RESUMO
If multiple-breath washout (MBW)-derived acinar ventilation heterogeneity (Sacin) really represents peripheral units, the N2 phase-III of the first MBW exhalation should be curvilinear. This is essentially due to the superposed effect of gas diffusion and convection resulting in an equilibration of N2 concentrations between neighboring lung units throughout exhalation. We investigated this in smokers with computed tomography (CT)-proven functional small airway disease. Instantaneous N2-slopes were computed over 40-ms intervals throughout phase-III and normalized by mean phase-III N2 concentration. N2 phase-III (concave) curvilinearity was quantified as the rate at which the instantaneous N2-slope decreases past the phase-II peak over a 1-s interval; for a linear N2 phase-III unaffected by diffusion, this rate would amount to 0 L-1/s. N2 phase-III curvilinearity was obtained on the experimental curves and on existing model simulations of N2 curves from a normal peripheral lung model and one with missing terminal bronchioles (either 50% or 30% TB left). In 46 smokers [66 (±8) yr; 49 (±26) pack·yr] with CT-based evidence of peripheral lung destruction, instantaneous N2-slope decrease was compared between those with (fSAD+fEmphys) > 20% [-0.26 ± 0.14 (SD) L-1/s; n = 24] and those with (fSAD+fEmphys) < 20% [-0.16 ± 0.12 (SD) L-1/s; n = 22] (P = 0.014). Experimental values fell in the range predicted by a realistic peripheral lung model with progressive reduction of terminal bronchioles: values of instantaneous N2-slope decrease obtained from model simulations were -0.09 L-1/s (normal lung; 100% TB left), -0.17 L-1/s (normal lung 50% TB left), and -0.29 L-1/s (30% TB left). In smokers with CT-based evidence of functional small airway alterations, it is possible to demonstrate that Sacin really does represent the most peripheral airspaces.NEW & NOTEWORTHY In smokers with computed tomography-based evidence of functional small airway alterations by parametric response mapping, it is possible to demonstrate that the multiple-breath washout-derived Sacin, an index of acinar ventilation heterogeneity, actually does represent the most peripheral airspaces. This is done by verifying on experimental N2 washout curves of the first breath, N2 phase-III concavity predicted by the diffusion-convection interdependence model.
Assuntos
Pulmão , Fumantes , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Pulmão/fisiopatologia , Pulmão/diagnóstico por imagem , Fumar/fisiopatologia , Testes Respiratórios/métodos , Tomografia Computadorizada por Raios X/métodos , Testes de Função Respiratória/métodos , Expiração/fisiologia , Bronquíolos/fisiopatologia , Bronquíolos/diagnóstico por imagem , NitrogênioRESUMO
BACKGROUND: Several studies have shown the importance of the complement and coagulation systems in the pathogenesis of asthma. OBJECTIVES: We explored whether we could detect differentially abundant complement and coagulation proteins in the samples obtained from the small airway lining fluid by collection of exhaled particles in patients with asthma and whether these proteins are associated with small airway dysfunction and asthma control. METHOD: Exhaled particles were obtained from 20 subjects with asthma and 10 healthy controls (HC) with the PExA method and analysed with the SOMAscan proteomics platform. Lung function was assessed by nitrogen multiple breath washout test and spirometry. RESULTS: 53 proteins associated with the complement and coagulation systems were included in the analysis. Nine of those proteins were differentially abundant in subjects with asthma as compared to HC, and C3 was significantly higher in inadequately controlled asthma as compared to well-controlled asthma. Several proteins were associated with physiological tests assessing small airways. CONCLUSIONS: The study highlights the role of the local activation of the complement and coagulation systems in the small airway lining fluid in asthma and their association with both asthma control and small airway dysfunction. The findings highlight the potential of complement factors as biomarkers to identify different sub-groups among patients with asthma that could potentially benefit from a therapeutic approach targeting the complement system.
Assuntos
Asma , Coagulação Sanguínea , Bronquíolos , Ativação do Complemento , Alvéolos Pulmonares , Asma/sangue , Asma/imunologia , Asma/fisiopatologia , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Alvéolos Pulmonares/imunologia , Alvéolos Pulmonares/fisiopatologia , Bronquíolos/imunologia , Bronquíolos/fisiopatologiaRESUMO
Rationale: To improve disease outcomes in idiopathic pulmonary fibrosis (IPF), it is essential to understand its early pathophysiology so that it can be targeted therapeutically. Objectives: Perform three-dimensional assessment of the IPF lung microstructure using stereology and multiresolution computed tomography (CT) imaging. Methods: Explanted lungs from patients with IPF (n = 8) and donor control subjects (n = 8) were inflated with air and frozen. CT scans were used to assess large airways. Unbiased, systematic uniform random samples (n = 8/lung) were scanned with microCT for stereological assessment of small airways (count number, and measure airway wall and lumen area) and parenchymal fibrosis (volume fraction of tissue, alveolar surface area, and septal wall thickness). Measurements and Main Results: The total number of airways on clinical CT was greater in IPF lungs than control lungs (P < 0.01), owing to an increase in the wall (P < 0.05) and lumen area (P < 0.05) resulting in more visible airways with a lumen larger than 2 mm. In IPF tissue samples without microscopic fibrosis, assessed by the volume fraction of tissue using microCT, there was a reduction in the number of the terminal (P < 0.01) and transitional (P < 0.001) bronchioles, and an increase in terminal bronchiole wall area (P < 0.001) compared with control lungs. In IPF tissue samples with microscopic parenchymal fibrosis, terminal bronchioles had increased airway wall thickness (P < 0.05) and dilated airway lumens (P < 0.001) leading to honeycomb cyst formations. Conclusions: This study has important implications for the current thinking on how the lung tissue is remodeled in IPF and highlights small airways as a potential target to modify IPF outcomes.
Assuntos
Bronquíolos/diagnóstico por imagem , Bronquíolos/fisiopatologia , Diagnóstico Precoce , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/fisiopatologia , Microtomografia por Raio-X/métodos , Idoso , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION AND OBJECTIVES: Most of the studies of the pathophysiology of Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS) focus on the collapsibility and obstruction of the upper airways. The aim of our study was the investigation of small airways' function in patients with OSAHS. MATERIALS AND METHODS: We studied 23 patients (mean age, 51.6 years) diagnosed with mild to severe OSAHS, without comorbidities and 8 controls (mean age, 45.9 years). All subjects underwent full polysomnography sleep study; spirometry and maximum flow/volume curves while breathing room air and a mixture of 80%He-20%O2. The volume of equal flows (VisoVâ ) of the two curves and the difference of flows at 50% of FVC (ΔVËmax50) were calculated, as indicates of small airways' function. RESULTS: The results showed that VisoVâ was significantly increased in patients with OSAHS compared with controls (18.79±9.39 vs. 4.72±4.68, p=0.004). No statistically significantly difference was found in ΔVËmax50% (p=0.551); or the maximum Expiratory flow at 25-75% of FVC (p=0.067) and the maximum expiratory flow at 50% of FVC (p=0.174) breathing air. CONCLUSIONS: We conclude that at the time of the diagnosis of OSAHS, the function of the small airways is affected. This could be due to breathing at low lung volumes and the cyclic closure/opening of the small airways and may affect the natural history of OSAHS. The findings could lead to new therapeutic implications, targeting directly the small airways.
Assuntos
Bronquíolos/fisiopatologia , Apneia Obstrutiva do Sono/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mecânica Respiratória , Taxa RespiratóriaRESUMO
BACKGROUND: Physiological lung ageing is associated with a gradual decline in dynamic lung volumes and a progressive increase in residual volume due to diminished elastic recoil of the lung, loss of alveolar tissue, and lower chest wall compliance. However, the effects of ageing on the small airways (ie, airways <2·0 mm in diameter) remain largely unknown. By using a combination of ex-vivo conventional CT (resolution 1 mm), whole lung micro-CT (resolution 150 µm), and micro-CT of extracted cores (resolution 10 µm), we aimed to provide a multiresolution assessment of the small airways in lung ageing in a large cohort of never smokers. METHODS: For this cross-sectional study, we included donor lungs collected from 32 deceased never-smoking donors (age range 16-83 years). Ex-vivo CT and whole lung high-resolution CT (micro-CT) were used to determine total airway numbers, stratified by airway diameter. Micro-CT was used to assess the number, length, and diameter of terminal bronchioles (ie, the last generation of conducting airways); mean linear intercept; and surface density in four lung tissue cores from each lung, extracted using a uniform sampling approach. Regression ß coefficients are calculated using linear regression and polynomial models. FINDINGS: Ex-vivo CT analysis showed an age-dependent decrease in the number of airways of diameter 2·0 mm to less than 2·5 mm (ß coefficient per decade -0·119, 95% CI -0·193 to -0·045; R2=0·29) and especially in airways smaller than 2·0 mm in diameter (-0·158, -0·233 to -0·084; R2=0·47), between 30 and 80 years of age, but not of the larger (≥2·5 mm) diameter airways (-0·00781, -0·04409 to 0·02848; R2=0·0007). In micro-CT analysis of small airways, the total number of terminal bronchioles per lung increased until the age of 30 years, after which an almost linear decline in the number of terminal bronchioles was observed (ß coefficient per decade -2035, 95% CI -2818 to -1252; R2=0·55), accompanied by a non-significant increase in alveolar airspace size (6·44, -0·57 to 13·45, R2=0·10). Moreover, this decrease in terminal bronchioles was associated with the age-related decline of pulmonary function predicted by healthy reference values. INTERPRETATION: Loss of terminal bronchioles is an important structural component of age-related decline in pulmonary function of healthy, non-smoking individuals. FUNDING: Research Foundation-Flanders, KU Leuven, Parker B Francis Foundation, UGent, Canadian Institutes for Health.
Assuntos
Envelhecimento/fisiologia , Bronquíolos/diagnóstico por imagem , Bronquíolos/fisiopatologia , Obtenção de Tecidos e Órgãos , Tomografia Computadorizada por Raios X/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bélgica , Estudos Transversais , Feminino , Humanos , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Medidas de Volume Pulmonar/métodos , Masculino , Pessoa de Meia-Idade , Microtomografia por Raio-X/métodos , Adulto JovemRESUMO
Idiopathic pulmonary fibrosis (IPF) may present comorbid obstructive lung diseases with small airway dysfunction (SAD). Existing guidelines suggest that inhaled bronchodilators should be used if the ratio of forced expiratory volume in the 1st second and forced vital capacity (FEV1/FVC) < 0.7 in IPF. However, most IPF patients have FEV1/FVC > 0.7 even with coexisting emphysema. We retrospectively enrolled IPF patients who were registered at our outpatient clinic. At baseline, 63 patients completed computed tomography (CT) scans, lung function measurements, and symptom questionnaires. Among these patients, 54 (85.71%) underwent antifibrotic treatment and 38 (60.32%) underwent long-acting bronchodilator treatment. The median FEV1/FVC was 0.86. Not all patients treated with bronchodilators showed significant changes in lung function. IPF patients with SAD, determined by IOS parameters, showed significant improvement in FEV1, FEF25-75%, and symptom scores after bronchodilator treatment. Bronchodilator efficacy was not observed in patients without SAD. CT-confirmed emphysema was seen in 34.92% of patients. There were no changes in lung function or symptom scores after bronchodilator treatment in patients with emphysema. In conclusion, FEV1/FVC cannot reflect the airflow limitation in IPF. Emphysema in IPF is not a deciding factor in whether patients should receive bronchodilator treatment. IOS parameters may be useful to guide bronchodilator therapy in patients with IPF coexisting with SAD.
Assuntos
Bronquíolos/fisiopatologia , Broncodilatadores/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Testes de Função RespiratóriaRESUMO
The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 infection is a serious global concern. Increased morbidity and mortality is associated with older age, male gender, cardiovascular disease, diabetes, and smoking. As COVID-19 spreads from coastal borders, both state to state and country to country, our understanding of its pathophysiology has evolved. Age and type 2 diabetes mellitus (T2DM) play especially important roles in COVID-19 progression. T2DM is an age-related disease associated with metabolic syndrome, obesity, insulin resistance (hyperinsulinemia), hyperlipidemia, hypertension, hyperglycemia, and endothelial activation and dysfunction. This review evaluates the relationships and intersection between endothelial cell activation and dysfunction in T2DM and COVID-19. COVID-19 induces multiple injuries of the terminal bronchioles and alveolar blood-gas barrier and associated ultrastructural tissue remodeling. COVID-19 may unmask multiple vulnerabilities associated with T2DM including damage to the endothelial glycocalyx and multiple end-organ macro and microvascular diseases. Unmasking existing vulnerabilities in diabetic patients with COVID-19 is important. Globally, we must come together to better understand why T2DM is associated with increased COVID-19 morbidity and mortality.
Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/fisiopatologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Células Endoteliais/fisiologia , Síndrome Metabólica/complicações , Síndrome Metabólica/fisiopatologia , Pneumonia Viral/complicações , Pneumonia Viral/fisiopatologia , Animais , Barreira Alveolocapilar/patologia , Barreira Alveolocapilar/fisiopatologia , Bronquíolos/patologia , Bronquíolos/fisiopatologia , COVID-19 , Comorbidade , Infecções por Coronavirus/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Reposicionamento de Medicamentos , Células Endoteliais/patologia , Humanos , Síndrome Metabólica/epidemiologia , Modelos Biológicos , Pandemias , Pneumonia Viral/epidemiologia , Alvéolos Pulmonares/fisiologia , Alvéolos Pulmonares/fisiopatologia , Ratos , SARS-CoV-2 , Cicatrização/fisiologiaRESUMO
Tissue stem cell exhaustion is a key hallmark of aging, and in this study, we characterised its manifestation in the distal lung. We compared the lungs of 3- and 22-month old mice. We examined the gross morphological changes in these lungs, the density and function of epithelial progenitor populations and the epithelial gene expression profile. Bronchioles became smaller in their cross-sectional area and diameter. Using long-term EdU incorporation analysis and immunohistochemistry, we found that bronchiolar cell density remained stable with aging, but inferred rates of bronchiolar club progenitor cell self-renewal and differentiation were reduced, indicative of an overall slowdown in cellular turnover. Alveolar Type II progenitor cell density and self-renewal were maintained per unit tissue area with aging, but rates of inferred differentiation into Type I cells, and indeed overall density of Type I cells was reduced. Microarray analysis revealed age-related changes in multiple genes, including some with roles in proliferation and differentiation, and in IGF and TGFß signalling pathways. By characterising how lung stem cell dynamics change with aging, this study will elucidate how they contribute to age-related loss of pulmonary function, and pathogenesis of common age-related pulmonary diseases.
Assuntos
Células Epiteliais Alveolares/fisiologia , Bronquíolos/fisiopatologia , Células-Tronco/fisiologia , Envelhecimento/fisiologia , Animais , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Fenômenos Fisiológicos Respiratórios , Transdução de Sinais/fisiologiaRESUMO
Bronchioles are noncartilaginous small airways with internal diameter of 2 mm or less, located from approximately the eighth generation of purely air conducting airways (membranous bronchioles) down to the terminal bronchioles (the smallest airways without alveoli) and respiratory bronchioles (which communicate directly with alveolar ducts and are in the range of 0.5 mm or less in diameter). Bronchiolar injury, inflammation, and fibrosis may occur in myriad disorders including connective tissue diseases, inflammatory bowel diseases, lung transplant allograft rejection, graft versus host disease in allogeneic stem cell recipients, neuroendocrine cell hyperplasia, infections, drug toxicity (e.g., penicillamine, busulfan), inhalation injury (e.g., cigarette smoke, nylon flock, mineral dusts, hard metals, Sauropus androgynous); idiopathic, common variable immunodeficiency disorder, and a host of other disorders or insults. The spectrum of bronchiolar disorders is wide, ranging from asymptomatic to fatal obliterative bronchiolitis. In this review, we discuss the salient clinical, radiographic, and histological features of these diverse bronchiolar disorders, and discuss a management approach.
Assuntos
Broncopatias/diagnóstico por imagem , Broncopatias/terapia , Bronquiolite/diagnóstico por imagem , Bronquiolite/terapia , Obstrução das Vias Respiratórias/etiologia , Broncopatias/classificação , Broncopatias/patologia , Bronquíolos/fisiopatologia , Bronquiolite/classificação , Bronquiolite/patologia , Bronquiolite Obliterante/etiologia , Humanos , Transplante de Pulmão , Tomografia Computadorizada por Raios XRESUMO
PURPOSE OF REVIEW: Small airway disease (SAD) is a common feature in chronic obstructive pulmonary disease (COPD) patients. Chronic exposure to cigarette smoking causes inflammation, damage, tissue remodelling and eventually airway loss. These features lead to airflow limitation and defective alveolar ventilation. The aim of this review is to provide clinicians with an up-to-date perspective of SAD in COPD. RECENT FINDINGS: In this review, we will discuss the key pathological features of SAD. We also review state-of-the-art techniques for measuring SAD, including impulse oscillometry and lung imaging methods. We discuss emerging concepts such as SAD in the earlier stages of COPD and the relationship between SAD and emphysema. SUMMARY: The current review highlights the importance of targeting small airways early in the course of COPD to tackle disease progression.
Assuntos
Bronquíolos , Pulmão , Doença Pulmonar Obstrutiva Crônica , Bronquíolos/patologia , Bronquíolos/fisiopatologia , Progressão da Doença , Intervenção Médica Precoce/métodos , Humanos , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/patologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/terapiaRESUMO
Squawks are lung adventitious sounds with a mix of both musical and nonmusical components heard during the inspiratory phase. Small series have described squawks in interstitial lung diseases. Hypersensitivity pneumonitis and other diseases involving small airways can result in squawks, but new interstitial lung diseases (ILDs) involving peripheral airways are being described. A retrospective analysis was performed on 1000 consecutive patients from a database of ILD of a tertiary referral center. Squawks were recorded in 49 cases (4.9%), hypersensitivity pneumonitis (23 cases), connective tissue disease (7), microaspiration (4), pleuroparenchymal fibroelastosis (4), fibrosing cryptogenic organizing pneumonia (, 3), familial ILD (2), sarcoidosis (2), idiopathic pulmonary fibrosis (IPF; 1), bronchiolitis (2), and nonspecific interstitial pneumonia (1). One patient had a final diagnosis of IPF. There was a significant association between mosaic pattern and squawks: 20 cases with squawks (40.8%) had mosaic pattern compared with 140 (14.7%) cases without squawks (x = 23.6, P < .001).Findings indicative of fibrosis were described on high-resolution chest tomography (HRCT) in 715 cases (71.5%). Squawks were more common in patients with findings indicative of fibrosis on HRCT: 45 of 715 (6.3%) compared with 4 of 285 (1.4%) of those without findings indicative of fibrosis (x = 10.46, P = .001).In conclusion, squawks are an uncommon finding on physical examination in patients with ILD, but when present suggest fibrosing ILD associated with bronchiolar involvement. However, squawks are rare in IPF.
Assuntos
Doenças Pulmonares Intersticiais , Fibrose Pulmonar , Sons Respiratórios , Auscultação/métodos , Bronquíolos/patologia , Bronquíolos/fisiopatologia , Estudos de Coortes , Feminino , Humanos , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fibrose Pulmonar/diagnóstico por imagem , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/fisiopatologia , Sons Respiratórios/diagnóstico , Sons Respiratórios/fisiopatologia , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodosRESUMO
Current therapeutic interventions for the treatment of respiratory infections are hampered by the evolution of multidrug resistance in pathogens as well as the lack of effective cellular targets. Despite the identification of multiple region-specific lung progenitor cells, the identity of molecules that might be therapeutically targeted in response to infections to promote activation of progenitor cell types remains elusive. Here, we report that loss of Abl1 specifically in SCGB1A1-expressing cells leads to a significant increase in the proliferation and differentiation of bronchiolar epithelial cells, resulting in dramatic expansion of an SCGB1A1+ airway cell population that coexpresses SPC, a marker for type II alveolar cells that promotes alveolar regeneration following bacterial pneumonia. Furthermore, treatment with an Abl-specific allosteric inhibitor enhanced regeneration of the alveolar epithelium and promoted accelerated recovery of mice following pneumonia. These data reveal a potential actionable target that may be exploited for efficient recovery after pathogen-induced infections.
Assuntos
Pulmão/metabolismo , Pulmão/fisiopatologia , Pneumonia Bacteriana/metabolismo , Proteínas Proto-Oncogênicas c-abl/metabolismo , Regeneração/fisiologia , Células-Tronco/metabolismo , Uteroglobina/metabolismo , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/fisiologia , Animais , Bronquíolos/metabolismo , Bronquíolos/fisiopatologia , Diferenciação Celular/fisiologia , Linhagem Celular , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia Bacteriana/fisiopatologia , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/fisiopatologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/fisiopatologia , Células-Tronco/fisiologiaRESUMO
Pulmonary emphysema is characterised by irreversible destruction and enlargement of alveolar structure distal to terminal bronchioles. Small conducting airways <â2âmm in diameter are the major site of chronic airway inflammation and obstruction in COPD patients. 80â-â90â% of the last generation of small conducting airways, the terminal bronchioles, are destroyed in patients with very severe COPD. Recent data showing, that small airways disease is also a pathological feature in patients with COPD GOLD stage 1 and 2.âAlthough 40â% of terminal and 60â% of transitional bronchioles were destroyed, there was no sign for emphysema. Only a significant loss of terminal and respiratory bronchioles seems to be able to induce pulmonary emphysema and respiratory symptoms.
Assuntos
Bronquíolos/fisiopatologia , Pulmão/patologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Enfisema Pulmonar/fisiopatologia , Humanos , Índice de Gravidade de DoençaRESUMO
This review presents updated information on small airways in the pathogenesis of chronic obstructive respiratory diseases. The lungs have a branching structure, segmentally divided from trachea down to the alveoli (generations 1â-â23). Airways can be divided into a conducting (generations 1â-â16) and a respiratory zone (generations 17â-â23). Conducting zone is mainly for air transportation, respiratory zone for gas exchange. Increasing attention has been directed to the role of small airways in chronic obstructive respiratory diseases. The small conducting airways <â2âmm in diameter are the major site of airway inflammation and obstruction in COPD. It has been shown that the last generation of small conducting airways, the terminal bronchioles, are significantly destroyed in patients with very severe COPD. At what stage in the development of COPD the loss of small airways occurs is not exactly known. The small airways represent the most important target for deposition of inhaled therapeutic particles. Currently there is no gold standard for detecting small airway dysfunction. Techniques such as spirometry and body plethysmography can provide information on air trapping. High-resolution CT enables the diagnosis of pulmonary emphysema and diseases of the large airways. Only micro-CT imaging offers the option to describe microstructure of terminal bronchioles. Impulse oscillometry, gas washout techniques and analysis of exhaled nitric oxide are diagnostic tools which have to be validated for diagnosis and treatment response of small airway diseases.
Assuntos
Bronquíolos/fisiopatologia , Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/terapia , Sistema Respiratório/fisiopatologia , Humanos , Testes de Função Respiratória , Espirometria , Resultado do TratamentoRESUMO
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). Patients with GOLD 1 or GOLD 2 COPD and smokers with normal lung function had undergone lobectomy and pneumonectomy, and patients with GOLD 4 COPD had undergone lung transplantation. Lung tissue samples were used for stereological assessment of the number and morphology of terminal and transitional bronchioles, airspace size (mean linear intercept), and alveolar surface area. FINDINGS: Of the 34 patients included in this study, ten were controls (smokers with normal lung function), ten patients had GOLD 1 COPD, eight had GOLD 2 COPD, and six had GOLD 4 COPD with centrilobular emphysema. The 34 lung specimens provided 262 lung samples. Compared with control smokers, the number of terminal bronchioles decreased by 40% in patients with GOLD 1 COPD (p=0·014) and 43% in patients with GOLD 2 COPD (p=0·036), the number of transitional bronchioles decreased by 56% in patients with GOLD 1 COPD (p=0·0001) and 59% in patients with GOLD 2 COPD (p=0·0001), and alveolar surface area decreased by 33% in patients with GOLD 1 COPD (p=0·019) and 45% in patients with GOLD 2 COPD (p=0·0021). These pathological changes were found to correlate with lung function decline. We also showed significant loss of terminal and transitional bronchioles in lung samples from patients with GOLD 1 or GOLD 2 COPD that had a normal alveolar surface area. Remaining small airways were found to have thickened walls and narrowed lumens, which become more obstructed with increasing COPD GOLD stage. INTERPRETATION: These data show that small airways disease is a pathological feature in mild and moderate COPD. Importantly, this study emphasises that early intervention for disease modification might be required by patients with mild or moderate COPD. FUNDING: Canadian Institutes of Health Research.
Assuntos
Bronquíolos/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Índice de Gravidade de Doença , Idoso , Análise de Variância , Bronquíolos/diagnóstico por imagem , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Medidas de Volume Pulmonar , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Fumantes/estatística & dados numéricos , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Small airways disease (SAD) is considered pivotal in the pathology of COPD. There are numerous publications describing physiological and Computed Tomography (CT) imaging markers to detect SAD. However, there is no agreed gold standard and limited understanding of the clinical associations of these measures to disease outcomes. METHODS: We conducted a systematic review using Embase, Medline and Pubmed to explore the relationship between physiological and CT SAD measures in COPD (GOLD Stages 1-4). Furthermore, evidence linking these physiological measures with defined clinical outcomes such as health status, functional assessment and exacerbation frequency were summarised. RESULTS: The search yielded 1160 abstracts of which 19 met the search criteria. Six studies examined physiological and CT measures while 13 publications identified physiological measures and clinical outcomes. Strong correlations were seen between CT and physiological measures of SAD. Varying associations between physiological measures and defined clinical outcomes were noted. CONCLUSIONS: Physiological and CT measures of SAD correlate and infer similar information. Physiological measures of SAD may offer valuable insight into clinical expression of the disease. A consensus on the standardisation and recommendation of tests to measure SAD is needed in order to better understand any clinical benefits of targeted drug therapy to the small airways.
Assuntos
Bronquíolos/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Bronquíolos/diagnóstico por imagem , Humanos , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Índice de Gravidade de DoençaAssuntos
Bronquíolos/fisiopatologia , Bronquiolite/etiologia , Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Testes de Função Respiratória , Fumar/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/etiologiaRESUMO
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.On MDCT, COPD lungs showed a decrease in the number of 2-2.5â mm diameter airways and the lumen area of fifth-generation airways, while on microCT there was a reduction in the number of terminal bronchioles as well as a decrease in the luminal areas, wall volumes and alveolar attachments to the walls of TB, TB-1 and TB-2 bronchioles. The combination of microCT and histology showed increased B-cell infiltration into the walls of TB-1 and TB-2 bronchioles, and this change was correlated with a reduced number of alveolar attachments in COPD.Small airways disease extends from 2â mm diameter airways to the terminal bronchioles in COPD. Destruction of alveolar attachments may be driven by a B-cell-mediated immune response in the preterminal bronchioles.
Assuntos
Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Tomografia Computadorizada por Raios X , Microtomografia por Raio-X , Idoso , Obstrução das Vias Respiratórias/fisiopatologia , Remodelação das Vias Aéreas/fisiologia , Linfócitos B/citologia , Bronquíolos/diagnóstico por imagem , Bronquíolos/fisiopatologia , Estudos de Casos e Controles , Feminino , Volume Expiratório Forçado , Humanos , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Transplante de Pulmão , Masculino , Pessoa de Meia-Idade , Alvéolos Pulmonares/diagnóstico por imagem , Alvéolos Pulmonares/fisiopatologiaRESUMO
BACKGROUND: The principal obstacle to long-term survival after lung transplant is chronic lung allograft dysfunction (CLAD), which primarily affects the small airways. After transplant, patients are monitored with spirometry, which is a generally insensitive detector of small airways obstruction. The lung clearance index (LCI) is a measure obtained during multiple breath washout (MBW) maneuvers. We hypothesized that among lung allograft recipients, LCI would detect small airways disease not detected with spirometry. METHODS: This study enrolled 15 patients, 5 of whom already had a diagnosis of CLAD. We added MBW as an additional index of peripheral airway function to the established post-transplant routine care protocol. RESULTS: Of trials, 87.9% yielded valid measurements, and single maneuvers were 2-8 minutes. LCI did not yield any false-negative findings-no patients were considered obstructed by forced expiratory volume in 1 second (FEV1) but normal by LCI. At enrollment, 6 patients without CLAD had an elevated LCI, and 4 progressed to CLAD. Only 2 of these 4 patients would have been identified by a decrease in FEV1. CONCLUSIONS: LCI identified lung allograft dysfunction in more patients than the use of standardized spirometric measures, including patients with abnormal FEV1. These data suggest that LCI from MBW may be a more sensitive means to detect allograft peripheral airway disease than standard methods for measurement of small airways function.