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

2021 ◽  
pp. 2101411
Author(s):  
Feng Xu ◽  
Dragoş M. Vasilescu ◽  
Daisuke Kinose ◽  
Naoya Tanabe ◽  
Kevin W. Ng ◽  
...  
Keyword(s):  
Immune Cells ◽  
Expression Profiling ◽  
Hot Spot ◽  
Chronic Obstructive ◽  
Micro Ct ◽  
Cellular Mechanisms ◽  
Obstructive Pulmonary Disease ◽  
Quantitative Histology ◽  
Peripheral Airway ◽  
Checkpoint Genes

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.

scholarly journals Regenerative pharmacology for COPD: breathing new life into old lungs

Thorax ◽  
2019 ◽  
Vol 74 (9) ◽  
pp. 890-897 ◽  
Author(s):  
John-Poul Ng-Blichfeldt ◽  
Reinoud Gosens ◽  
Charlotte Dean ◽  
Mark Griffiths ◽  
Matthew Hind
Keyword(s):  
Large Scale ◽  
Biologically Active ◽  
Health Concern ◽  
Chronic Obstructive ◽  
Small Airways ◽  
Obstructive Pulmonary Disease ◽  
Molecular Control ◽  
Mild Disease ◽  
Peripheral Airway ◽  
Alveolar Tissue

Chronic obstructive pulmonary disease (COPD) is a major global health concern with few effective treatments. Widespread destruction of alveolar tissue contributes to impaired gas exchange in severe COPD, and recent radiological evidence suggests that destruction of small airways is a major contributor to increased peripheral airway resistance in disease. This important finding might in part explain the failure of conventional anti-inflammatory treatments to restore lung function even in patients with mild disease. There is a clear need for alternative pharmacological strategies for patients with COPD/emphysema. Proposed regenerative strategies such as cell therapy and tissue engineering are hampered by poor availability of exogenous stem cells, discouraging trial results, and risks and cost associated with surgery. An alternative therapeutic approach is augmentation of lung regeneration and/or repair by biologically active factors, which have potential to be employed on a large scale. In favour of this strategy, the healthy adult lung is known to possess a remarkable endogenous regenerative capacity. Numerous preclinical studies have shown induction of regeneration in animal models of COPD/emphysema. Here, we argue that given the widespread and irreversible nature of COPD, serious consideration of regenerative pharmacology is necessary. However, for this approach to be feasible, a better understanding of the cell-specific molecular control of regeneration, the regenerative potential of the human lung and regenerative competencies of patients with COPD are required.

Frequency characteristics of airway and tissue impedances in respiratory diseases

1991 ◽  
Vol 71 (1) ◽  
pp. 259-270 ◽  
Author(s):  
M. Mishima ◽  
K. Kawakami ◽  
K. Higashiya ◽  
T. Fukunaga ◽  
T. Ooka ◽  
...  
Keyword(s):  
Chest Wall ◽  
Random Noise ◽  
Peripheral Resistance ◽  
Normal Subjects ◽  
Frequency Characteristics ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
The Real ◽  
Peripheral Airway ◽  
Chronic Pulmonary Emphysema

We measured the frequency characteristics (at 10–40 Hz) of airway (Za) and tissue (Zt) impedances in cases of chronic obstructive pulmonary disease [asthmatic bronchitis (AB), chronic pulmonary emphysema (CPE)] and interstitial pneumonitis (IP) by use of an improved random noise oscillation and body box method. The results were then compared with those obtained for normal subjects. The real part of Za was markedly elevated in patients with AB but only slightly elevated in those with CPE. To interpret these data we used an electromechanical analogue including serial inhomogeneity with shunt impedance. From this model we concluded that AB causes both the central and peripheral airway resistances to increase, while CPE brings about a rise mainly in peripheral resistance. In IP patients, only the imaginary part of Zt decreased, which might reflect the decrease in both lung and chest wall compliance. In CPE patients, but not in AB patients, the real part of Zt fell. These data were consistent with the assumption that the decrease in mass per unit volume of lung tissue and hyperinflation of the chest wall in CPE patients might lower the tissue resistances.

scholarly journals Spatial Distribution of COVID-19 and Comorbidities in New England

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 736-737
Author(s):  
Chae Man Lee ◽  
Taylor Jansen ◽  
Shu Xu ◽  
Maki Karakida ◽  
Frank Porell ◽  
...  
Keyword(s):  
Spatial Distribution ◽  
New England ◽  
Hot Spots ◽  
Healthy Aging ◽  
Spatial Clustering ◽  
Hot Spot ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Control And Prevention ◽  
And Control

Abstract At the onset of the COVID-19 pandemic, the Centers for Disease Control and Prevention (CDC) identified chronic conditions which elevated the risk of COVID-19 complications: chronic obstructive pulmonary disease (COPD), diabetes, heart disease, kidney disease, and obesity. The aim of this study is to visualize the spatial distribution of confirmed cases of COVID-19 and local rates of comorbidities in CT, MA, NH, and RI and to identify the spatial clustering of hot spot between COVID-19 cases and rates of a summary measure of comorbidities across communities. This study collected data from state’s departments of public health in 4 New England states of confirmed COVID-19 cases as of February 25th, 2021 and extracted community-level rates of comorbidities among adults age 65+ from recent Healthy Aging Data Report (www.healthyagingdatareports.org). Results showed that the cities Bridgeport, CT (n=14,637), Boston, MA (n=57,912), Manchester, NH (n=9,658), and Providence, RI (n=26,792) had the highest rates of COVID-19 and the highest population density. The GIS based map illustrated that the largest cities with the highest population densities had both relatively high incidences of COVID-19 and heavy burdens of comorbidities. This study found that the hot spot areas of COVID-19 were observed in communities with the highest chronic disease burdens. These hot spots of COVID-19 and comorbidities are areas where resources (testing, masks, vaccines) should be surged to protect the community. The identification of hot spots may motivate residents to take every mitigation step to prevent and control COVID-19.

scholarly journals New Pharmacological Tools to Target Leukocyte Trafficking in Lung Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Kylie B. R. Belchamber ◽  
Michael J. Hughes ◽  
Daniella A. Spittle ◽  
Eloise M. Walker ◽  
Elizabeth Sapey
Keyword(s):  
Lung Disease ◽  
Immune Cells ◽  
Lung Diseases ◽  
Immune Cell ◽  
Current Evidence ◽  
Chronic Obstructive ◽  
Cellular Functions ◽  
Obstructive Pulmonary Disease ◽  
Microbial Invasion ◽  
Infection And Inflammation

Infection and inflammation of the lung results in the recruitment of non-resident immune cells, including neutrophils, eosinophils and monocytes. This swift response should ensure clearance of the threat and resolution of stimuli which drive inflammation. However, once the threat is subdued this influx of immune cells should be followed by clearance of recruited cells through apoptosis and subsequent efferocytosis, expectoration or retrograde migration back into the circulation. This cycle of cell recruitment, containment of threat and then clearance of immune cells and repair is held in exquisite balance to limit host damage. Advanced age is often associated with detrimental changes to the balance described above. Cellular functions are altered including a reduced ability to traffic accurately towards inflammation, a reduced ability to clear pathogens and sustained inflammation. These changes, seen with age, are heightened in lung disease, and most chronic and acute lung diseases are associated with an exaggerated influx of immune cells, such as neutrophils, to the airways as well as considerable inflammation. Indeed, across many lung diseases, pathogenesis and progression has been associated with the sustained presence of trafficking cells, with examples including chronic diseases such as Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis and acute infections such as Pneumonia and Pneumonitis. In these instances, there is evidence that dysfunctional and sustained recruitment of cells to the airways not only increases host damage but impairs the hosts ability to effectively respond to microbial invasion. Targeting leukocyte migration in these instances, to normalise cellular responses, has therapeutic promise. In this review we discuss the current evidence to support the trafficking cell as an immunotherapeutic target in lung disease, and which potential mechanisms or pathways have shown promise in early drug trials, with a focus on the neutrophil, as the quintessential trafficking immune cell.

Evaluation of cigarette smoke-induced emphysema in mice using quantitative micro-computed tomography

2015 ◽  
Vol 308 (10) ◽  
pp. L1039-L1045 ◽  
Author(s):  
Mamoru Sasaki ◽  
Shotaro Chubachi ◽  
Naofumi Kameyama ◽  
Minako Sato ◽  
Mizuha Haraguchi ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Cigarette Smoke ◽  
Structural Changes ◽  
Chronic Obstructive ◽  
Micro Ct ◽  
Micro Computed Tomography ◽  
Obstructive Pulmonary Disease ◽  
Calculated Volume ◽  
Lung Ct ◽  
Time Point

Chronic cigarette smoke (CS) exposure provokes variable changes in the lungs, and emphysema is an important feature of chronic obstructive pulmonary disease. The usefulness of micro-computed tomography (CT) to assess emphysema in different mouse models has been investigated, but few studies evaluated the dynamic structural changes in a CS-induced emphysema mouse model. A novel micro-CT technique with respiratory and cardiac gating has resulted in high-quality images that enable processing for further quantitative and qualitative analyses. Adult female C57BL/6J mice were repeatedly exposed to mainstream CS, and micro-CT scans were performed at 0, 4, 12, and 20 wk. Emphysema was also histologically quantified at each time point. Air-exposed mice and mice treated with intratracheal elastase served as controls and comparisons, respectively. End-expiratory lung volume, corresponding to functional residual volume, was defined as the calculated volume at the phase of end-expiration, and it evaluated air trapping. The end-expiratory lung volumes of CS-exposed mice were significantly larger than those of air controls at 12 and 20 wk, which was in line with alveolar enlargement and destruction by histological quantification. However, CS exposure neither increased low attenuation volume nor decreased the average lung CT value at any time point, unlike the elastase-instilled emphysema model. CS-exposed mice had rather higher average lung CT values at 4 and 12 wk. This is the first study characterizing a CS-induced emphysema model on micro-CT over time in mice. Moreover, these findings extend our understanding of the distinct pathophysiology of CS-induced emphysema in mice.

scholarly journals Mucin Concentrations and Peripheral Airway Obstruction in Chronic Obstructive Pulmonary Disease

2018 ◽  
Vol 198 (11) ◽  
pp. 1453-1456 ◽  
Author(s):  
Mehmet Kesimer ◽  
Benjamin M. Smith ◽  
Agathe Ceppe ◽  
Amina A. Ford ◽  
Wayne H. Anderson ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Airway Obstruction ◽  
Pulmonary Disease ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Peripheral Airway

Central and peripheral airway nitric oxide in patients with stable and exacerbated chronic obstructive pulmonary disease

2018 ◽  
Vol 12 (3) ◽  
pp. 036017 ◽  
Author(s):  
Zsófia Lázár ◽  
Ágnes Kelemen ◽  
Gabriella Gálffy ◽  
György Losonczy ◽  
Ildikó Horváth ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Peripheral Airway

scholarly journals New Insights into the Pathophysiology of Mild Chronic Obstructive Pulmonary Disease

2014 ◽  
Vol 21 (1) ◽  
pp. 25-27 ◽  
Author(s):  
Jordan A Guenette
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Forced Expiratory Volume ◽  
Exercise Intolerance ◽  
Chronic Obstructive ◽  
Activity Levels ◽  
Obstructive Pulmonary Disease ◽  
Peripheral Airway ◽  
Reduced Physical Activity

The classification of mild chronic obstructive pulmonary disease (COPD) requires a postbronchodilator forced expiratory volume in 1 s (FEV1) to forced vital capacity ratio <0.7 and an FEV1≥80% predicted. Given their relatively well-preserved spirometry, some have argued that respiratory symptoms in patients with mild COPD are unlikely to be related to pulmonary function abnormalities and that early detection of COPD is a ‘waste of resources’. Despite this viewpoint, there is emerging clinical and physiological evidence of peripheral airway dysfunction, diminished quality of life and reduced physical activity levels, and increased mortality, hospitalizations, dyspnea and exercise intolerance in patients with mild COPD compared with healthy controls. The purpose of the present focused review was to summarize recent research regarding the pathophysiology and treatment of mild COPD.

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