The molecular and cellular mechanisms associated with the destruction of terminal bronchioles in chronic obstructive pulmonary disease

RationalePeripheral airway obstruction is a key feature of chronic obstructive pulmonary disease (COPD), but the mechanisms of airway loss are unknown. This study aims to identify the molecular and cellular mechanisms associated with peripheral airway obstruction in COPD.MethodsTen explanted lung specimens donated by patients with very-severe COPD treated by lung transplantation and 5 unused donor control lungs were sampled using systematic uniform random sampling (SURS) resulting in 240 samples. These samples were further examined by micro-CT, quantitative histology, and gene expression profiling.ResultsThe micro-CT analysis showed that the loss of terminal bronchioles in COPD occurs in regions of microscopic emphysematous destruction with an average airspace size of ≥500<1000 µm, which we have termed a “hot spot”. Based on Microarray gene expression profiling, the “hot spot” was associated with an 11 gene signature, the up-regulation of pro-inflammatory genes, and the down-regulation of inhibitory immune checkpoint genes, indicating immune response activation. Results from both quantitative histology and the bioinformatics computational tool CIBERSORT which predicts the percentage of immune cells in tissues from transcriptomic data showed that the “hot spot” regions were associated with increased infiltration of CD4, CD8, and B cell lymphocytes.InterpretationThe reduction in terminal bronchioles observed in lungs from patients with COPD occurs in a “hot spot” of microscopic emphysema, where there is upregulation of IFNG signaling, costimulatory immune checkpoint genes, genes related to the inflammasome pathway, and increased infiltration of immune cells, profiles which could be potential targets for therapeutic interventions in COPD.

Positive Expiratory Pressure: A Potential Therapy to Mitigate Acute Bronchoconstriction in the Asthma of Obesity

Late-onset non-allergic (LONA) asthma in obesity is characterized by increased peripheral airway closure secondary to abnormally collapsible airways. We hypothesized that positive expiratory pressure (PEP) would mitigate the tendency to airway closure during bronchoconstriction, potentially serving as rescue therapy for LONA asthma of obesity. The PC20 dose of methacholine was determined in 18 obese participants with LONA asthma. At each of 4 subsequent visits, we used oscillometry to measure input respiratory impedance (Zrs) over 8 minutes; participants received their PC20 concentration of methacholine aerosol during the first 4.5 minutes. PEP combinations of either 0 or 10 cmH2O either during and/or after the methacholine delivery were applied, randomized between visits. Parameters characterizing respiratory system mechanics were extracted from the Zrs spectra. In 18 LONA asthma patients (14 females, BMI: 39.6±3.4 kg/m2), 10 cmH2O PEP during methacholine reduced elevations in the central airway resistance, peripheral airway resistance and elastance, and breathing frequency was also reduced. During the 3.5 min following methacholine delivery, PEP of 10 cmH2O reduced Ax and peripheral elastance compared to no PEP. PEP mitigates the onset of airway narrowing brought on by methacholine challenge, and airway closure once it is established. PEP thus might serve as a non-pharmacologic therapy to manage acute airway narrowing for obese LONA asthma.

Comparative evaluation of expiratory airflow limitation between patients with COPD and BE using IOS

Impulse oscillometry (IOS) allows evaluation of the compartmentalized resistance and reactance of the respiratory system, distinguishing central and peripheral obstruction. The IOS measurements are getting attention in the diagnosis and differentiation of chronic respiratory diseases. However, no data are available in the literature to differentiate between COPD and BE using IOS parameters. We aimed to evaluate the feasibility of IOS in the diagnosis of bronchiectasis non-cystic fibrosis (BE) in comparison to COPD. Whole breath, inspiration, expiration, and inspiratory-expiratory difference (Δ) were evaluated based on the IOS parameters: total resistance (R5), central airway resistance (R20), peripheral airway resistance (R5-R20), reactance (X5), reactance area (AX), and resonance frequency (Fres). Fifty-nine subjects (21 Healthy, 19 BE, and 19 COPD) participated in this study. It was observed a significant difference in the comparison of healthy and pulmonary disease groups (BE and COPD) for total breathing (R5-R20, X5, AX, and Fres), inspiratory phase (R5 and R5-R5), and expiratory phase (R5-R20 and X5). The comparison between BE and COPD groups showed significant difference in the expiratory phase for resistance at 5 and 20 Hz and, ΔR5 and ΔR20. The IOS evidenced an increase of R5, R20 and R5-R20 in patients with BE and COPD when compared to healthy subjects. Expiratory measures of IOS revealed increased airway resistance in COPD compared to BE patients who had similar FEV1 measured by spirometry, however, further studies are needed to confirm these differences.

Lung function testing assessment by impulse oscillometry in chronic lung disease

Impulse oscillometry (IOS) is a variant of forced oscillation technique described by Dubois 50 years ago, which allows us to measure the reactance of the airways and the resistance of the small and large airways during tidal breathing. It requires minimal patient cooperation from subjects who are unable to perform spirometry, like elders, children and patients with neurologic disorders. IOS can outline the diagnosis of obstructive airway disease, differentiate small airway obstruction from large airway obstruction. It is more sensitive than spirometry for peripheral airway disease in determining the severity of the disease, the exacerbations and evaluate the therapeutic response. Other applications include early evaluation of transplant rejection, cystic fibrosis, vocal cord disorder, bronchiectasis, hypersensitivity pneumonitis, obstructive sleep apnea.