Location of eosinophils in the airway wall is critical for specific features of airway hyperresponsiveness and T2 inflammation in asthma

Eosinophils are implicated as effector cells in asthma but the functional implications of the precise location of eosinophils in the airway wall is poorly understood. We aimed to quantify eosinophils in the different compartments of the airway wall and associate these findings with clinical features of asthma and markers of airway inflammation.In this cross-sectional study, we utilised design-based stereology to accurately partition the numerical density of eosinophils in both the epithelial compartment and the subepithelial space (airway wall area below the basal lamina including the submucosa) in individuals with and without asthma and related these findings to airway hyperresponsiveness (AHR) and features of airway inflammation.Intraepithelial eosinophils were linked to the presence of asthma and endogenous AHR, the type of AHR that is most specific for asthma. In contrast, both intraepithelial and subepithelial eosinophils were associated with type-2 (T2) inflammation, with the strongest association between IL5 expression and intraepithelial eosinophils. Eosinophil infiltration of the airway wall was linked to a specific mast cell phenotype that has been described in asthma. We found that IL-33 and IL-5 additively increased cysteinyl leukotriene (CysLT) production by eosinophils and that the CysLT LTC4 along with IL-33 increased IL13 expression in mast cells and altered their protease profile.We conclude that intraepithelial eosinophils are associated with endogenous AHR and T2 inflammation and may interact with intraepithelial mast cells via CysLTs to regulate airway inflammation.

Capillary instability of a two-layer annular film: an airway closure model

Capillary instability of a two-layer liquid film lining a rigid tube is studied computationally as a model for liquid plug formation and closure of human airways. The two-layer liquid consists of a serous layer, also called the periciliary liquid layer, at the inner side and a mucus layer at the outer side. Together, they form the airway surface liquid lining the airway wall and surrounding an air core. Liquid plug formation occurs due to Plateau–Rayleigh instability when the liquid film thickness exceeds a critical value. Numerical simulations are performed for the entire closure process, including the pre- and post-coalescence phases. The mechanical stresses and their gradients on the airway wall are investigated for physiologically relevant ranges of the mucus-to-serous thickness ratio, the viscosity ratio, and the air–mucus and serous–mucus surface tensions encompassing healthy and pathological conditions of a typical adult human lung. The growth rate of the two-layer model is found to be higher in comparison with a one-layer equivalent configuration. This leads to a much sooner closure in the two-layer model than that in the corresponding one-layer model. Moreover, it is found that the serous layer generally provides an effective protection to the pulmonary epithelium against high shear stress excursions and their gradients. A linear stability analysis is also performed, and the results are found to be in good qualitative agreement with the simulations. Finally, a secondary coalescence that may occur during the post-closure phase is investigated.

Severe pediatric asthma with a poor response to omalizumab: a report of three cases and three-dimensional bronchial wall analysis

Omalizumab is used for the treatment of persistent severe allergic asthma in adults and children. However, some patients remain symptomatic even after omalizumab treatment. In bronchial asthma, chronic inflammation of the bronchial wall causes thickening of the airway wall, resulting from irreversible airway remodeling. Progression of airway remodeling causes airflow obstruction, leading to treatment resistance. We report three Japanese children with severe asthma who had a poor response to omalizumab treatment. They had a long period of inadequate management of asthma before initiating omalizumab. Even after omalizumab treatment, their symptoms persisted, and the parameters of spirometry tests did not improve. We hypothesized that omalizumab was less effective in these patients because airway wall remodeling had already progressed. We retrospectively evaluated the bronchial wall thickness using a three-dimensional bronchial wall analysis with chest computed tomography. The bronchial wall thickness was increased in these cases compared with six responders. Progressed airway wall thickness caused by airway remodeling may be associated with a poor response to omalizumab in children with severe asthma.

Airway Wall Remodeling in Childhood Asthma—A Personalized Perspective from Cell Type-Specific Biology

Airway wall remodeling is a pathology occurring in chronic inflammatory lung diseases including asthma, chronic obstructive pulmonary disease, and fibrosis. In 2017, the American Thoracic Society released a research statement highlighting the gaps in knowledge and understanding of airway wall remodeling. The four major challenges addressed in this statement were: (i) the lack of consensus to define “airway wall remodeling” in different diseases, (ii) methodologic limitations and inappropriate models, (iii) the lack of anti-remodeling therapies, and (iv) the difficulty to define endpoints and outcomes in relevant studies. This review focuses on the importance of cell-cell interaction, especially the bronchial epithelium, in asthma-associated airway wall remodeling. The pathology of “airway wall remodeling” summarizes all structural changes of the airway wall without differentiating between different pheno- or endo-types of asthma. Indicators of airway wall remodeling have been reported in childhood asthma in the absence of any sign of inflammation; thus, the initiation event remains unknown. Recent studies have implied that the interaction between the epithelium with immune cells and sub-epithelial mesenchymal cells is modified in asthma by a yet unknown epigenetic mechanism during early childhood.

Potential Value of Expiratory CT in Quantitative Assessment of Pulmonary Vessels in COPD

Objective: To investigate the associations between intrapulmonary vascular volume (IPVV) depicted on inspiratory and expiratory CT scans and disease severity in COPD patients, and to determine which CT parameters can be used to predict IPVV.Methods: We retrospectively collected 89 CT examinations acquired on COPD patients from an available database. All subjects underwent both inspiratory and expiratory CT scans. We quantified the IPVV, airway wall thickness (WT), the percentage of the airway wall area (WA%), and the extent of emphysema (LAA%−950) using an available pulmonary image analysis tool. The underlying relationship between IPVV and COPD severity, which was defined as mild COPD (GOLD stage I and II) and severe COPD (GOLD stage III and IV), was analyzed using the Student's t-test (or Mann-Whitney U-test). The correlations of IPVV with pulmonary function tests (PFTs), LAA%−950, and airway parameters for the third to sixth generation bronchus were analyzed using the Pearson or Spearman's rank correlation coefficients and multiple stepwise regression.Results: In the subgroup with only inspiratory examinations, the correlation coefficients between IPVV and PFT measures were −0.215 ~ −0.292 (p < 0.05), the correlation coefficients between IPVV and WT3−6 were 0.233 ~ 0.557 (p < 0.05), and the correlation coefficient between IPVV and LAA%−950 were 0.238 ~ 0.409 (p < 0.05). In the subgroup with only expiratory scan, the correlation coefficients between IPVV and PFT measures were −0.238 ~ −0.360 (p < 0.05), the correlation coefficients between IPVV and WT3−6 were 0.260 ~ 0.566 (p < 0.05), and the correlation coefficient between IPVV and LAA%−950 were 0.241 ~ 0.362 (p < 0.05). The multiple stepwise regression analyses demonstrated that WT were independently associated with IPVV (P < 0.05).Conclusion: The expiratory CT scans can provide a more accurate assessment of COPD than the inspiratory CT scans, and the airway wall thickness maybe an independent predictor of pulmonary vascular alteration in patients with COPD.

An interferon inducible signature of airway disease from blood gene expression profiling

BackgroundThe molecular basis of airway remodeling in chronic obstructive pulmonary disease remains poorly understood. We identified gene expression signatures associated with chest CT scan airway measures to understand molecular pathways associated with airway disease.MethodsIn 2,396 subjects in the COPDGene Study, we examined the relationship between quantitative CT airway phenotypes and blood transcriptomes to identify airway disease-specific genes and to define an airway wall thickness (AWT) gene set score. Multivariable regression analyses were performed to identify associations of the AWT score with clinical phenotypes, bronchial gene expression and genetic variants.ResultsType 1 interferon induced genes were consistently associated with airway wall thickness, Pi10, and wall area percent, with the strongest enrichment in airway wall thickness. A score derived from 18 genes whose expression was associated with AWT was associated with COPD-related phenotypes including reduced lung function (FEV1% predicted −3.4, p<0.05) and increased exacerbations (incidence rate ratio 1.6, p<0.05). The AWT score was reproducibly associated with airway wall thickness in bronchial samples from 23 subjects (beta 3.22, p<0.05). The blood AWT score was associated with genetic variant rs876039, an expression quantitative trait locus (eQTL) for IKZF1, a gene which regulates interferon signaling and is associated with inflammatory diseases.ConclusionA gene expression signature with interferon stimulated genes from peripheral blood and bronchial brushings is associated with CT airway wall thickness, lung function, and exacerbations. Shared genes and genetic associations suggest viral responses and/or autoimmune dysregulation as potential underlying mechanisms of airway disease in COPD.

Functional respiratory imaging in relation to classical outcome measures in cystic fibrosis: a cross-sectional study

Background Functional Respiratory Imaging (FRI) combines HRCT scans with computational fluid dynamics to provide objective and quantitative information about lung structure and function. FRI has proven its value in pulmonary diseases such as COPD and asthma, but limited studies have focused on cystic fibrosis (CF). This study aims to investigate the relation of multiple FRI parameters to validated imaging parameters and classical respiratory outcomes in a CF population. Methods CF patients aged > 5 years scheduled for a chest CT were recruited in a cross-sectional study. FRI outcomes included regional airway volume, airway wall volume, airway resistance, lobar volume, air trapping and pulmonary blood distribution. Besides FRI, CT scans were independently evaluated by 2 readers using the CF-CT score. Spirometry and the 6-Minute Walk Test (6MWT) were also performed. Statistical tests included linear mixed-effects models, repeated measures correlations, Pearson and Spearman correlations. Results 39 CT scans of 24 (17M/7F) subjects were analyzed. Patients were 24 ± 9 years old and had a ppFEV1 of 71 ± 25% at the time of the first CT. All FRI parameters showed significant low-to-moderate correlations with the total CF-CT score, except for lobar volume. When considering the relation between FRI parameters and similar CF-CT subscores, significant correlations were found between parameters related to airway volume, air trapping and airway wall thickening. Air trapping, lobar volume after normal expiration and pulmonary blood distribution showed significant associations with all spirometric parameters and oxygen saturation at the end of 6MWT. In addition, air trapping was the only parameter related to the distance covered during 6MWT. A subgroup analysis showed considerably higher correlations in patients with mild lung disease (ppFEV1 ≥ 70%) compared to patients with moderate to severe lung disease (ppFEV1 < 70%) when comparing FRI to CF-CT scores. Conclusions Multiple structural characteristics determined by FRI were associated with abnormalities determined by CF-CT score. Air trapping and pulmonary blood distribution appeared to be the most clinically relevant FRI parameters for CF patients due to their associations with classical outcome measures. The FRI methodology could particularly be of interest for patients with mild lung disease, although this should be confirmed in future research.