, which helped differentiate patients with asthma with increasing severity from those with milder forms of the disease. Expiratory thin-section CT is a useful objective method to quantify air-trapping in people with asthma. The air-trapping score measured in "pixel indices" correlates well with PFT results and can successfully identify patients with severe asthma. Further studies are needed to confirm if this parameter can serve as a potential marker for airway remodeling and declining lung function.

Epithelial coxsackievirus adenovirus receptor promotes house dust mite-induced lung inflammation

Airway inflammation and remodelling are important pathophysiologic features in asthma and other respiratory conditions. An intact epithelial cell layer is crucial to maintain lung homoeostasis, and this depends on intercellular adhesion, whilst damaged respiratory epithelium is the primary instigator of airway inflammation. The Coxsackievirus Adenovirus Receptor (CAR) is highly expressed in the epithelium where it modulates cell-cell adhesion stability and facilitates immune cell transepithelial migration. However, the contribution of CAR to lung inflammation remains unclear. Here we investigate the mechanistic contribution of CAR in mediating responses to the common aeroallergen, House Dust Mite (HDM). We demonstrate that administration of HDM in mice lacking CAR in the respiratory epithelium leads to loss of peri-bronchial inflammatory cell infiltration, fewer goblet-cells and decreased pro-inflammatory cytokine release. In vitro analysis in human lung epithelial cells confirms that loss of CAR leads to reduced HDM-dependent inflammatory cytokine release and neutrophil migration. Epithelial CAR depletion also promoted smooth muscle cell proliferation mediated by GSK3β and TGF-β, basal matrix production and airway hyperresponsiveness. Our data demonstrate that CAR coordinates lung inflammation through a dual function in leucocyte recruitment and tissue remodelling and may represent an important target for future therapeutic development in inflammatory lung diseases.

Distribution of type 2 biomarkers and association with severity, clinical characteristics and comorbidities in the BREATHE real-life asthma population.

Type 2 (T2) high asthma is recognised as a heterogenous entity consisting of several endotypes; however, the prevalence and distribution of the T2 biomarkers in the general asthma population, across asthma severity, and across compartments is largely unknown. The objective of the present study was to describe expression and overlaps of airway and systemic T2 biomarkers in a clinically representative asthma population. Patients with asthma from the real-life BREATHE cohort referred to a specialist centre were included and grouped according to T2 biomarkers: blood and sputum eosinophilia (≥0.3×109 cells·L-1 and 3% respectively), total IgE (≥150 U·mL-1), and fractional exhaled nitric oxide (≥25 ppb). Patients with mild-to-moderate asthma were younger (41 versus 49 years, p<0.001), had lower body mass index (25.9 versus 28.0 kg·m-2, p=0.002) and less atopy (47% versus 58%, p=0.05), higher forced expiratory volume in 1 s (3.2 versus 2.8 L, p<0.001) and forced vital capacity (4.3 versus 3.9 L, p<0.001) compared with patients with severe asthma, who had higher blood (0.22×109 versus 0.17×109 cells·L-1, p=0.01) and sputum (3.0% versus 1.5%, p=0.01) eosinophils. Co-expression of all T2 biomarkers was a particular characteristic of severe asthma (p<0.001). In patients with eosinophilia, sputum eosinophilia without blood eosinophilia was present in 45% of patients with mild-to-moderate asthma and 35% with severe asthma. Severe asthma is more commonly associated with activation of several T2 pathways, indicating that treatments targeting severe asthma may need to act more broadly on T2 inflammatory pathways. Implementation of airway inflammometry in clinical care is of paramount importance, as the best treatable trait is otherwise is overlooked in a large proportion of patients irrespective of disease severity.

Interleukin-11 receptor subunit α-1 is required for maximal airway responsiveness to methacholine after acute exposure to ozone.

Interleukin (IL)-11, a multifunctional cytokine, contributes to numerous biological processes, including adipogenesis, hematopoiesis, and inflammation. Asthma, a respiratory disease, is notably characterized by reversible airway obstruction, persistent lung inflammation, and airway hyperresponsiveness (AHR). Nasal insufflation of IL-11 causes AHR in wild-type mice while lung inflammation induced by antigen sensitization and challenge, which mimics features of atopic asthma in humans, is attenuated in mice genetically deficient in IL-11 receptor subunit α-1 (IL-11Rα1-deficient mice), a transmembrane receptor that is required conjointly with glycoprotein 130 to transduce IL-11 signaling. Nevertheless, the contribution of IL-11Rα1 to characteristics of nonatopic asthma is unknown. Thus, based on the aforementioned observations, we hypothesized that genetic deficiency of IL-11Rα1 attenuates lung inflammation and increases airway responsiveness after acute inhalation exposure to ozone (O3), a criteria pollutant and nonatopic asthma stimulus. Accordingly, 4 and/or 24 h after cessation of exposure to filtered room air or O3, we assessed lung inflammation and airway responsiveness in wild-type and IL-11Rα1-deficient mice. With the exception of bronchoalveolar lavage macrophages and adiponectin, which were significantly increased and decreased, respectively, in O3-exposed IL-11Rα1-deficient as compared with O3-exposed wild-type mice, no other genotype-related differences in lung inflammation indices that we quantified were observed in O3-exposed mice. However, airway responsiveness to acetyl-β-methylcholine chloride (methacholine) was significantly diminished in IL-11Rα1-deficient as compared with wild-type mice after O3 exposure. In conclusion, these results demonstrate that IL-11Rα1 minimally contributes to lung inflammation but is required for maximal airway responsiveness to methacholine in a mouse model of nonatopic asthma.

Overprescription of short-acting β2 -agonists among patients with asthma in Saudi Arabia: Results from the SABINA III cohort study.

Despite near-universal health care and timely updates to treatment guidelines in Saudi Arabia, asthma control remains suboptimal, warranting deeper exploration of its management practices. This study describes asthma characteristics and prescription patterns of short-acting β2 -agonists (SABAs) in the Saudi Arabia cohort of the SABA use IN Asthma (SABINA) III study. Patients with asthma (aged ≥12 years) from seven sites across Saudi Arabia participated in this cross-sectional study. Asthma severity was classified by study investigators, guided by the 2017 Global Initiative for Asthma (GINA) recommendations. Of 511 patients enrolled, 502 patients, treated by respiratory medicine specialists, were analyzed (mean [standard deviation] age, 47.5 [14.8] years; female, 68.5%). Most patients had moderate-to-severe asthma (89.6%, GINA treatment steps 3-5), were overweight/obese (78.9%), and received full health care reimbursement (83.4%). Asthma was partially controlled/uncontrolled among 64.3% of patients; 62.3% experienced ≥1 severe asthma exacerbation(s), and 60.6% and 41.2% were prescribed ≥3 (overprescription) and ≥10 SABA canisters, respectively, in the 12 months preceding study initiation. Additionally, 21.9% of patients purchased SABA over the counter (OTC), of whom 66.4% purchased ≥3 SABA canisters. Ninety-seven (88.2%) patients who purchased SABA OTC also received SABA prescriptions, and 80.4% and 56.7% of these were prescribed ≥3 and ≥10 SABA canisters, respectively. Overall, compared with SABINA III, a higher percentage of patients from Saudi Arabia were overprescribed SABA (60.6% vs. 38.0%, respectively) and purchased SABA OTC (21.9% vs. 18.0%, respectively), underscoring the need to align asthma treatment practices with current evidence-based recommendations and regulate SABA OTC sales in Saudi Arabia.

SRSF1 promotes ASMC proliferation in asthma by competitively binding CCND2 with miRNA-135a

BackgroundAsthma is an inflammatory syndrome characterized by airway hyperresponsiveness, bronchial inflammation, and airway remodeling. Abnormal proliferation of airway smooth muscle cells (ASMCs) is the main pathological feature of asthma. This study investigated the function and mechanism of serine arginine-rich splicing factor 1 (SRSF1) in ASMC proliferation in asthma. MethodsSRSF1 expressions in the bronchi of ovalbumin-induced asthmatic mice and IgE-treated mouse ASMCs (mASMCs) were evaluated using quantitative real-time PCR and Western blot. The localization and expression of SRSF1 in the bronchi of asthmatic mice were assessed by immunohistochemistry. Functionally, gain- and loss-of-function assays, flow cytometry, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays were conducted. Mechanistically, RNA degradation assay, RNA immunoprecipitation, RNA pull-down, and dual-luciferase reporter gene assays were carried out. ResultsSRSF1 was highly expressed in the bronchi of ovalbumin-induced asthma mice and IgE-treated mASMCs and was mainly located in the nucleus. Experiments on the function of SRSF1 showed that the silencing of SRSF1 induced the cell cycle of mASMC arrest and restrained mASMC proliferation. Investigations into the mechanism of SRSF1 revealed that SRSF1 and miR-135a are competitively bound to the 3′UTR region of Cyclin D2 (CCND2). SRSF1 overexpression repressed the degradation of CCND2 mRNA, and miR-135a negatively regulated CCND2 expression. Furthermore, SRSF1 knockdown inhibited ASMC proliferation in asthma mouse models by regulating the levels of miR-135a and CCND2. ConclusionSRSF1 knockdown repressed ASMC proliferation in asthma by regulating miR-135a/CCND2 levels.

Low-dose 5-fluorouracil ameliorates Th2 responses through the induction of apoptotic cell death of lung monocyte-derived dendritic cells in asthma

5-Fluorouracil (5-FU) is an analog of pyrimidine and has been shown to display antitumor and immunomodulatory effects. However, the impacts of 5-FU in regulating asthma, an inflammatory disease associated with T helper cell 2 (Th2) responses, remain unclear. Here, we determine the modulatory effects of low-dose 5-FU on Th2 cell responses in asthma and delineate the underlying mechanisms using adoptive cell transfer and in vitro culture experiments. Our data show that low-dose 5-FU treatment not only inhibits the induction of asthma in allergen-sensitized mice but also abrogates the major features of asthma in mice with established disease. We find that this protection of 5-FU treatment against asthma is accompanied by a decrease in the number of lung monocyte-derived dendritic cells (moDCs) in the asthmatic murine. Furthermore, we show that adoptive transfer of moDCs reverses the inhibitory effects of 5-FU treatment on Th2 cell responses in asthmatic mice. Surprisingly, 5-FU treatment does not suppress surface maturation markers and immunogenicity of moDCs in the lungs of asthmatic mice. Instead, it induces apoptotic cell death of mouse moDCs both in vitro and in vivo. In addition to its impact on mouse moDCs, we observe that low-dose 5-FU treatment can induce apoptotic cell death of human moDCs derived from peripheral blood mononuclear cells in vitro. Together, our findings reveal that low-dose 5-FU ameliorates Th2 cell responses, which may be at least partially related to the induction of apoptotic cell death of moDCs in asthma.

Multifocal bronchial stenosis and extensive lobar atelectasis as a rare radiologic feature of severe eosinophilic asthma

Bronchial abnormalities on high-resolution computed tomography (CT) are frequent but heterogeneous in severe asthma,1 with airway wall thickening, diffuse airway narrowing, or, conversely, mild bronchiectasia and mucus pluggings being the most frequently observed.2 Focal bronchial stenosis has also been described.3 Although some degree of air trapping is frequently observed on expiratory CT, lung atelectasis is scarcely observed, is considered reversible,4 and is related to mucus plugging, only in the setting of asthma exacerbation.

The role of mathematical models in designing mechanopharmacological therapies for asthma

Healthy lung function depends on a complex system of interactions which regulate the mechanical and biochemical environment of individual cells to the whole organ. Perturbations from these regulated processes give rise to significant lung dysfunction such as chronic inflammation, airway hyperresponsiveness and airway remodelling characteristic of asthma. Importantly, there is ongoing mechanobiological feedback where mechanical factors including airway stiffness and oscillatory loading have considerable influence over cell behavior. The recently proposed area of mechanopharmacology recognises these interactions and aims to highlight the need to consider mechanobiology when identifying and assessing pharmacological targets. However, these multiscale interactions can be difficult to study experimentally due to the need for measurements across a wide range of spatial and temporal scales. On the other hand, integrative multiscale mathematical models have begun to show success in simulating the interactions between different mechanobiological mechanisms or cell/tissue-types across multiple scales. When appropriately informed by experimental data, these models have the potential to serve as extremely useful predictive tools, where physical mechanisms and emergent behaviours can be probed or hypothesised and, more importantly, exploited to propose new mechanopharmacological therapies for asthma and other respiratory diseases. In this review, we first demonstrate via an exemplar, how a multiscale mathematical model of acute bronchoconstriction in an airway could be exploited to propose new mechanopharmacological therapies. We then review current mathematical modelling approaches in respiratory disease and highlight hypotheses generated by such models that could have significant implications for therapies in asthma, but that have not yet been the subject of experimental attention or investigation. Finally we highlight modelling approaches that have shown promise in other biological systems that could be brought to bear in developing mathematical models for optimisation of mechanopharmacological therapies in asthma, with discussion of how they could complement and accelerate current experimental approaches.

Functional Predictors Discriminating Asthma-COPD Overlap (ACO) from Chronic Obstructive Pulmonary Disease (COPD).

BackgroundA significant proportion of patients with obstructive lung disease have clinical and functional features of both asthma and chronic obstructive pulmonary disease (COPD), referred to as the asthma–COPD overlap (ACO). The distinction of these phenotypes, however, is not yet well-established due to the lack of defining clinical and/or functional criteria. The aim of our investigations was to assess the discriminating power of various lung function parameters on the assessment of ACO.MethodsFrom databases of 4 pulmonary centers, a total of 540 patients (231 males, 309 females), including 372 patients with asthma, 77 patients with ACO and 91 patients with COPD, were retrospectively collected, and gradients among combinations of explanatory variables of spirometric (FEV1, FEV1/FVC, FEF25-75), plethysmographic (sReff, sGeff, the aerodynamic work of breathing at rest; sWOB), static lung volumes, including trapped gases and measurements of the carbon monoxide transfer (DLCO, KCO) were explored using multiple factor analysis (MFA). The discriminating power of lung function parameters with respect to ACO was assessed using linear discriminant analysis (LDA).ResultsLDA revealed that parameters of airway dynamics (sWOB, sReff, sGeff) combined with parameters of static lung volumes such as functional residual capacity (FRCpleth) and trapped gas at FRC (VTGFRC) are valuable and potentially important tools discriminating between asthma, ACO and COPD. Moreover, sWOB significantly contributes to the diagnosis of obstructive airway diseases, independent from the state of pulmonary hyperinflation, whilst the diffusion capacity for carbon monoxide (DLCO) significantly differentiates between the 3 diagnostic classes.ConclusionThe complexity of COPD with its components of interaction and their heterogeneity, especially in discrimination from ACO, may well be differentiated if patients are explored by a whole set of target parameters evaluating, interactionally, flow limitation, airway dynamics, pulmonary hyperinflation, small airways dysfunction and gas exchange disturbances assessing specific functional deficits.

Immunological and Biochemical Features in Bronchial Asthma in Children

The aim of our study was to study the indicators of cytokine status and to determine the features of the hemostasis system and the acid-base state in children with bronchial asthma. We examined 25 children with bronchial asthma aged 7 to 14 years. The study program included: the determination of the level of cytokines: IL-1β and IL-8, the determination of the activity of the acid-base state of the blood. The results of the study showed that the development of bronchial asthma is facilitated by the unfavorable course of the peri- and intranatal periods, aggravated premorbid background, concomitant and past diseases, and significantly high levels of pro-inflammatory cytokines IL-1β and IL-8 were revealed. From the side of biochemical indicators, a very low level of prothrombin time, mild metabolic alkalosis, low partial pressure of oxygen in the blood, and a decrease in the concentration of potassium and calcium ions were detected.

African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans

BackgroundAsthma is the most common chronic disease in children, occurring at higher frequencies and with more severe disease in children with African ancestry.MethodsWe tested for association with haplotypes at the most replicated and significant childhood-onset asthma locus at 17q12-q21 and asthma in European American and African American children. Following this, we used whole-genome sequencing data from 1060 African American and 100 European American individuals to identify novel variants on a high-risk African American–specific haplotype. We characterized these variants in silico using gene expression and ATAC-seq data from airway epithelial cells, functional annotations from ENCODE, and promoter capture (pc)Hi-C maps in airway epithelial cells. Candidate causal variants were then assessed for correlation with asthma-associated phenotypes in African American children and adults.ResultsOur studies revealed nine novel African-specific common variants, enriched on a high-risk asthma haplotype, which regulated the expression of GSDMA in airway epithelial cells and were associated with features of severe asthma. Using ENCODE annotations, ATAC-seq, and pcHi-C, we narrowed the associations to two candidate causal variants that are associated with features of T2 low severe asthma.ConclusionsPreviously unknown genetic variation at the 17q12-21 childhood-onset asthma locus contributes to asthma severity in individuals with African ancestries. We suggest that many other population-specific variants that have not been discovered in GWAS contribute to the genetic risk for asthma and other common diseases.

Role of airway epithelial cell miRNAs in asthma.

The airway epithelial cells and overlying layer of mucus are the first point of contact for particles entering the lung. The severity of environmental contributions to pulmonary disease initiation, progression, and exacerbation is largely determined by engagement with the airway epithelium. Despite the cellular cross-talk and cargo exchange in the microenvironment, epithelial cells produce miRNAs associated with the regulation of airway features in asthma. In line with this, there is evidence indicating miRNA alterations related to their multifunctional regulation of asthma features in the conducting airways. In this review, we discuss the cellular components and functions of the airway epithelium in asthma, miRNAs derived from epithelial cells in disease pathogenesis, and the cellular exchange of miRNA-bearing cargo in the airways.

Mast Cell Proteases Promote Diverse Effects on the Plasminogen Activation System and Wound Healing in A549 Alveolar Epithelial Cells.

Tissue damage, epithelial alterations, and intraepithelial presence of mast cells (MCs) are characteristics of asthma pathogenesis. Increased alveolar infiltration of MC populations has also been identified as a feature of asthma and other chronic respiratory diseases. The asthma associated receptor, urokinase plasminogen activator receptor (uPAR), has been shown to regulate bronchial epithelial repair responses. However, the impact of MC tryptase and chymase on functional properties and expression of uPAR in alveolar epithelial cells have not been fully investigated. Alveolar epithelial cell migration and wound healing were investigated using holographic live cell imaging of A549 cells in a wound scratch model post stimulation with tryptase or chymase. The expression of uPAR was investigated on the protein and gene level from cellular supernatants and in bronchoalveolar lavage fluid fractions from allergic asthmatics. We found that tryptase improved wound healing capacity, cellular migration and membrane bound uPAR expression. Chymase reduced gap closure capacity, cellular migration and membrane bound uPAR expression but increased soluble uPAR release. Our data suggest a dual regulatory response from the MC proteases in events related to uPAR expression and wound healing which could be important features in asthmatic disease.