The pathogenesis of chronic obstructive pulmonary disease (COPD) is based on the innate and adaptive inflammatory immune response to the inhalation of toxic particles and gases. Although tobacco ...smoking is the primary cause of this inhalation injury, many other environmental and occupational exposures contribute to the pathology of COPD. The immune inflammatory changes associated with COPD are linked to a tissue-repair and -remodeling process that increases mucus production and causes emphysematous destruction of the gas-exchanging surface of the lung. The common form of emphysema observed in smokers begins in the respiratory bronchioles near the thickened and narrowed small bronchioles that become the major site of obstruction in COPD. The mechanism(s) that allow small airways to thicken in such close proximity to lung tissue undergoing emphysematous destruction remains a puzzle that needs to be solved.
The hypothesis that the small conducting airways were the major site of obstruction to airflow in normal lungs was introduced by Rohrer in 1915 and prevailed until Weibel introduced a quantitative ...method of studying lung anatomy in 1963. Green repeated Rohrer's calculations using Weibels new data in 1965 and found that the smaller conducting airways offered very little resistance to airflow. This conflict was resolved by seminal experiments conducted by Macklem and Mead in 1967, which confirmed that a small proportion of the total lower airways resistance is attributable to small airways <2 mm in diameter. Shortly thereafter, Hogg, Macklem, and Thurlbeck used this technique to show that small airways become the major site of obstruction in lungs affected by emphysema. These and other observations led Mead to write a seminal editorial in 1970 that postulated the small airways are a silent zone within normal lungs where disease can accumulate over many years without being noticed. This review provides a progress report since the 1970s on methods for detecting chronic obstructive pulmonary disease, the structural nature of small airways' disease, and the cellular and molecular mechanisms that are thought to underlie its pathogenesis.
The purpose of this statement is to describe and define the phenotypic abnormalities that can be identified on visual and quantitative evaluation of computed tomographic (CT) images in subjects with ...chronic obstructive pulmonary disease (COPD), with the goal of contributing to a personalized approach to the treatment of patients with COPD. Quantitative CT is useful for identifying and sequentially evaluating the extent of emphysematous lung destruction, changes in airway walls, and expiratory air trapping. However, visual assessment of CT scans remains important to describe patterns of altered lung structure in COPD. The classification system proposed and illustrated in this article provides a structured approach to visual and quantitative assessment of COPD. Emphysema is classified as centrilobular (subclassified as trace, mild, moderate, confluent, and advanced destructive emphysema), panlobular, and paraseptal (subclassified as mild or substantial). Additional important visual features include airway wall thickening, inflammatory small airways disease, tracheal abnormalities, interstitial lung abnormalities, pulmonary arterial enlargement, and bronchiectasis.
The airflow limitation that defines chronic obstructive pulmonary disease (COPD) is the result of a prolonged time constant for lung emptying, caused by increased resistance of the small conducting ...airways and increased compliance of the lung as a result of emphysematous destruction. These lesions are associated with a chronic innate and adaptive inflammatory immune response of the host to a lifetime exposure to inhaled toxic gases and particles. Processes contributing to obstruction in the small conducting airways include disruption of the epithelial barrier, interference with mucociliary clearance apparatus that results in accumulation of inflammatory mucous exudates in the small airway lumen, infiltration of the airway walls by inflammatory cells, and deposition of connective tissue in the airway wall. This remodelling and repair thickens the airway walls, reduces lumen calibre, and restricts the normal increase in calibre produced by lung inflation. Emphysematous lung destruction is associated with an infiltration of the same type of inflammatory cells found in the airways. The centrilobular pattern of emphysematous destruction is most closely associated with cigarette smoking, and although it is initially focused on respiratory bronchioles, separate lesions coalesce to destroy large volumes of lung tissue. The panacinar pattern of emphysema is characterised by a more even involvement of the acinus and is associated with α1 antitrypsin deficiency. The technology needed to diagnose and quantitate the individual small airway and emphysema phenotypes present in people with COPD is being developed, and should prove helpful in the assessment of therapeutic interventions designed to modify the progress of either phenotype.
Based on surface brushings and bronchoalveolar lavage fluid, Hilty and coworkers demonstrated microbiomes in the human lung characteristic of asthma and chronic obstructive pulmonary disease (COPD), ...which have now been confirmed by others.
To extend these findings to human lung tissue samples.
DNA from lung tissue samples was obtained from nonsmokers (n = 8); smokers without COPD (n = 8); patients with very severe COPD (Global Initiative for COPD GOLD 4) (n = 8); and patients with cystic fibrosis (CF) (n = 8). The latter served as a positive control, with sterile water as a negative control. All bacterial community analyses were based on polymerase chain reaction amplifying 16S rRNA gene fragments. Total bacterial populations were measured by quantitative polymerase chain reaction and bacterial community composition was assessed by terminal restriction fragment length polymorphism analysis and pyrotag sequencing.
Total bacterial populations within lung tissue were small (20-1,252 bacterial cells per 1,000 human cells) but greater in all four sample groups versus the negative control group (P < 0.001). Terminal restriction fragment length polymorphism analysis and sequencing distinguished three distinct bacterial community compositions: one common to the nonsmoker and smoker groups, a second to the GOLD 4 group, and the third to the CF-positive control group. Pyrotag sequencing identified greater than 1,400 unique bacterial sequences and showed an increase in the Firmicutes phylum in GOLD 4 patients versus all other groups (P < 0.003) attributable to an increase in the Lactobacillus genus (P < 0.0007).
There is a detectable bacterial community within human lung tissue that changes in patients with very severe COPD.
Abstract
Summary
Mian is a web application to interactively visualize, run statistical tools and train machine learning models on operational taxonomic unit (OTU) or amplicon sequence variant (ASV) ...datasets to identify key taxonomic groups, diversity trends or taxonomic composition shifts in the context of provided categorical or numerical sample metadata. Tools, including Fisher’s exact test, Boruta feature selection, alpha and beta diversity, and random forest and deep neural network classifiers, facilitate open-ended data exploration and hypothesis generation on microbial datasets.
Availability
Mian is freely available at: miandata.org. Mian is an open-source platform licensed under the MIT license with source code available at github.com/tbj128/mian.
Supplementary information
Supplementary data are available at Bioinformatics online.
The small conducting airways are the major site of airflow obstruction in chronic obstructive pulmonary disease and may precede emphysema development.
We hypothesized a novel computed tomography (CT) ...biomarker of small airway disease predicts FEV1 decline.
We analyzed 1,508 current and former smokers from COPDGene with linear regression to assess predictors of change in FEV1 (ml/yr) over 5 years. Separate models for subjects without and with airflow obstruction were generated using baseline clinical and physiologic predictors in addition to two novel CT metrics created by parametric response mapping (PRM), a technique pairing inspiratory and expiratory CT images to define emphysema (PRM(emph)) and functional small airways disease (PRM(fSAD)), a measure of nonemphysematous air trapping.
Mean (SD) rate of FEV1 decline in ml/yr for GOLD (Global Initiative for Chronic Obstructive Lung Disease) 0-4 was as follows: 41.8 (47.7), 53.8 (57.1), 45.6 (61.1), 31.6 (43.6), and 5.1 (35.8), respectively (trend test for grades 1-4; P < 0.001). In multivariable linear regression, for participants without airflow obstruction, PRM(fSAD) but not PRM(emph) was associated with FEV1 decline (P < 0.001). In GOLD 1-4 participants, both PRM(fSAD) and PRM(emph) were associated with FEV1 decline (P < 0.001 and P = 0.001, respectively). Based on the model, the proportional contribution of the two CT metrics to FEV1 decline, relative to each other, was 87% versus 13% and 68% versus 32% for PRM(fSAD) and PRM(emph) in GOLD 1/2 and 3/4, respectively.
CT-assessed functional small airway disease and emphysema are associated with FEV1 decline, but the association with functional small airway disease has greatest importance in mild-to-moderate stage chronic obstructive pulmonary disease where the rate of FEV1 decline is the greatest. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).
Understanding the three-dimensional (3-D) micro-architecture of lung tissue can provide insights into the pathology of lung disease. Micro computed tomography (µCT) has previously been used to ...elucidate lung 3D histology and morphometry in fixed samples that have been stained with contrast agents or air inflated and dried. However, non-destructive microstructural 3D imaging of formalin-fixed paraffin embedded (FFPE) tissues would facilitate retrospective analysis of extensive tissue archives of lung FFPE lung samples with linked clinical data.
FFPE human lung tissue samples (n = 4) were scanned using a Nikon metrology µCT scanner. Semi-automatic techniques were used to segment the 3D structure of airways and blood vessels. Airspace size (mean linear intercept, Lm) was measured on µCT images and on matched histological sections from the same FFPE samples imaged by light microscopy to validate µCT imaging.
The µCT imaging protocol provided contrast between tissue and paraffin in FFPE samples (15 mm x 7 mm). Resolution (voxel size 6.7 µm) in the reconstructed images was sufficient for semi-automatic image segmentation of airways and blood vessels as well as quantitative airspace analysis. The scans were also used to scout for regions of interest, enabling time-efficient preparation of conventional histological sections. The Lm measurements from µCT images were not significantly different to those from matched histological sections.
We demonstrated how non-destructive imaging of routinely prepared FFPE samples by laboratory µCT can be used to visualize and assess the 3D morphology of the lung including by morphometric analysis.
Previous reports have shown that the gastrointestinal (GI) bacterial microbiota can have profound effects on the lungs, which has been described as the "gut-lung axis". However, whether a "lung-gut" ...axis exists wherein acute lung inflammation perturbs the gut and blood microbiota is unknown.
Adult C57/Bl6 mice were exposed to one dose of LPS or PBS instillation (n=3 for each group) directly into lungs. Bacterial microbiota of the bronchoalveolar lavage fluid, blood, and cecum were determined using 454 pyrotag sequencing and quantitative polymerase chain reaction (qPCR) at 4 through 168 hours post-instillation. We then investigated the effects of oral neomycin and streptomycin (n=8) on the microbiota at 4 and 24 hours post LPS instillation versus control treatment (n=5 at baseline and 4 hours, n=7 at 24 hours).
At 24 hours post LPS instillation, the total bacterial count was significantly increased in the cecum (P<0.05); whereas the total bacterial count in blood was increased at 4, 48, and 72 hours (P<0.05). Antibiotic treatment reduced the total bacteria in blood but not in the cecum. The increase in total bacteria in the blood correlated with Phyllobacteriaceae OTU 40 and was significantly reduced in the blood for both antibiotic groups (P<0.05).
LPS instillation in lungs leads to acute changes in the bacterial microbiota in the blood and cecum, which can be modulated with antibiotics.
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