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1.
Lima; Perú. Ministerio de Salud; 20191100. 22 p. graf, ilus.
Monografia em Espanhol | LILACS, LIPECS | ID: biblio-1005172

RESUMO

La publicación describe los criterios para el diagnóstico y tratamiento de bronquiolitis, contribuyendo a la reducción de la morbilidad y mortalidad en menores de 2 años. Asimismo, las medidas de prevención, atención y control de la Bronquiolitis, mejorando así su calidad de vida.


Assuntos
Prevenção Primária , Infecções Respiratórias , Bronquiolite , Guia de Prática Clínica , Assistência Integral à Saúde , Bronquíolos
2.
Medicine (Baltimore) ; 98(29): e16419, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31335692

RESUMO

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/métodos
3.
Environ Pollut ; 253: 864-871, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349195

RESUMO

It is estimated that 10% of the worldwide population lives in the vicinity of an active volcano. However, volcanogenic air pollution studies are still outnumbered when compared with anthropogenic air pollution studies, representing an unknown risk to human populations inhabiting volcanic areas worldwide. This study was carried out in the Azorean archipelago of Portugal, in areas with active non-eruptive volcanism. The hydrothermal emissions within the volcanic complex of Furnas (São Miguel Island) are responsible for the emission of nearly 1000 tons of CO2 per day, along with H2S, the radioactive gas - radon, among others. Besides the gaseous emissions, metals (e.g., Hg, Cd, Al, Ni) and particulate matter are also released into the environment. We test the hypothesis that chronic exposure to volcanogenic air pollution alters the histomorphology of the bronchioles and terminal bronchioles, using the house mouse, Mus musculus, as bioindicator species. Mus musculus were live-captured at three different locations: two villages with active volcanism and a village without any type of volcanic activity (reference site). The histomorphology of the bronchioles (diameter, epithelium thickness, smooth muscle layer thickness, submucosa thickness and the histological evaluation of the peribronchiolar inflammation) and of the terminal bronchioles (epithelium thickness and classification) were evaluated. Mice chronically exposed to volcanogenic air pollution presented bronchioles with increased epithelial thickness, increased smooth muscle layer, increased submucosa thickness and increased peribronchiolar inflammation. Similarly, terminal bronchioles presented structural alterations consistent with bronchodysplasia. For the first time we demonstrate that chronic exposure to non-eruptive volcanically active environments causes inflammation and histomorphological alterations in mice lower airways consistent with asthma and chronic bronchitis. These results reveal that chronic exposure to non-eruptive volcanic activity represents a risk factor that can affect the health of the respiratory system of humans inhabiting hydrothermal areas.


Assuntos
Poluentes Atmosféricos/toxicidade , Poluição do Ar/análise , Testes de Toxicidade Crônica , Erupções Vulcânicas , Poluentes Atmosféricos/análise , Animais , Asma , Bronquíolos/patologia , Gases , Humanos , Inflamação , Metais , Camundongos , Material Particulado , Portugal
4.
Int J Mol Sci ; 20(11)2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31141956

RESUMO

Small airways were historically considered to be almost irrelevant in the development and control of pulmonary chronic diseases but, as a matter of fact, in the past few years we have learned that they are not so "silent". Asthma is still a worldwide health issue due to the great share of patients being far from optimal management. Several studies have shown that the deeper lung inflammation plays a critical role in asthma pathogenesis, mostly in these not well-controlled subjects. Therefore, assessing the degree of small airways inflammation and impairment appears to be a pivotal step in the asthmatic patient's management. It is now possible to evaluate them through direct and indirect measurements, even if some obstacles still affect their clinical application. The success of any treatment obviously depends on several factors but reaching the deeper lung has become a priority and, for inhaled drugs, this is strictly connected to the molecule's size. The aim of the present review is to summarize the recent evidence concerning the small airway involvement in asthma, its physiopathological characteristics and how it can be evaluated in order to undertake a personalized pharmacological treatment and achieve a better disease control.


Assuntos
Antiasmáticos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Bronquíolos/patologia , Administração por Inalação , Antiasmáticos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Asma/diagnóstico , Humanos
6.
PLoS One ; 14(1): e0204191, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30703086

RESUMO

In the airway network of a human lung, the airway diameter gradually decreases through multiple branching. The diameter reduction ratio of the conducting airways that transport gases without gas exchange is 0.79, but this reduction ratio changes to 0.94 in acinar airways beyond transitional bronchioles. While the reduction in the conducting airways was previously rationalized on the basis of Murray's law, our understanding of the design principle behind the acinar airways has been far from clear. Here we elucidate that the change in gas transfer mode is responsible for the transition in the diameter reduction ratio. The oxygen transfer rate per unit surface area is maximized at the observed geometry of acinar airways, which suggests the minimum cost for the construction and maintenance of the acinar airways. The results revitalize and extend the framework of Murray's law over an entire human lung.


Assuntos
Bronquíolos/anatomia & histologia , Modelos Biológicos , Oxigênio/metabolismo , Alvéolos Pulmonares/anatomia & histologia , Respiração , Células Acinares/fisiologia , Bronquíolos/citologia , Bronquíolos/fisiologia , Humanos , Tamanho do Órgão/fisiologia , Alvéolos Pulmonares/fisiologia
7.
J Pediatr Surg ; 54(5): 937-944, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30792093

RESUMO

PURPOSE: Tracheal occlusion (TO) reverses pulmonary hypoplasia (PH) in congenital diaphragmatic hernia (CDH), but its mechanism of action remains poorly understood. Wnt signaling plays a critical role in lung development, but few studies exist. The purpose of our study was to a) confirm that our CDH rabbit model produced PH which was reversed by TO and b) determine the effects of CDH +/- TO on Wnt signaling. METHODS: CDH was created in fetal rabbits at 23 days, TO at 28 days, and lung collection at 31 days. Lung body weight ratio (LBWR) and mean terminal bronchiole density (MTBD) were determined. mRNA and miRNA expression was determined in the left lower lobe using RT-qPCR. RESULTS: Fifteen CDH, 15 CDH + TO, 6 sham CDH, and 15 controls survived and were included in the study. LBWR was low in CDH, while CDH + TO was similar to controls (p = 0.003). MTBD was higher in CDH fetuses and restored to control levels in CDH + TO (p < 0.001). Reference genes TOP1, SDHA, and ACTB were consistently expressed within and between treatment groups. miR-33 and MKI67 were increased, and Lgl1 was decreased in CDH + TO. CONCLUSION: TO reversed pulmonary hypoplasia and stimulated early Wnt signaling in CDH fetal rabbits. TYPE OF STUDY: Basic science, prospective. LEVEL OF EVIDENCE: II.


Assuntos
Obstrução das Vias Respiratórias/metabolismo , Bronquíolos/patologia , Modelos Animais de Doenças , Hérnias Diafragmáticas Congênitas/metabolismo , Pulmão/patologia , Via de Sinalização Wnt , Obstrução das Vias Respiratórias/complicações , Animais , DNA Topoisomerases Tipo I/genética , Complexo II de Transporte de Elétrons/genética , Feto , Expressão Gênica , Glicoproteínas/genética , Hérnias Diafragmáticas Congênitas/complicações , Pulmão/embriologia , MicroRNAs/genética , Tamanho do Órgão , Cuidado Pré-Natal , Estudos Prospectivos , Coelhos , Traqueia
8.
Nat Genet ; 51(4): 728-738, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30778223

RESUMO

Characterizing the stem cells responsible for lung repair and regeneration is important for the treatment of pulmonary diseases. Recently, a unique cell population located at the bronchioalveolar-duct junctions has been proposed to comprise endogenous stem cells for lung regeneration. However, the role of bronchioalveolar stem cells (BASCs) in vivo remains debated, and the contribution of such cells to lung regeneration is not known. Here we generated a genetic lineage-tracing system that uses dual recombinases (Cre and Dre) to specifically track BASCs in vivo. Fate-mapping and clonal analysis showed that BASCs became activated and responded distinctly to different lung injuries, and differentiated into multiple cell lineages including club cells, ciliated cells, and alveolar type 1 and type 2 cells for lung regeneration. This study provides in vivo genetic evidence that BASCs are bona fide lung epithelial stem cells with deployment of multipotency and self-renewal during lung repair and regeneration.


Assuntos
Bronquíolos/fisiologia , Líquido da Lavagem Broncoalveolar/citologia , Pulmão/fisiologia , Células-Tronco Multipotentes/fisiologia , Regeneração/genética , Animais , Diferenciação Celular/genética , Linhagem da Célula/genética , Células Cultivadas , Células Epiteliais/fisiologia , Genótipo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
9.
Proc Natl Acad Sci U S A ; 116(5): 1603-1612, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30655340

RESUMO

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/fisiologia
11.
Pneumologie ; 73(2): 81-86, 2019 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-30508847

RESUMO

Pulmonary emphysema is characterised by irreversible destruction and enlargement of alveolar structure distal to terminal bronchioles. Small conducting airways < 2 mm in diameter are the major site of chronic airway inflammation and obstruction in COPD patients. 80 - 90 % 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. Although 40 % of terminal and 60 % 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 Doença
13.
Pneumologie ; 72(11): 790-796, 2018 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-30408831

RESUMO

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 1 - 23). Airways can be divided into a conducting (generations 1 - 16) and a respiratory zone (generations 17 - 23). 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 < 2 mm 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 Tratamento
14.
Sci Rep ; 8(1): 16387, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30401963

RESUMO

The atmospheric particles from different sources, and the therapeutic particles from various drug delivery devices, exhibit a complex size distribution, and the particles are mostly polydisperse. The limited available in vitro, and the wide range of in silico models have improved understanding of the relationship between monodisperse particle deposition and therapeutic aerosol transport. However, comprehensive polydisperse transport and deposition (TD) data for the terminal airways is still unavailable. Therefore, to benefit future drug therapeutics, the present numerical model illustrates detailed polydisperse particle TD in the terminal bronchioles for the first time. Euler-Lagrange approach and Rosin-Rammler diameter distribution is used for polydisperse particles. The numerical results show higher deposition efficiency (DE) in the right lung. Specifically, the larger the particle diameter (dp > 5 µm), the higher the DE at the bifurcation area of the upper airways is, whereas for the smaller particle (dp < 5 µm), the DE is higher at the bifurcation wall. The overall deposition pattern shows a different deposition hot spot for different diameter particle. These comprehensive lobe-specific polydisperse particle deposition studies will increase understanding of actual inhalation for particle TD, which could potentially increase the efficiency of pharmaceutical aerosol delivery at the targeted position of the terminal airways.


Assuntos
Vasos Sanguíneos/anatomia & histologia , Vasos Sanguíneos/metabolismo , Bronquíolos/anatomia & histologia , Bronquíolos/irrigação sanguínea , Microesferas , Ar , Transporte Biológico , Modelos Anatômicos
15.
Exp Cell Res ; 372(2): 141-149, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30268759

RESUMO

Distal airway stem cells (DASCs) in the mouse lung can differentiate into bronchioles and alveoli. However, it remains unclear whether the same stem cells exist in the human lung. Here, we found that human lung epithelial (HuL) cells, derived from normal, peripheral lung tissue, in monolayer, mostly express both the N-terminally truncated isoform of p63 (∆Np63), a marker for airway basal cells, and thyroid transcription factor-1 (TTF-1), a marker for alveolar epithelial cells, even though these two molecules are usually expressed in a mutually exclusive way. Three-dimensionally cultured HuL cells differentiated to form bronchiole-like and alveolus-like organoids. We also uncovered a few bronchiolar epithelial cells expressing both ∆Np63 and TTF-1 in the human lung, suggesting that these cells are the cells of origin for HuL cells. Taken together, ΔNp63+ TTF-1+ peripheral airway epithelial cells are possibly the human counterpart of mouse DASCs and may offer potential for future regenerative medicine.


Assuntos
Pulmão/citologia , Células-Tronco/citologia , Fator Nuclear 1 de Tireoide/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Animais , Bronquíolos/citologia , Bronquíolos/crescimento & desenvolvimento , Diferenciação Celular , Linhagem Celular , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Pulmão/crescimento & desenvolvimento , Camundongos , Alvéolos Pulmonares/citologia , Alvéolos Pulmonares/crescimento & desenvolvimento , Medicina Regenerativa , Células-Tronco/metabolismo
16.
Early Hum Dev ; 127: 58-68, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30312861

RESUMO

INTRODUCTION: Hyaluronan (HA) and the receptor for hyaluronan-mediated motility (RHAMM) may play an important role in lung development. We examined the expression of HA content and RHAMM during postnatal lung development by analyzing human lung specimens from newborn infants with a variety of lung diseases at different gestational (GA) and postnatal (PNA) ages. MATERIALS AND METHODS: Ninety-four patients were evaluated. Immunohistochemical RHAMM expression was studied with digital image analysis, followed by hierarchical cluster analysis of both these data and clinical data to define subgroups. The air content of the lung was determined by computerized analysis. HA content was estimated by radiometric assay. RESULTS: Cluster analysis defined six distinct patient groups (Group 1-2: 34-41 weeks GA; Group 3-5: 23-27 weeks GA; Group 6: mixed population). Group 1-5 showed individual patterns in RHAMM expression and HA content (Group 1: high RHAMM/low HA; Group 2: low RHAMM/low HA; Group 3: low RHAMM/low HA; Group 4: low RHAMM/high HA; Group 5: high RHAMM/high HA). HA content decreased with increasing PNA independently of GA. Negative correlation was observed between air content and RHAMM expression in the bronchiolar epithelium irrespective of clustered groups. Lung hypoplasia appeared in two distinctive groups, with significant differences in lung development and RHAMM expression. CONCLUSIONS: RHAMM expression may show dynamic changes during pathological processes in the neonatal lung. The distribution of RHAMM in the lung tissue is heterogeneous with a predominance to the bronchiolar epithelium. We found a negative correlation between lung air content and RHAMM expression in bronchiolar epithelium.


Assuntos
Bronquíolos/metabolismo , Movimento Celular/fisiologia , Proteínas da Matriz Extracelular/metabolismo , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/metabolismo , Epitélio/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Recém-Nascido , Masculino
17.
Int J Chron Obstruct Pulmon Dis ; 13: 3031-3044, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30319251

RESUMO

Background: Spirometry confers limited value for identifying small-airway disorders (SADs) in early-stage COPD, which can be detected with impulse oscillometry (IOS) and endobronchial optical coherence tomography (EB-OCT). Whether IOS is useful for reflecting small-airway morphological abnormalities in COPD remains unclear. Objectives: To compare the diagnostic value of spirometry and IOS for identifying SADs in heavy-smokers and COPD based on the objective assessment with EB-OCT. Methods: We recruited 59 COPD patients (stage I, n=17; stage II, n=18; stage III-IV, n=24), 26 heavy-smokers and 21 never-smokers. Assessments of clinical characteristics, spirometry, IOS and EB-OCT were performed. Receiver operation characteristic curve was employed to demonstrate the diagnostic value of IOS and spirometric parameters. Results: More advanced staging of COPD was associated with greater abnormality of IOS and spirometric parameters. Resonant frequency (Fres) and peripheral airway resistance (R5-R20) conferred greater diagnostic values than forced expiratory volume in one second (FEV1%) and maximal (mid-)expiratory flow (MMEF%) predicted in discriminating SADs in never-smokers from heavy-smokers (area under curve [AUC]: 0.771 and 0.753 vs 0.570 and 0.558, respectively), and heavy-smokers from patients with stage I COPD (AUC: 0.726 and 0.633 vs 0.548 and 0.567, respectively). The combination of IOS (Fres and R5-R20) and spirometric parameters (FEV1% and MMEF% predicted) contributed to a further increase in the diagnostic value for identifying SADs in early-stage COPD. Small airway wall area percentage (Aw% 7-9), an EB-OCT parameter, correlated significantly with Fres and R5-R20 in COPD and heavy-smokers, whereas EB-OCT parameters correlated with FEV1% and MMEF% in advanced, rather than early-stage, COPD. Conclusions: IOS parameters correlated with the degree of morphologic abnormalities of small airways assessed with EB-OCT in COPD and heavy-smokers. Fres and R5-R20 might be sensitive parameters that reliably reflect SADs in heavy-smokers and early-stage COPD.


Assuntos
Obstrução das Vias Respiratórias/diagnóstico por imagem , Bronquíolos/diagnóstico por imagem , Oscilometria/métodos , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Espirometria/métodos , Tomografia de Coerência Óptica/métodos , Idoso , Resistência das Vias Respiratórias/fisiologia , Área Sob a Curva , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Doença Pulmonar Obstrutiva Crônica/patologia , Curva ROC , Sensibilidade e Especificidade , Índice de Gravidade de Doença
18.
Arkh Patol ; 80(5): 63-68, 2018.
Artigo em Russo | MEDLINE | ID: mdl-30335064

RESUMO

The review of the literature deals with the participation of Clara cells now called club cells (CCs) of the epithelium in the respiratory and terminal bronchioles in the pathogenesis and morphogenesis of chronic inflammatory diseases, precancer, and cancer of the lung, which develop in the respiratory segments. The review summarizes data on the histophysiology of CCs and their participation in the pathogenesis and morphogenesis of chronic interstitial lung diseases, pneumoconiosis, chronic obstructive diseases, adenomatosis, and adenocarcinoma of the lung. In this area, there is a bronchioloalveolar junction area (BAJA), one of the most important stem cell niches. CCs are located in the BAJA; they are progenitor tissue stem cells and play an important role in the regeneration of the epithelium of the respiratory bronchioles and alveoli. Pathology of CCs in the BAJA leads to the maintenance of chronic inflammation, to the destruction of the lung elastic frame, and to impaired epithelial regeneration, interstitial fibrosis, and adenomatosis. In this case, decompensated inflammation, pathological regeneration, and fibrosis develop, which, along with the action of carcinogenic agents, can contribute to the accumulation of mutations and epigenetic rearrangements in the CCs, which subsequently results in atypical adenomatous hyperplasia and adenocarcinoma of the lung.


Assuntos
Bronquíolos , Neoplasias Pulmonares , Bronquíolos/citologia , Doença Crônica , Células Epiteliais , Humanos , Neoplasias Pulmonares/patologia
19.
Expert Rev Respir Med ; 12(11): 931-939, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30241450

RESUMO

INTRODUCTION: Acute exacerbations of chronic lung disease account for substantial morbidity and health costs. Repeated inflammatory episodes and attendant bronchoconstriction cause structural remodeling of the airway. Remodeling is a multicellular response to mucosal injury that results in epithelial cell-state changes, enhanced extracellular deposition, and expansion of pro-fibrotic myofibroblast populations. Areas covered: This manuscript overviews mechanistic studies identifying key sentinel cell populations in the airway and how pattern recognition signaling induces maladaptive mucosal changes and airway remodeling. Studies elucidating how NFκB couples with an atypical histone acetyltransferase, bromodomain-containing protein 4 (BRD4) that reprograms mucosal fibrogenic responses, are described. The approaches to development and characterization of selective inhibitors of epigenetic reprogramming on innate inflammation and structural remodeling in preclinical models are detailed. Expert commentary: Bronchiolar cells derived from Scgb1a1-expressing progenitors function as major sentinel cells of the airway, responsible for initiating antiviral and aeroallergen responses. In these sentinel cells, activation of innate inflammation is coupled to neutrophilic recruitment, mesenchymal transition and myofibroblast expansion. Therapeutics targeting the NFkB-BRD4 may be efficacious in reducing pathological effects of acute exacerbations in chronic lung disease.


Assuntos
Remodelação das Vias Aéreas/imunologia , Asma/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Imunidade Adaptativa/fisiologia , Alérgenos/imunologia , Hiper-Reatividade Brônquica/imunologia , Bronquíolos/citologia , Proteínas de Ciclo Celular , Exposição Ambiental/efeitos adversos , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal , Humanos , Imunidade Inata/fisiologia , Miofibroblastos/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Receptores de Reconhecimento de Padrão/metabolismo , Mucosa Respiratória/imunologia , Receptores Toll-Like/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Viroses/imunologia
20.
Lancet Respir Med ; 6(8): 591-602, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30072106

RESUMO

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 X
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