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1.
J Int Med Res ; 48(7): 300060520939746, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32722979

RESUMO

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 , 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 , Cicatrização/fisiologia
2.
PLoS One ; 15(5): e0226233, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32379832

RESUMO

Allergic asthma is the most common phenotype of the pathology, having an early-onset in childhood and producing a Th2-driven airways remodeling process that leads to symptoms and pathophysiological changes. The avoidance of aeroallergen exposure in early life has been shown to prevent asthma, but without repeated success and with the underlying preventive mechanisms at the beginning of asthma far to be fully recognized. In the present study, we aimed to evaluate if neonatal LPS-induced boost in epithelial host defenses contribute to prevent OVA-induced asthma in adult mice. To this, we focused on the response of bronchiolar club cells (CC), which are highly specialized in maintaining the epithelial homeostasis in the lung. In these cells, neonatal LPS administration increased the expression of TLR4 and TNFα, as well as the immunodulatory/antiallergic proteins: club cell secretory protein (CCSP) and surfactant protein D (SP-D). LPS also prevented mucous metaplasia of club cells and reduced the epidermal growth factor receptor (EGFR)-dependent mucin overproduction, with mice displaying normal breathing patterns after OVA challenge. Furthermore, the overexpression of the epithelial Th2-related molecule TSLP was blunted, and normal TSLP and IL-4 levels were found in the bronchoalveolar lavage. A lower eosinophilia was detected in LPS-pretreated mice, along with an increase in phagocytes and regulatory cells (CD4+CD25+FOXP3+ and CD4+IL-10+), together with higher levels of IL-12 and TNFα. In conclusion, our study demonstrates stable asthma-preventive epithelial effects promoted by neonatal LPS stimulation, leading to the presence of regulatory cells in the lung. These anti-allergic dynamic mechanisms would be overlaid in the epithelium, favored by an adequate epidemiological environment, during the development of asthma.


Assuntos
Asma/imunologia , Bronquíolos/efeitos dos fármacos , Bronquíolos/imunologia , Citocinas/metabolismo , Epitélio/imunologia , Imunidade Inata , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Alérgenos/imunologia , Animais , Animais Recém-Nascidos , Asma/prevenção & controle , Modelos Animais de Doenças , Epitélio/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Ovalbumina/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia
4.
Cell Stem Cell ; 26(3): 295-296, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32142655

RESUMO

The landscape of lung epithelial stem cells is getting more nuanced. In this issue of Cell Stem Cell, Kathiriya et al. (2020) describe a novel distal airway epithelial cell population with high regenerative potential.


Assuntos
Células Epiteliais , Células-Tronco , Bronquíolos , Diferenciação Celular , Pulmão
5.
Lancet Respir Med ; 8(6): 573-584, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32061334

RESUMO

BACKGROUND: The observation that patients with idiopathic pulmonary fibrosis (IPF) can have higher than normal expiratory flow rates at low lung volumes led to the conclusion that the airways are spared in IPF. This study aimed to re-examine the hypothesis that airways are spared in IPF using a multiresolution imaging protocol that combines multidetector CT (MDCT), with micro-CT and histology. METHODS: This was a retrospective cohort study comparing explanted lungs from patients with severe IPF treated by lung transplantation with a cohort of unused donor (control) lungs. The donor control lungs had no known lung disease, comorbidities, or structural lung injury, and were deemed appropriate for transplantation on review of the clinical files. The diagnosis of IPF in the lungs from patients was established by a multidisciplinary consensus committee according to existing guidelines, and was confirmed by video-assisted thoracic surgical biopsy or by pathological examination of the contralateral lung. The control and IPF groups were matched for age, sex, height, and bodyweight. Samples of lung tissue were compared using the multiresolution imaging approach: a cascade of clinical MDCT, micro-CT, and histological imaging. We did two experiments: in experiment 1, all the lungs were randomly sampled; in experiment 2, samples were selected from regions of minimal and established fibrosis. The patients and donors were recruited from the Katholieke Universiteit Leuven (Leuven, Belgium) and the University of Pennsylvania Hospital (Philadelphia, PA, USA). The study took place at the Katholieke Universiteit Leuven, and the University of British Columbia (Vancouver, BC, Canada). FINDINGS: Between Oct 5, 2009, and July 22, 2016, explanted lungs from patients with severe IPF (n=11), were compared with a cohort of unused donor (control) lungs (n=10), providing 240 samples of lung tissue for comparison using the multiresolution imaging approach. The MDCT specimen scans show that the number of visible airways located between the ninth generation (control 69 [SD 22] versus patients with IPF 105 [33], p=0·0023) and 14th generation (control 9 [6] versus patients with IPF 49 [28], p<0·0001) of airway branching are increased in patients with IPF, which we show by micro-CT is due to thickening of their walls and distortion of their lumens. The micro-CT analysis showed that compared with healthy (control) lung anatomy (mean 5·6 terminal bronchioles per mL [SD 1·6]), minimal fibrosis in IPF tissue was associated with a 57% loss of the terminal bronchioles (mean 2·4 terminal bronchioles per mL [SD 1·0]; p<0·0001), the appearance of fibroblastic foci, and infiltration of the tissue by inflammatory immune cells capable of forming lymphoid follicles. Established fibrosis in IPF tissue had a similar reduction (66%) in the number of terminal bronchioles (mean 1·9 terminal bronchioles per mL [SD 1·4]; p<0·0001) and was dominated by increased airspace size, Ashcroft fibrosis score, and volume fractions of tissue and collagen. INTERPRETATION: Small airways disease is a feature of IPF, with significant loss of terminal bronchioles occuring within regions of minimal fibrosis. On the basis of these findings, we postulate that the small airways could become a potential therapeutic target in IPF. FUNDING: Katholieke Universiteit Leuven, US National Institutes of Health, BC Lung Association, and Genentech.


Assuntos
Fibrose Pulmonar Idiopática/patologia , Bronquíolos/diagnóstico por imagem , Bronquíolos/patologia , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Fibrose Pulmonar Idiopática/cirurgia , Pulmão/diagnóstico por imagem , Pulmão/patologia , Transplante de Pulmão , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada Multidetectores , Imagem Multimodal , Estudos Retrospectivos , Microtomografia por Raio-X
7.
Respir Res ; 20(1): 269, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31791337

RESUMO

Impaired single breath carbon monoxide diffusing capacity (DLCO) is associated with emphysema. Small airways disease (SAD) may be a precursor lesion to emphysema, but the relationship between SAD and DLCO is undescribed. We hypothesized that in mild COPD, functional SAD (fSAD) defined by computed tomography (CT) and Parametric Response Mapping methodology would correlate with impaired DLCO. Using data from ever-smokers in the COPDGene cohort, we established that fSAD correlated significantly with lower DLCO among both non-obstructed and GOLD 1-2 subjects. The relationship between DLCO with CT-defined emphysema was present in all GOLD stages, but most prominent in severe disease. TRIAL REGISTRATION: NCT00608764. Registry: COPDGene. Registered 06 February 2008, retrospectively registered.


Assuntos
Obstrução das Vias Respiratórias/diagnóstico por imagem , Bronquíolos/patologia , Doença Pulmonar Obstrutiva Crônica/genética , Enfisema Pulmonar/genética , Idoso , Obstrução das Vias Respiratórias/patologia , Remodelação das Vias Aéreas/fisiologia , Bronquíolos/anormalidades , Monóxido de Carbono/metabolismo , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Capacidade de Difusão Pulmonar , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Enfisema Pulmonar/diagnóstico por imagem , Análise de Regressão , Testes de Função Respiratória , Estudos Retrospectivos , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X/métodos
8.
PLoS One ; 14(9): e0221899, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31513609

RESUMO

INTRODUCTION: Genome-Wide Association Studies suggest glutathione S transferase C terminal domain (GSTCD) may play a role in development of Chronic Obstructive Pulmonary Disease. We aimed to define the potential role of GSTCD in airway inflammation and contraction using precision cut lung slice (PCLS) from wild-type (GSTCD+/+) and GSTCD knockout mice (GSTCD-/-). METHODS: PCLS from age and gender matched GSTCD+/+ and GSTCD-/- mice were prepared using a microtome. Contraction was studied after applying either a single dose of Methacholine (Mch) (1 µM) or different doses of Mch (0.001 to 100 µM). Each slice was then treated with lipopolysaccharide (LPS) or vehicle (PBS) for 24 hours. PCLS contraction in the same airway was repeated before and after stimulation. Levels of TNFα production was also measured. RESULTS: There were no differences in contraction of PCLS from GSTCD+/+ and GSTCD-/- mice in response to Mch (EC50 of GSTCD+/+ vs GSTCD-/- animals: 100.0±20.7 vs 107.7±24.5 nM, p = 0.855, n = 6 animals/group). However, after LPS treatment, there was a 31.6% reduction in contraction in the GSTCD-/- group (p = 0.023, n = 6 animals). There was no significant difference between PBS and LPS treatment groups in GSTCD+/+ animals. We observed a significant increase in TNFα production induced by LPS in GSTCD-/- lung slices compared to the GSTCD+/+ LPS treated slices. CONCLUSION: GSTCD knockout mice showed an increased responsiveness to LPS (as determined by TNFα production) that was accompanied by a reduced contraction of small airways in PCLS. These data highlight an unrecognised potential function of GSTCD in mediating inflammatory signals that affect airway responses.


Assuntos
Bronquíolos/fisiologia , Glutationa Transferase/genética , Lipopolissacarídeos/efeitos adversos , Cloreto de Metacolina/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Bronquíolos/efeitos dos fármacos , Bronquíolos/imunologia , Modelos Animais de Doenças , Feminino , Técnicas de Inativação de Genes , Masculino , Camundongos , Contração Muscular/efeitos dos fármacos , Regulação para Cima
9.
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
10.
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
11.
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
12.
Am J Physiol Lung Cell Mol Physiol ; 317(2): L259-L270, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31116580

RESUMO

Epithelial cells that line lung airways produce and secrete proteins with important roles in barrier function and host defense. Secretion of airway goblet cells is controlled by autophagy proteins during inflammatory conditions, resulting in accumulation of mucin proteins. We hypothesized that autophagy proteins would also be important in the function of club cells, dominant secretory airway epithelial cells that are dysregulated in chronic lung disease. We found that in the absence of an inflammatory stimulus, mice with club cells deficient for the autophagy protein Atg5 had a markedly diminished expression of secreted host defense proteins secretoglobulin family 1A, member 1 (Scgb1a1) and surfactant proteins A1 and D (Sftpa1 and Sftpd), as well as abnormal club cell morphology. Adult mice with targeted loss of Atg5 also showed diminished levels of host defense proteins in regenerating cells following ablation with naphthalene. A mouse strain with global deficiency of Atg16-like 1 (Atg16l1), an Atg5 binding partner, had a similar loss of host defense proteins and abnormal club cell morphology. Cigarette smoke exposure reduced levels of Scgb1a1 in wild-type mice as expected. Smoke exposure was not required to trigger club cell abnormalities in mice bearing the human ATG16 variant Atg16l1T300A/T300A, which had low Scgb1a1 levels independent of this environmental stress. Evaluation of lung tissues from former smokers with severe chronic obstructive pulmonary disease showed evidence of reduced autophagy and SCGB1A1 expression in club cells. Thus, autophagy proteins are required for the function of club cells, independent of the cellular stress of cigarette smoke, with roles that appear to be distinct from those of other secretory cell types.


Assuntos
Autofagia/fisiologia , Células Epiteliais/metabolismo , Células Caliciformes/metabolismo , Pulmão/metabolismo , Animais , Bronquíolos/metabolismo , Feminino , Humanos , Masculino , Camundongos Transgênicos , Doença Pulmonar Obstrutiva Crônica/metabolismo , Proteína A Associada a Surfactante Pulmonar/metabolismo , Mucosa Respiratória/metabolismo
13.
Am J Physiol Lung Cell Mol Physiol ; 316(5): L953-L960, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30838869

RESUMO

Although small airways account for the largest fraction of the total conducting airway surfaces, the epithelial fluid and electrolyte transport in small, native airway epithelia has not been well characterized. Investigations have been limited, no doubt, by the complex tissue architecture as well as by its inaccessibility, small dimensions, and lack of applicable assays, especially in human tissues. To better understand how the critically thin layer of airway surface liquid (ASL) is maintained, we applied a "capillary"-Ussing chamber (area ≈1 mm2) to measure ion transport properties of bronchioles with diameters of ~2 mm isolated from resected specimens of excised human lungs. We found that the small human airway, constitutively and concurrently, secretes and absorbs fluid as observed in porcine small airways (50). We found that the human bronchiolar epithelium is also highly anion selective and constitutively secretes bicarbonate ( HCO3- ), which can be enhanced pharmacologically by cAMP as well as Ca2+-mediated agonists. Concurrent secretion and absorption of surface liquid along with HCO3- secretion help explain how the delicate volume of the fluid lining the human small airway is physiologically buffered and maintained in a steady state that avoids desiccating or flooding the small airway with ASL.


Assuntos
Bicarbonatos/metabolismo , Bronquíolos/metabolismo , Líquido Extracelular/metabolismo , Mucosa Respiratória/metabolismo , Animais , Humanos , Transporte de Íons , Suínos
14.
Histol Histopathol ; 34(11): 1217-1227, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30848476

RESUMO

A normal counterpart and precancerous lesion that non-terminal respiratory unit (TRU) lung adenocarcinomas (LADCs) develop from have not been clarified. Non-TRU LADCs specifically express hepatocyte nuclear factor 4α (HNF4α). Thus, we have been interested in airway epithelial cells that express HNF4α as the potential precursor of non-TRU LADC. The purposes of the present study are to report the frequency and distribution of HNF4α-expressing cells at the different airway levels, and to investigate the potential significance of the expression of HNF4α in the histogenesis of non-TRU LADC with a special reference to the relationship to bronchiolar metaplasia in idiopathic interstitial pneumonia. We herein identified a minor subpopulation of epithelial cells that express HNF4α in a physiological state. This subpopulation was mainly located in the terminal bronchioles and had the appearance of ciliated cells, which were mutually exclusive from Clara cells and others that strongly expressed thyroid transcription factor 1. Furthermore, the expression of HNF4α was similar in bronchiolar metaplastic lesions and the terminal bronchioles, and some of the metaplastic lesions showed an unequivocally higher frequency and expression level of HNF4α, which was comparable to non-TRU LADC. In summary, this is the first study to describe a subpopulation of ciliated cells that express HNF4α as a potential normal counterpart for non-TRU LADCs and suggests that bronchiolar metaplastic lesions that strongly express HNF4α are a precancerous lesion for non-TRU LADCs.


Assuntos
Adenocarcinoma de Pulmão/etiologia , Células Epiteliais/metabolismo , Fatores Nucleares de Hepatócito , Neoplasias Pulmonares/etiologia , Lesões Pré-Cancerosas/metabolismo , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Bronquíolos/citologia , Bronquíolos/metabolismo , Bronquíolos/patologia , Células Epiteliais/citologia , Fatores Nucleares de Hepatócito/metabolismo , Humanos , Pneumonias Intersticiais Idiopáticas/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Metaplasia/metabolismo , Metaplasia/patologia , Sistema Respiratório/citologia , Sistema Respiratório/metabolismo , Sistema Respiratório/patologia , Fator Nuclear 1 de Tireoide/metabolismo
15.
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
16.
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
18.
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
19.
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
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