Small airway fibroblasts from patients with chronic obstructive pulmonary disease exhibit cellular senescence.

Small airway disease (SAD) is a key early-stage pathology of chronic obstructive pulmonary disease (COPD). COPD is associated with cellular senescence whereby cells undergo growth arrest and express the senescence-associated secretory phenotype (SASP) leading to chronic inflammation and tissue remodeling. Parenchymal-derived fibroblasts have been shown to display senescent properties in COPD, however small airway fibroblasts (SAFs) have not been investigated. Therefore, this study investigated the role of these cells in COPD and their potential contribution to SAD. To investigate the senescent and fibrotic phenotype of SAF in COPD, SAFs were isolated from nonsmoker, smoker, and COPD lung resection tissue (n = 9-17 donors). Senescence and fibrotic marker expressions were determined using iCELLigence (proliferation), qPCR, Seahorse assay, and ELISAs. COPD SAFs were further enriched for senescent cells using FACSAria Fusion based on cell size and autofluorescence (10% largest/autofluorescent vs. 10% smallest/nonautofluorescent). The phenotype of the senescence-enriched population was investigated using RNA sequencing and pathway analysis. Markers of senescence were observed in COPD SAFs, including senescence-associated ß-galactosidase, SASP release, and reduced proliferation. Because the pathways driving this phenotype were unclear, we used cell sorting to enrich senescent COPD SAFs. This population displayed increased p21CIP1 and p16INK4a expression and mitochondrial dysfunction. RNA sequencing suggested these senescent cells express genes involved in oxidative stress response, fibrosis, and mitochondrial dysfunction pathways. These data suggest COPD SAFs are senescent and may be associated with fibrotic properties and mitochondrial dysfunction. Further understanding of cellular senescence in SAFs may lead to potential therapies to limit SAD progression.NEW & NOTEWORTHY Fibroblasts and senescence are thought to play key roles in the pathogenesis of small airway disease and COPD; however, the characteristics of small airway-derived fibroblasts are not well explored. In this study we isolate and enrich the senescent small airway-derived fibroblast (SAF) population from COPD lungs and explore the pathways driving this phenotype using bulk RNA-seq.

TGFß1, SMAD and ß-Catenin in pulmonary arteries of smokers, patients with small airway disease and COPD: potential drivers of EndMT.

We previously reported pulmonary arterial remodelling and active endothelial to mesenchymal transition (EndMT) in smokers and patients with early COPD. In this study, we aimed to evaluate the role of different drivers of EndMT. Immunohistochemical staining for EndMT drivers, TGF-ß1, pSMAD-2/3, SMAD-7, and ß-catenin, was performed on lung resections from 46 subjects. Twelve were non-smoker-controls (NC), six normal lung function smokers (NLFS), nine patients with small-airway diseases (SAD), nine mild-moderate COPD-current smokers (COPD-CS) and ten COPD-ex-smokers (COPD-ES). Histopathological measurements were done using Image ProPlus softwarev7.0. We observed lower levels of total TGF-ß1 (p<0.05) in all smoking groups than in the non-smoking control (NC). Across arterial sizes, smoking groups exhibited significantly higher (p <0.05) total and individual layer pSMAD-2/3 and SMAD-7 than in the NC group. The ratio of SAMD-7 to pSMAD-2/3 was higher in COPD patients compared to NC. Total ß-catenin expression was significantly higher in smoking groups across arterial sizes (p <0.05), except for COPD-ES and NLFS groups in small and medium arteries, respectively. Increased total ß-catenin was positively correlated with total S100A4 in small and medium arteries (r= 0.35, 0.50; p=0.02, 0.01, respectively), with vimentin in medium arteries (r=0.42, p=0.07), and with arterial thickness of medium and large arteries (r= 0.34, 0.41, p=0.02, 0.01, respectively). This is the first study uncovering active endothelial SMAD pathway independent of TGF-ß1 in smokers, SAD, and COPD patients. Increased expression of ß-catenin indicates its potential interaction with SMAD pathway, warranting further research to identify the deviation of this classical pathway.

Clinical features and outcomes of small airway disease in ANCA-associated vasculitis.

BACKGROUND AND OBJECTIVE: To clarify the prevalence, features and outcomes of small airway disease (SAD) in a Chinese cohort with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) related pulmonary involvement. METHODS: SAD was recorded when the manifestations of either centrilobular nodules or air trapping were observed according to CT scans, except for infection or other airway-related comorbidities. Baseline and follow-up data were collected retrospectively. RESULTS: Of the 359 newly diagnosed AAV patients with pulmonary involvement, 92 (25.6%) had SAD, including 79 (85.9%) cases of anti-MPO-ANCA positive, 9 (9.8%) cases of anti-PR3-ANCA positive and 2 (2.2%) cases of double positive. Patients with SAD were more likely to be younger, female, non-smokers, have more ear-nose-throat (ENT) involvement, and have higher baseline Birmingham Vasculitis Activity Score (BVAS) compared to patients without SAD. Several AAV-related SAD patients have improved lung function and CT scans after immunosuppressive therapy. Patients with SAD had a better prognosis compared to those without SAD. When dividing all patients into three groups: isolated SAD (only small airway involvements), SAD with other lower airway involvements, and non-SAD, patients in the SAD with other lower airway involvements group had the highest risk of infection, while patients in the non-SAD group had the worst long-term outcomes. Similar results were observed in anti-MPO-ANCA positive patients when performing subgroup analyses. CONCLUSION: SAD is a unique manifestation of AAV-related lung involvement and exhibits distinct clinical features. It is vital to focus on SAD because of its association with prognosis and infection in AAV patients, especially in anti-MPO-ANCA positive patients. Moreover, SAD might represent a better response to immunosuppressors.

Assessing the relationship between cardiovascular and small airway disease and acute events in COPD: The ARCADIA study protocol.

The initial alterations of chronic obstructive pulmonary disease (COPD) involve the small airways. Small airway disease (SAD) is related to lung hyperinflation and air trapping. Several lung function tests may detect the presence of SAD, namely forced mid-expiratory flows, residual volume (RV), RV/total lung capacity (TLC) ratio, functional residual capacity, airway resistances obtained with body-plethysmography and oscillometry, and the single-breath nitrogen washout test. Additionally, high-resolution computed tomography can detect SAD. In addition to SAD, COPD is related to cardiovascular disease (CVD) such as heart failure, peripheral vascular disease, and ischemic heart disease. No studies have assessed the relationship between CVD, COPD, and SAD. Therefore, the main objective of the Assessing the Relationship between Cardiovascular and small Airway Disease and Acute events in COPD (ARCADIA) study is to assess the risk of CVD in COPD patients according to SAD in a real-life setting. The correlation between CVD, mortality, and acute exacerbation of COPD (AECOPD) is also evaluated. ARCADIA is a 52-week prospective, multicentre, pilot, observational, cohort study conducted in ≥22 pulmonary centres in Italy and that enrols ≥500 COPD patients, regardless of disease severity (protocol registration: ISRCTN49392136). SAD is evaluated at baseline, after that CVD, mortality, and AECOPD are recorded at 6 and 12 months. Bayesian inference is used to quantify the risk and correlation of the investigated outcomes in COPD patients according to SAD. The ARCADIA study provides relevant findings in the daily clinical management of COPD patients.

Small airway disease and asthma control.

AIM: Maximum mid-expiratory flow (MMEF) is one of the pulmonary function tests that report small airway disease. Our study aimed to investigate the role of MMEF values in asthma control, the prevalence of small airway disease, and their effect on asthma control in patients with asthma with normal forced expiratory volume in one second (FEV1) values. MATERIAL AND METHOD: Patients who presented to the Chest Diseases outpatient clinic of our hospital between 2018 and 2019 and were diagnosed as having asthma were included in the study. The characteristics of the patients, pulmonary function tests, their asthma treatment, and asthma control test (ACT) scores were recorded. Patients with FEV1 <80 in the pulmonary function test, those with additional lung disease, those who had an attack in the last 4 weeks, and patients who smoked were excluded from the study. MMEF <65 was defined as small airway disease. RESULTS: The MMEF% and MMEF (L/s) values of the group with uncontrolled asthma were found to be statistically significantly lower than those of the controlled asthma group (p = 0.016 and p = 0.003, respectively). MMEF% and MMEF (L/s) values in those with wheezing were found to be significantly lower compared with those without wheezing (p = 0.025 and p = 0.049, respectively). The MMEF% and MMEF (L/s) values of the patients with nocturnal symptoms were found to be statistically significantly lower than in patients without nocturnal symptoms (p = 0.023 and p = 0.041, respectively). ACT values of patients with MMEF <65 were found to be statistically lower than those of patients with MMEF >65 (0.047). CONCLUSION: Considering small airway disease in patients with asthma may be beneficial in clinical practice.

Computer-assisted evaluation of small airway disease in CT scans of Iran-Iraq war victims of chemical warfare by a locally developed software: comparison between different quantitative methods.

OBJECTIVE: Diagnosis of small airway disease on computed tomography (CT) scans is challenging in patients with a history of chemical warfare exposure. We developed a software package based on different methodologies to identify and quantify small airway disease in CT images. The primary aim was to identify the best automatic methodology for detecting small airway disease in CT scans of Iran-Iraq War victims of chemical warfare. METHODS: This retrospective case-control study enrolled 46 patients with a history of chemical warfare exposure and 27 controls with inspiratory/expiratory (I/E) CT scans and spirometry tests. Image data were automatically segmented, and inspiratory images were registered into the expiratory images' frame using the locally developed software. Parametric response mapping (PRM) and air trapping index (ATI) mapping were performed on the CT images. Conventional QCT methods, including expiratory/inspiratory mean lung attenuation (E/I MLA) ratio, normal density E/I (ND E/I) MLA ratio, attenuation volume Index (AVI), %low attenuation areas (LAA) < -856 in exhale scans, and %LAA < -950 in inhale scans were also computed. QCT measurements were correlated with spirometry results and compared across the two study groups. RESULTS: The correlation analysis showed a significant negative relationship between three air trapping (AT) measurements (PRM, ATI, and %LAAExp < -856) and spirometry parameters (Fev1, Fvc, Fev1/Fvc, and MMEF). Moreover, %LAAExp < -856 had the highest significant negative correlation with Fev1/Fvc (r = -0.643, P-value < 0.001). Three AT measurements demonstrated a significant difference between the study groups. The E/I ratio was also significantly different between the two groups (P-value < 0.001). Binary logistic regression models showed PRMFsad, %LAAExp < -856, and ATI as significant and strong predictors of the study outcome. Optimal cut-points for PRMFsad = 19%, %LAAExp < -856 = 23%, and ATI = 27% were identified to classify the participants into two groups with high accuracy. CONCLUSION: QCT methods, including PRM, ATI, and %LAAExp < -856 can greatly advance the identification and quantification of SAD in chemical warfare victims. The results should be verified in well-designed prospective studies involving a large population.

Characterization of Immunopathology and Small Airway Remodeling in Constrictive Bronchiolitis.

Rationale: Constrictive bronchiolitis (ConB) is a relatively rare and understudied form of lung disease whose underlying immunopathology remains incompletely defined. Objectives: Our objectives were to quantify specific pathological features that differentiate ConB from other diseases that affect the small airways and to investigate the underlying immune and inflammatory phenotype present in ConB. Methods: We performed a comparative histomorphometric analysis of small airways in lung biopsy samples collected from 50 soldiers with postdeployment ConB, 8 patients with sporadic ConB, 55 patients with chronic obstructive pulmonary disease, and 25 nondiseased control subjects. We measured immune and inflammatory gene expression in lung tissue using the NanoString nCounter Immunology Panel from six control subjects, six soldiers with ConB, and six patients with sporadic ConB. Measurements and Main Results: Compared with control subjects, we found shared pathological changes in small airways from soldiers with postdeployment ConB and patients with sporadic ConB, including increased thickness of the smooth muscle layer, increased collagen deposition in the subepithelium, and lymphocyte infiltration. Using principal-component analysis, we showed that ConB pathology was clearly separable both from control lungs and from small airway disease associated with chronic obstructive pulmonary disease. NanoString gene expression analysis from lung tissue revealed T-cell activation in both groups of patients with ConB with upregulation of proinflammatory pathways, including cytokine-cytokine receptor interactions, NF-κB (nuclear factor-κB) signaling, TLR (Toll-like receptor) signaling, T-cell receptor signaling, and antigen processing and presentation. Conclusions: These findings indicate shared immunopathology among different forms of ConB and suggest that an ongoing T-helper cell type 1-type adaptive immune response underlies airway wall remodeling in ConB.

Application of impulse oscillometry to detect interstitial lung disease and airway disease in adults with rheumatoid arthritis.

BACKGROUND: We conducted a retrospective observational study to explore the potential application of impulse oscillometry (IOS) as an alternative to high-resolution computed tomography (HRCT) for detecting pulmonary involvement in patients with rheumatoid arthritis (RA) because clinically evident interstitial lung disease (ILD) and airway involvement are common in this population. METHODS: We enrolled 72 patients with RA who underwent pulmonary function tests (PFTs) and IOS between September 2021 and September 2022. We aimed to identify the PFT and IOS variables associated with lung diseases shown on HRCT images. RESULTS: In our cohort of 72 patients, 48 underwent HRCT; of these, 35 had airway disease or ILD and 13 showed no obvious abnormalities on HRCT. Abnormal IOS and PFT parameters were observed in 34 and 23 patients, respectively, with abnormal HRCT images. The predicted percentages for forced vital capacity, the ratio of forced expiratory volume in the first one second to forced vital capacity, and forced mid-expiratory flow value were significantly lower in patients with abnormal HRCT. Lung resistance at 5 Hz, difference in resistance between 5 and 20 Hz, resonant frequency (Fres), and reactance area were higher in these patients and reactance at 5 Hz was lower. Compared to other parameters, Fres > 14.14 was significantly associated with alterations in HRCT and may be used as an indicator for monitoring disease. CONCLUSION: Fres > 14.14 is significantly associated with lung involvement in RA patients. Performance of spirometry with IOS is more beneficial than spirometry alone for evaluating lung involvement in RA patients.

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

Rationale: 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.Objectives: To assess the pathological differences between PSE and CLE in chronic obstructive pulmonary disease (COPD).Methods: Air-inflated frozen lung specimens (n = 6) obtained from patients with severe COPD treated by lung transplantation were scanned with MDCT. Frozen tissue cores were taken from central (n = 8) and peripheral (n = 8) regions of each lung, scanned with micro-computed tomography (microCT), and processed for histology. The core locations were registered to the MDCT, and a percentage of PSE or CLE was assigned by radiologists to each of the regions. MicroCT scans were used to measure number and structural change of terminal bronchioles. Furthermore, microCT-based volume fractions of CLE and PSE allowed classifying cores into mild emphysema, CLE-dominant, and PSE-dominant.Measurements and Main Results: The percentages of PSE measured on MDCT and microCT were positively associated (P = 0.015). The number of terminal bronchioles per milliliter of lung and cross-sectional lumen area were significantly lower and wall area percentage was significantly higher in CLE-dominant regions compared with mild emphysema and PSE-dominant regions (all P < 0.05), whereas no difference was found between PSE-dominant and mild emphysema samples (all P > 0.5). Immunohistochemistry showed significantly higher infiltration of neutrophils (P = 0.002), but not of macrophages, CD4, CD8, or B cells, in PSE compared with CLE regions.Conclusions: The terminal bronchioles are relatively preserved, whereas neutrophilic inflammation is increased in PSE-dominant regions compared with CLE-dominant regions in patients with COPD.

Determining Response to Treatment for Drug-Induced Bronchocentric Granulomatosis by the Forced Oscillation Technique.

Anti-tumor necrosis factor alpha (TNFα) therapy is widely used to treat various inflammatory conditions. Paradoxically, there are several case reports describing the development of bronchocentric granulomatosis treated with TNFα inhibitors, and it is difficult to determine the effect of treatment using conventional spirometry because the lesions are located in small airways. However, it has been reported that the forced oscillation technique (FOT) is useful in the evaluation of small airway disease in bronchial asthma or chronic obstructive pulmonary disease. We performed the FOT to determine the effect of treatment on bronchocentric granulomatosis and found it to be useful. We report the case of a 55-year-old female with ulcerative colitis who was treated with golimumab and who developed bronchocentric granulomatosis as a sarcoid-like reaction to golimumab. She was successfully treated with prednisone, and the treatment efficacy was confirmed by the FOT. The FOT may be useful in the evaluation of small airway disease in bronchocentric granulomatosis. This case may help inform clinicians of the usefulness of the FOT to assess small airway disease in various diseases.

Phenotypic comparison between smoking and non-smoking chronic obstructive pulmonary disease.

BACKGROUND: Although COPD among non-smokers (NS-COPD) is common, little is known about this phenotype. We compared NS-COPD subjects with smoking COPD (S-COPD) patients in a rural Indian population using a variety of clinical, physiological, radiological, sputum cellular and blood biomarkers. METHODS: Two hundred ninety subjects (118 healthy, 79 S-COPD, 93 NS-COPD) performed pre- and post-bronchodilator spirometry and were followed for 2 years to study the annual rate of decline in lung function. Body plethysmography, impulse oscillometry, inspiratory-expiratory HRCT, induced sputum cellular profile and blood biomarkers were compared between 49 healthy, 45 S-COPD and 55 NS-COPD subjects using standardized methods. Spirometric response to oral corticosteroids was measured in 30 female NS-COPD patients. RESULTS: Compared to all male S-COPD subjects, 47% of NS-COPD subjects were female, were younger by 3.2 years, had greater body mass index, a slower rate of decline in lung function (80 vs 130 mL/year), more small airways obstruction measured by impulse oscillometry (p < 0.001), significantly less emphysema (29% vs 11%) on CT scans, lower values in lung diffusion parameters, significantly less neutrophils in induced sputum (p < 0.05) and tended to have more sputum eosinophils. Hemoglobin and red cell volume were higher and serum insulin lower in S-COPD compared to NS-COPD. Spirometric indices, symptoms and quality of life were similar between S-COPD and NS-COPD. There was no improvement in spirometry in NS-COPD patients after 2 weeks of an oral corticosteroid. CONCLUSIONS: Compared to S-COPD, NS-COPD is seen in younger subjects with equal male-female predominance, is predominantly a small-airway disease phenotype with less emphysema, preserved lung diffusion and a slower rate of decline in lung function.

Imaging-based clusters in former smokers of the COPD cohort associate with clinical characteristics: the SubPopulations and intermediate outcome measures in COPD study (SPIROMICS).

BACKGROUND: Quantitative computed tomographic (QCT) imaging-based metrics enable to quantify smoking induced disease alterations and to identify imaging-based clusters for current smokers. We aimed to derive clinically meaningful sub-groups of former smokers using dimensional reduction and clustering methods to develop a new way of COPD phenotyping. METHODS: An imaging-based cluster analysis was performed for 406 former smokers with a comprehensive set of imaging metrics including 75 imaging-based metrics. They consisted of structural and functional variables at 10 segmental and 5 lobar locations. The structural variables included lung shape, branching angle, airway-circularity, airway-wall-thickness, airway diameter; the functional variables included regional ventilation, emphysema percentage, functional small airway disease percentage, Jacobian (volume change), anisotropic deformation index (directional preference in volume change), and tissue fractions at inspiration and expiration. RESULTS: We derived four distinct imaging-based clusters as possible phenotypes with the sizes of 100, 80, 141, and 85, respectively. Cluster 1 subjects were asymptomatic and showed relatively normal airway structure and lung function except airway wall thickening and moderate emphysema. Cluster 2 subjects populated with obese females showed an increase of tissue fraction at inspiration, minimal emphysema, and the lowest progression rate of emphysema. Cluster 3 subjects populated with older males showed small airway narrowing and a decreased tissue fraction at expiration, both indicating air-trapping. Cluster 4 subjects populated with lean males were likely to be severe COPD subjects showing the highest progression rate of emphysema. CONCLUSIONS: QCT imaging-based metrics for former smokers allow for the derivation of statistically stable clusters associated with unique clinical characteristics. This approach helps better categorization of COPD sub-populations; suggesting possible quantitative structural and functional phenotypes.

Spirometric assessment of emphysema presence and severity as measured by quantitative CT and CT-based radiomics in COPD.

BACKGROUND: The mechanisms underlying airflow obstruction in COPD cannot be distinguished by standard spirometry. We ascertain whether mathematical modeling of airway biomechanical properties, as assessed from spirometry, could provide estimates of emphysema presence and severity, as quantified by computed tomography (CT) metrics and CT-based radiomics. METHODS: We quantified presence and severity of emphysema by standard CT metrics (VIDA) and co-registration analysis (ImbioLDA) of inspiratory-expiratory CT in 194 COPD patients who underwent pulmonary function testing. According to percentages of low attenuation area below - 950 Hounsfield Units (%LAA-950insp) patients were classified as having no emphysema (NE) with %LAA-950insp < 6, moderate emphysema (ME) with %LAA-950insp ≥ 6 and < 14, and severe emphysema (SE) with %LAA-950insp ≥ 14. We also obtained stratified clusters of emphysema CT features by an automated unsupervised radiomics approach (CALIPER). An emphysema severity index (ESI), derived from mathematical modeling of the maximum expiratory flow-volume curve descending limb, was compared with pulmonary function data and the three CT classifications of emphysema presence and severity as derived from CT metrics and radiomics. RESULTS: ESI mean values and pulmonary function data differed significantly in the subgroups with different emphysema degree classified by VIDA, ImbioLDA and CALIPER (p < 0.001 by ANOVA). ESI differentiated NE from ME/SE CT-classified patients (sensitivity 0.80, specificity 0.85, AUC 0.86) and SE from ME CT-classified patients (sensitivity 0.82, specificity 0.87, AUC 0.88). CONCLUSIONS: Presence and severity of emphysema in patients with COPD, as quantified by CT metrics and radiomics can be estimated by mathematical modeling of airway function as derived from standard spirometry.

Total Airway Count on Computed Tomography and the Risk of Chronic Obstructive Pulmonary Disease Progression. Findings from a Population-based Study.

RATIONALE: Studies of excised lungs show that significant airway attrition in the "quiet" zone occurs early in chronic obstructive pulmonary disease (COPD). OBJECTIVES: To determine if the total number of airways quantified in vivo using computed tomography (CT) reflects early airway-related disease changes and is associated with lung function decline independent of emphysema in COPD. METHODS: Participants in the multicenter, population-based, longitudinal CanCOLD (Canadian Chronic Obstructive Lung Disease) study underwent inspiratory/expiratory CT at visit 1; spirometry was performed at four visits over 6 years. Emphysema was quantified as the CT inspiratory low-attenuation areas below -950 Hounsfield units. CT total airway count (TAC) was measured as well as airway inner diameter and wall area using anatomically equivalent airways. MEASUREMENTS AND MAIN RESULTS: Participants included never-smokers (n = 286), smokers with normal spirometry at risk for COPD (n = 298), Global Initiative for Chronic Obstructive Lung Disease (GOLD) I COPD (n = 361), and GOLD II COPD (n = 239). TAC was significantly reduced by 19% in both GOLD I and GOLD II compared with never-smokers (P < 0.0001) and by 17% in both GOLD I and GOLD II compared with at-risk participants (P < 0.0001) after adjusting for low-attenuation areas below -950 Hounsfield units. Further analysis revealed parent airways with missing daughter branches had reduced inner diameters (P < 0.0001) and thinner walls (P < 0.0001) compared with those without missing daughter branches. Among all CT measures, TAC had the greatest influence on FEV1 (P < 0.0001), FEV1/FVC (P < 0.0001), and bronchodilator responsiveness (P < 0.0001). TAC was independently associated with lung function decline (FEV1, P = 0.02; FEV1/FVC, P = 0.01). CONCLUSIONS: TAC may reflect the airway-related disease changes that accumulate in the "quiet" zone in early/mild COPD, indicating that TAC acquired with commercially available software across various CT platforms may be a biomarker to predict accelerated COPD progression.

SMALLa AIRWAY DISEASE IN COPD ASSOCIATED TO BIOMASS EXPOSURE.

Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous entity that may result from different causative agents and risk factors and may follow diverse clinical courses, including COPD secondary to biomass smoke exposure. At present, this phenotype is becoming more important for two reasons: first, because at least almost half of the world's population is exposed to biomass smoke, and second, because the possibility of it being diagnosed is increasing. Biomass smoke exposure COPD affects primarily women and is related with insults to the airways occurred during early life. Although constituents of biomass smoke and tobacco smoke are similar, the physiopathological changes they induce differ depending not only on the chemical composition (related with the type of fuel used) but also on the particle size and the inhalation pattern. Evidence has shown that biomass smoke exposure affects the airway, predominantly the small airways causing anthracofibrosis and peribronchiolar fibrosis changes that will clinically translate into chronic bronchitis symptoms, with a high impact on the quality of life. In this review, we focus especially on the main epidemiological and clinical differences between COPD secondary to biomass exposure and COPD caused by tobacco exposure.

Mice overexpressing latent matrix metalloproteinase-2 develop lung emphysema after short-term exposure to cigarette smoke extract.

Chronic obstructive pulmonary disease is the major growing cause of mortality and morbidity worldwide, and it is going to become the third most common cause of death by 2020. Chronic obstructive pulmonary disease is pathologically characterized by lung emphysema and small airway inflammation. Animal models are very important to get insights into the disease pathogenesis but current models of chronic obstructive pulmonary disease take a long time to develop. The need of a new model is compelling. In the present study we focus on the role of matrix metalloproteinases in the pathogenesis of chronic obstructive pulmonary disease and hypothesized that lung overexpression of latent matrix metalloproteinases-2 would allow the development of emphysema after short-term exposure to cigarette smoke extract inhalation. Human latent matrix metalloproteinases-2 transgenic mouse expressing high level of the protein in the lungs and wild type mouse were exposed to aerosolized cigarette smoke extract for two weeks. Transgenic mice showed significant lung emphysematous changes, increased infiltration of inflammatory cells and enhanced lung concentrations of inflammatory cytokines in the lungs compared to their wild type counterparts after inhalation of cigarette smoke extract. This novel mouse model will be a very useful tool for evaluating the mechanistic pathways and for development of novel therapies in cigarette smoke-associated lung emphysema.

Imaging-based clusters in current smokers of the COPD cohort associate with clinical characteristics: the SubPopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS).

BACKGROUND: Classification of COPD is usually based on the severity of airflow, which may not sensitively differentiate subpopulations. Using a multiscale imaging-based cluster analysis (MICA), we aim to identify subpopulations for current smokers with COPD. METHODS: Among the SPIROMICS subjects, we analyzed computed tomography images at total lung capacity (TLC) and residual volume (RV) of 284 current smokers. Functional variables were derived from registration of TLC and RV images, e.g. functional small airways disease (fSAD%). Structural variables were assessed at TLC images, e.g. emphysema and airway wall thickness and diameter. We employed an unsupervised method for clustering. RESULTS: Four clusters were identified. Cluster 1 had relatively normal airway structures; Cluster 2 had an increase of fSAD% and wall thickness; Cluster 3 exhibited a further increase of fSAD% but a decrease of wall thickness and airway diameter; Cluster 4 had a significant increase of fSAD% and emphysema. Clinically, Cluster 1 showed normal FEV1/FVC and low exacerbations. Cluster 4 showed relatively low FEV1/FVC and high exacerbations. While Cluster 2 and Cluster 3 showed similar exacerbations, Cluster 2 had the highest BMI among all clusters. CONCLUSIONS: Association of imaging-based clusters with existing clinical metrics suggests the sensitivity of MICA in differentiating subpopulations.

Signs of Gas Trapping in Normal Lung Density Regions in Smokers.

RATIONALE: A substantial proportion of subjects without overt airflow obstruction have significant respiratory morbidity and structural abnormalities as visualized by computed tomography. Whether regions of the lung that appear normal using traditional computed tomography criteria have mild disease is not known. OBJECTIVES: To identify subthreshold structural disease in normal-appearing lung regions in smokers. METHODS: We analyzed 8,034 subjects with complete inspiratory and expiratory computed tomographic data participating in the COPDGene Study, including 103 lifetime nonsmokers. The ratio of the mean lung density at end expiration (E) to end inspiration (I) was calculated in lung regions with normal density (ND) by traditional thresholds for mild emphysema (-910 Hounsfield units) and gas trapping (-856 Hounsfield units) to derive the ND-E/I ratio. Multivariable regression analysis was used to measure the associations between ND-E/I, lung function, and respiratory morbidity. MEASUREMENTS AND MAIN RESULTS: The ND-E/I ratio was greater in smokers than in nonsmokers, and it progressively increased from mild to severe chronic obstructive pulmonary disease severity. A proportion of 26.3% of smokers without airflow obstruction had ND-E/I greater than the 90th percentile of normal. ND-E/I was independently associated with FEV1 (adjusted ß = -0.020; 95% confidence interval [CI], -0.032 to -0.007; P = 0.001), St. George's Respiratory Questionnaire scores (adjusted ß = 0.952; 95% CI, 0.529 to 1.374; P < 0.001), 6-minute-walk distance (adjusted ß = -10.412; 95% CI, -12.267 to -8.556; P < 0.001), and body mass index, airflow obstruction, dyspnea, and exercise capacity index (adjusted ß = 0.169; 95% CI, 0.148 to 0.190; P < 0.001), and also with FEV1 change at follow-up (adjusted ß = -3.013; 95% CI, -4.478 to -1.548; P = 0.001). CONCLUSIONS: Subthreshold gas trapping representing mild small airway disease is prevalent in normal-appearing lung regions in smokers without airflow obstruction, and it is associated with respiratory morbidity. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).