A Single-Cell Atlas of Small Airway Disease in Chronic Obstructive Pulmonary Disease: A Cross-Sectional Study.

Emerging data demonstrate that the smallest conducting airways, terminal bronchioles, are the early site of tissue destruction in chronic obstructive pulmonary disease (COPD) and are reduced by as much as 41% by the time someone is diagnosed with mild (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 1) COPD. To develop a single-cell atlas that describes the structural, cellular, and extracellular matrix alterations underlying terminal bronchiole loss in COPD. This cross-sectional study of 262 lung samples derived from 34 ex-smokers with normal lung function ( = 10) or GOLD stage 1 ( = 10), stage 2 ( = 8), or stage 4 ( = 6) COPD was performed to assess the morphology, extracellular matrix, single-cell atlas, and genes associated with terminal bronchiole reduction using stereology, micro-computed tomography, nonlinear optical microscopy, imaging mass spectrometry, and transcriptomics.

Airway and parenchymal tissue resistance and elastance in ex vivo sheep lungs: effects of bronchochallenge and deep inspiration.

Lung resistance () is determined by airway and parenchymal tissue resistance, as well as the degree of heterogeneity in airway constriction. Deep inspirations (DIs) are known to reverse experimentally induced increase in , but the mechanism is not entirely clear. The first step toward understanding the effect of DI is to determine how each of the resistance components is affected by DI.

Lung resistance and elastance are different in ex vivo sheep lungs ventilated by positive and negative pressures.

Lung resistance () and elastance () can be measured during positive or negative pressure ventilation. Whether the different modes of ventilation produce different and is still being debated. Although negative pressure ventilation (NPV) is more physiological, positive pressure ventilation (PPV) is more commonly used for treating respiratory failure.

Small Airway Reduction and Fibrosis Is an Early Pathologic Feature of Idiopathic Pulmonary Fibrosis.

To improve disease outcomes in idiopathic pulmonary fibrosis (IPF), it is essential to understand its early pathophysiology so that it can be targeted therapeutically. Perform three-dimensional assessment of the IPF lung microstructure using stereology and multiresolution computed tomography (CT) imaging. Explanted lungs from patients with IPF ( = 8) and donor control subjects ( = 8) were inflated with air and frozen.

Airway diameter at different transpulmonary pressures in ex vivo sheep lungs: implications for deep inspiration-induced bronchodilation and bronchoprotection.

Deep inspiration (DI)-induced bronchodilation is the first line of defense against bronchoconstriction in healthy subjects. A hallmark of asthma is the lack of this beneficial effect of DI. The mechanism underlying the bronchodilatory effect of DI is not clear.

Pathological Comparisons of Paraseptal and Centrilobular Emphysema in Chronic Obstructive Pulmonary Disease.

Although centrilobular emphysema (CLE) and paraseptal emphysema (PSE) are commonly identified on multidetector computed tomography (MDCT), little is known about the pathology associated with PSE compared with that of CLE. To assess the pathological differences between PSE and CLE in chronic obstructive pulmonary disease (COPD). Air-inflated frozen lung specimens ( = 6) obtained from patients with severe COPD treated by lung transplantation were scanned with MDCT.

Ratio of Maximal Inspiratory to Expiratory Flow Aids in the Separation of COPD from Asthma.

Patients who have chronic obstructive pulmonary disease (COPD) and bronchial asthma (BA) share symptoms such as, dyspnoea, cough and wheeze. Differentiating these diseases in the ambulatory setting can be challenging especially in older adult smokers who are being treated with a variety of medications. The objective of this study was to test the value of adding a maximal inspiratory manoeuvre to basic spirometry to differentiate COPD and BA.

The pharmacogenomics of inhaled corticosteroids and lung function decline in COPD.

Inhaled corticosteroids (ICS) are widely prescribed for patients with chronic obstructive pulmonary disease (COPD), yet have variable outcomes and adverse reactions, which may be genetically determined. The primary aim of the study was to identify the genetic determinants for forced expiratory volume in 1 s (FEV) changes related to ICS therapy.In the Lung Health Study (LHS)-2, 1116 COPD patients were randomised to the ICS triamcinolone acetonide (n=559) or placebo (n=557) with spirometry performed every 6 months for 3 years.

The Huxley crossbridge model as the basic mechanism for airway smooth muscle contraction.

The cyclic interaction between myosin crossbridges and actin filaments underlies smooth muscle contraction. Phosphorylation of the 20-kDa myosin light chain (MLC20) is a crucial step in activating the crossbridge cycle. Our current understanding of smooth muscle contraction is based on observed correlations among MLC20 phosphorylation, maximal shortening velocity (), and isometric force over the time course of contraction.

Limited overlap in significant hits between genome-wide association studies on two airflow obstruction definitions in the same population.

Background: Airflow obstruction is a hallmark of chronic obstructive pulmonary disease (COPD), and is defined as either the ratio between forced expiratory volume in one second and forced vital capacity (FEV/FVC) < 70% or < lower limit of normal (LLN). This study aimed to assess the overlap between genome-wide association studies (GWAS) on airflow obstruction using these two definitions in the same population stratified by smoking.

Methods: GWASes were performed in the LifeLines Cohort Study for both airflow obstruction definitions in never-smokers (NS = 5071) and ever-smokers (ES = 4855).

Mechanopharmacology and Synergistic Relaxation of Airway Smooth Muscle.

Asthmatic airways are stiffer than normal. We have shown that the cytoskeletal passive stiffness of airway smooth muscle (ASM) can be regulated by intracellular signaling pathways, especially those associated with Rho kinase (ROCK). We have also shown that an oscillatory strain reduces the passive stiffness of ASM and its ability to generate force.

Genome-wide interaction study of gene-by-occupational exposures on respiratory symptoms.

Respiratory symptoms are important indicators of respiratory diseases. Both genetic and environmental factors contribute to respiratory symptoms development but less is known about gene-environment interactions. We aimed to assess interactions between single nucleotide polymorphisms (SNPs) and occupational exposures on respiratory symptoms cough, dyspnea and phlegm.

The DNA repair transcriptome in severe COPD.

Inadequate DNA repair is implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the mechanisms that underlie inadequate DNA repair in COPD are poorly understood. We applied an integrative genomic approach to identify DNA repair genes and pathways associated with COPD severity.

The Overlap of Lung Tissue Transcriptome of Smoke Exposed Mice with Human Smoking and COPD.

Genome-wide mRNA profiling in lung tissue from human and animal models can provide novel insights into the pathogenesis of chronic obstructive pulmonary disease (COPD). While 6 months of smoke exposure are widely used, shorter durations were also reported. The overlap of short term and long-term smoke exposure in mice is currently not well understood, and their representation of the human condition is uncertain.

Small airways disease in mild and moderate chronic obstructive pulmonary disease: a cross-sectional study.

Background: The concept that small conducting airways less than 2 mm in diameter become the major site of airflow obstruction in chronic obstructive pulmonary disease (COPD) is well established in the scientific literature, and the last generation of small conducting airways, terminal bronchioles, are known to be destroyed in patients with very severe COPD. We aimed to determine whether destruction of the terminal and transitional bronchioles (the first generation of respiratory airways) occurs before, or in parallel with, emphysematous tissue destruction.

Methods: In this cross-sectional analysis, we applied a novel multiresolution CT imaging protocol to tissue samples obtained using a systematic uniform sampling method to obtain representative unbiased samples of the whole lung or lobe of smokers with normal lung function (controls) and patients with mild COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 1), moderate COPD (GOLD 2), or very severe COPD (GOLD 4).

Whole exome sequencing analysis in severe chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD), one of the leading causes of death worldwide, is substantially influenced by genetic factors. Alpha-1 antitrypsin deficiency demonstrates that rare coding variants of large effect can influence COPD susceptibility. To identify additional rare coding variants in patients with severe COPD, we conducted whole exome sequencing analysis in 2543 subjects from two family-based studies (Boston Early-Onset COPD Study and International COPD Genetics Network) and one case-control study (COPDGene).

The genetics of smoking in individuals with chronic obstructive pulmonary disease.

Background: Smoking is the principal modifiable environmental risk factor for chronic obstructive pulmonary disease (COPD) which affects 300 million people and is the 3rd leading cause of death worldwide. Most of the genetic studies of smoking have relied on self-reported smoking status which is vulnerable to reporting and recall bias. Using data from the Lung Health Study (LHS), we sought to identify genetic variants associated with quantitative smoking and cessation in individuals with mild to moderate COPD.

Leveraging lung tissue transcriptome to uncover candidate causal genes in COPD genetic associations.

Causal genes of chronic obstructive pulmonary disease (COPD) remain elusive. The current study aims at integrating genome-wide association studies (GWAS) and lung expression quantitative trait loci (eQTL) data to map COPD candidate causal genes and gain biological insights into the recently discovered COPD susceptibility loci. Two complementary genomic datasets on COPD were studied.

Analysis of airway pathology in COPD using a combination of computed tomography, micro-computed tomography and histology.

The small conducting airways are the major site of obstruction in chronic obstructive pulmonary disease (COPD). This study examined small airway pathology using a novel combination of multidetector row computed tomography (MDCT), micro-computed tomography (microCT) and histology.Airway branches visible on specimen MDCT were counted and the dimensions of the third- to fifth-generation airways were computed, while the terminal bronchioles (designated TB), preterminal bronchioles (TB-1) and pre-preterminal bronchioles (TB-2) were examined with microCT and histology in eight explanted lungs with end-stage COPD and seven unused donor lungs that served as controls.

Gene expression analysis in asthma using a targeted multiplex array.

Background: Gene expression changes in the structural cells of the airways are thought to play a role in the development of asthma and airway hyperresponsiveness. This includes changes to smooth muscle contractile machinery and epithelial barrier integrity genes. We used a targeted gene expression arrays to identify changes in the expression and co-expression of genes important in asthma pathology.

Surfactant protein D is a causal risk factor for COPD: results of Mendelian randomisation.

Surfactant protein D (SP-D) is produced primarily in the lung and is involved in regulating pulmonary surfactants, lipid homeostasis and innate immunity. Circulating SP-D levels in blood are associated with chronic obstructive pulmonary disease (COPD), although causality remains elusive.In 4061 subjects with COPD, we identified genetic variants associated with serum SP-D levels.

Hyperresponsiveness: Relating the Intact Airway to the Whole Lung.

We relate changes of the airway wall to the response of the intact airway and the whole lung. We address how mechanical conditions and specific structural changes for an airway contribute to hyperresponsiveness resistant to deep inspiration. This review conveys that the origins of hyperresponsiveness do not devolve into an abnormality at single structural level but require examination of the complex interplay of all the parts.

Smooth muscle function and myosin polymerization.

Smooth muscle is able to function over a much broader length range than striated muscle. The ability to maintain contractility after a large length change is thought to be due to an adaptive process involving restructuring of the contractile apparatus to maximize overlap between the contractile filaments. The molecular mechanism for the length-adaptive behavior is largely unknown.