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.

Alveolar Airspace Size in Healthy and Diseased Infant Lungs Measured via Hyperpolarized 3He Gas Diffusion Magnetic Resonance Imaging

<b><i>Background:</i></b> Alveolar development and lung parenchymal simplification are not well characterized in vivo in neonatal patients with respiratory morbidities, such as bronchopulmonary dysplasia (BPD). Hyperpolarized (HP) gas diffusion magnetic resonance imaging (MRI) is a sensitive, safe, nonionizing, and noninvasive biomarker for measuring airspace size in vivo but has not yet been implemented in young infants. <b><i>Objective:</i></b> This work quantified alveolar airspace size via HP gas diffusion MRI in healthy and diseased explanted infant lung specimens, with comparison to histological morphometry. <b><i>Methods:</i></b> Lung specimens from 8 infants were obtained: 7 healthy left upper lobes (0–16 months, post-autopsy) and 1 left lung with filamin-A mutation, closely representing BPD lung disease (11 months, post-transplantation). Specimens were imaged using HP ³He diffusion MRI to generate apparent diffusion coefficients (ADCs) as biomarkers of alveolar airspace size, with comparison to mean linear intercept (<i>L</i>_m) via quantitative histology. <b><i>Results:</i></b> Mean ADC and <i>L</i>_m were significantly increased throughout the diseased specimen (ADC = 0.26 ± 0.06 cm²/s, <i>L</i>_m = 587 ± 212 µm) compared with healthy specimens (ADC = 0.14 ± 0.03 cm²/s, <i>L</i>_m = 133 ± 37 µm; <i>p</i> &#x3c; 1 × 10⁻⁷); increased values reflect enlarged airspaces. Mean ADCs in healthy specimens were significantly correlated to <i>L</i>_m (<i>r</i> = 0.69, <i>p</i> = 0.041). <b><i>Conclusions:</i></b> HP gas diffusion MRI is sensitive to healthy and diseased regional alveolar airspace size in infant lungs, with good comparison to quantitative histology in ex vivo specimens. This work demonstrates the translational potential of gas MRI techniques for in vivo assessment of normal and abnormal alveolar development in neonates with pulmonary disease.

Initiation of reticular and spider veins, incompetent perforantes and varicose veins in the saphenous vein network of the rat

In an attempt to induce experimental varicosity, reverse perforant vein development was initiated in the rat leg by applying a chronic (14 and 32 weeks) partial stricture on the main branch of the deep femoral vein. At surfacing of the incompetent perforantes, typical reticular vein plaques and spider veins were identified by video-microscopy and quantitative histology. Deep vein blood was channeled by them into the saphenous vein system, the extra flow deforming these vessels, causing local dilations and broken course, even undulations of larger branches.