Abstract:
:Rationale: The bHLH (basic helix-loop-helix) transcription factor TWIST1 (Twist-related protein 1) controls cell proliferation and differentiation in tissue development and disease processes. Recently, endothelial TWIST1 has been linked to pulmonary hypertension (PH) and endothelial-to-mesenchymal transition, yet the role of TWIST1 in smooth muscle cells (SMCs) remains so far unclear.Objectives: To define the role of TWIST1 in SMCs in the pathogenesis of PH.Methods: SMC-specific TWIST1-deficient mice, SMC-specific TWIST1 silencing in rats, mass spectrometry, immunoprecipitation, and chromatin immunoprecipitation were used to delineate the role of SMC TWIST1 in PH.Measurements and Main Results: In pulmonary vessels from patients with PH and rodent PH models, TWIST1 expression was markedly increased and predominantly localized to SMCs. SMC-specific TWIST1 deficiency or silencing attenuated the development of PH and distal vessel muscularization in chronically hypoxic mice and in monocrotaline-treated rats. In vitro, TWIST1 inhibition or silencing prevented pulmonary artery SMC proliferation and migration. Mechanistically, the observed effects were mediated, at least in part, by TWIST1-dependent degradation of GATA-6 (GATA-binding protein 6). BMPR2 (bone morphogenetic protein receptor-2) was identified as a novel downstream target of GATA-6, which directly binds to its promoter. Inhibition of TWIST1 promoted the recruitment of GATA-6 to the BMPR2 promoter and restored BMPR2 functional expression.Conclusions: Our findings identify a key role for SMC TWIST1 in the pathogenesis of lung vascular remodeling and in PH that is partially mediated via reduced GATA-6-dependent BMPR2 expression. Inhibition of SMC TWIST1 may constitute a new therapeutic strategy for the treatment of PH.
journal_name
Am J Respir Crit Care Medauthors
Fan Y,Gu X,Zhang J,Sinn K,Klepetko W,Wu N,Foris V,Solymosi P,Kwapiszewska G,Kuebler WMdoi
10.1164/rccm.201909-1884OCsubject
Has Abstractpub_date
2020-11-01 00:00:00pages
1283-1296issue
9eissn
1073-449Xissn
1535-4970journal_volume
202pub_type
杂志文章abstract::The upper airway undergoes progressive changes during childhood. Using magnetic resonance imaging (MRI), we studied the growth relationships of the tissues surrounding the upper airway (bone and soft tissues) in 92 normal children (47% males; range, 1 to 11 yr) who underwent brain MRI. None had symptoms of sleep-disor...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
doi:10.1164/ajrccm.165.1.2107140
更新日期:2002-01-01 00:00:00
abstract:RATIONALE:Comorbidities contribute to disease severity and mortality in patients with chronic obstructive pulmonary disease (COPD). Comorbidities have been studied individually and were mostly based on self-reports. The coexistence of objectively identified comorbidities and the role of low-grade systemic inflammation ...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
doi:10.1164/rccm.201209-1665OC
更新日期:2013-04-01 00:00:00
abstract::In anaphylactic shock (AS), the relative effects of the autacoids including histamine, prostaglandins, and leukotrienes on causing cardiovascular collapse and the extent to which receptor blocking agents and pathway inhibitors may prevent this collapse are not clear. In a ragweed model of anaphylaxis, we examined whet...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
doi:10.1164/ajrccm.160.4.9901021
更新日期:1999-10-01 00:00:00
abstract::The place of surgical treatment in obstructive sleep apnea syndrome (OSAS) remains unclear. Uvulopalatopharyngoplasty (UPPP) has a response rate of 41% overall and only 5% when retrolingual narrowing is present. Thus, in cases with suspected hypopharyngeal collapse maxillofacial surgery has been proposed with improved...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
doi:10.1164/ajrccm.162.2.9904058
更新日期:2000-08-01 00:00:00
abstract:RATIONALE:The effect of early life wheezing on respiratory function and continued symptoms through adolescence has not been fully described. Using data from a population-based birth cohort in Tucson, Arizona, we previously described four phenotypes based on the occurrence of wheezing lower respiratory illnesses before ...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
doi:10.1164/rccm.200504-525OC
更新日期:2005-11-15 00:00:00
abstract::Although all the well-recognized muscles of expiration are paralyzed after traumatic transection of the lower cervical cord, tetraplegic subjects can still empty their lungs actively by contracting the clavicular portion of the pectoralis major. It is not known, however, whether contraction of this muscle bundle may r...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
doi:10.1164/ajrccm.150.4.7921440
更新日期:1994-10-01 00:00:00
abstract::This study aimed to estimate exposure-response relationships for mesothelioma and environmental exposure to crocidolite. All 4,659 former residents of Wittenoom, Western Australia (WA) who lived there between 1943 and 1993 for at least 1 mo and were not directly employed in the crocidolite industry, were followed-up t...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
doi:10.1164/ajrccm.157.1.96-11086
更新日期:1998-01-01 00:00:00
abstract::Patients in whom acid-fast bacilli smear-positive pulmonary tuberculosis was newly diagnosed were randomized to receive 400 mg moxifloxacin, 300 mg isonaizid, or 600 mg rifampin daily for 5 days. Sixteen-hour overnight sputa collections were made for the 2 days before and for 5 days of monotherapy. Bactericidal activi...
journal_title:American journal of respiratory and critical care medicine
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1164/rccm.200305-682OC
更新日期:2003-12-01 00:00:00
abstract::The use of noninvasive methods of monitoring airway inflammation, such as exhaled nitric oxide (eNO) and induced sputum, has been shown to improve asthma monitoring and optimize treatment in adult patients with asthma. There is a lack of comparable data in children. Forty children with stable asthma eligible for inhal...
journal_title:American journal of respiratory and critical care medicine
pub_type: 临床试验,杂志文章
doi:10.1164/rccm.200409-1242OC
更新日期:2005-05-15 00:00:00
abstract:RATIONALE:A loss of function mutation in the cystic fibrosis transmembrane conductance regulator gene is believed to be an independent risk factor for bone disease in patients with cystic fibrosis. OBJECTIVES:The objective of this work was to use congenic mice as a preclinical model to examine the bone phenotype of Cf...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
doi:10.1164/rccm.200705-659OC
更新日期:2008-02-01 00:00:00
abstract:RATIONALE:Tezacaftor (formerly VX-661) is an investigational small molecule that improves processing and trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR) in vitro, and improves CFTR function alone and in combination with ivacaftor. OBJECTIVES:To evaluate the safety and efficacy of tezacaft...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1164/rccm.201704-0717OC
更新日期:2018-01-15 00:00:00
abstract:RATIONALE:Numerous studies have been published on the new Mycobacterium tuberculosis (MTB)-specific IFN-gamma release assays. However, their prognostic value for progression from latent tuberculosis infection (LTBI) to active TB has yet to be established. OBJECTIVES:To compare the QuantiFERON-TB Gold In-Tube assay (QF...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
doi:10.1164/rccm.200711-1613OC
更新日期:2008-05-15 00:00:00
abstract::There is intriguing evidence suggesting pathophysiologic relationships among dyspnea, hyperventilation, and panic anxiety. The symptoms of panic attacks and pulmonary disease overlap, so that panic anxiety can reflect underlying cardiopulmonary disease and dyspnea can reflect an underlying anxiety disorder. The pathog...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章,评审
doi:10.1164/ajrccm.154.1.8680700
更新日期:1996-07-01 00:00:00
abstract:RATIONALE:The allergen inhalation challenge is used in clinical trials to test the efficacy of new treatments in attenuating the late-phase asthmatic response (LAR) and associated airway inflammation in subjects with allergic asthma. However, not all subjects with allergic asthma develop the LAR after allergen inhalati...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
doi:10.1164/rccm.201701-0110OC
更新日期:2018-02-15 00:00:00
abstract::This study aimed to compare O2 consumption (VO2) determination by the gas-exchange (VO2GE) and Fick (VO2F) methods in cardiac surgical patients. A total of 10 mechanically ventilated postoperative patients were studied prospectively. Thermodilution was performed using three randomly applied techniques: room temperatur...
journal_title:American journal of respiratory and critical care medicine
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1164/ajrccm.149.5.8173750
更新日期:1994-05-01 00:00:00
abstract::Noninvasive and invasive diagnostic techniques have been shown to achieve comparable performances in the evaluation of suspected ventilator-associated pneumonia (VAP). We studied the impact of both approaches on outcome in a prospective, open, and randomized study in three intensive care units (ICUs) of a 1,000-bed te...
journal_title:American journal of respiratory and critical care medicine
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1164/ajrccm.162.1.9907090
更新日期:2000-07-01 00:00:00
abstract::We examined the influence of gender on the polysomnographic features of obstructive sleep apnea (OSA) in a retrospective study of 830 patients with OSA diagnosed by overnight polysomnography (PSG). The severity of OSA was determined from the apnea- hypopnea index (AHI) for total sleep time (AHI(TST)), and was classifi...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
doi:10.1164/ajrccm.161.5.9904121
更新日期:2000-05-01 00:00:00
abstract::The long-acting beta 2-agonist salmeterol has been suggested to have other pharmacologic activities, that is, antiinflammatory capacities, in addition to its bronchodilator properties. We investigated the protective effect of 50 micrograms salmeterol in a placebo-controlled study on house dust mite-induced early- and ...
journal_title:American journal of respiratory and critical care medicine
pub_type: 临床试验,杂志文章
doi:10.1164/ajrccm.150.5.7952550
更新日期:1994-11-01 00:00:00
abstract:RATIONALE:Poor adherence is common in difficult-to-control asthma. Distinguishing patients with difficult-to-control asthma who respond to inhaled corticosteroids (ICS) from refractory asthma is an important clinical challenge. OBJECTIVES:Suppression of fractional exhaled nitric oxide (FeNO) with directly observed ICS...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
doi:10.1164/rccm.201806-1182OC
更新日期:2019-02-15 00:00:00
abstract::Allergen inhalation causes airway hyperresponsiveness and airway inflammation in dogs. The purpose of this study was to determine whether allergen-induced airway hyperresponsiveness is associated with increases in oxygen radical production from bronchoalveolar lavage (BAL) cells. A group of 10 random-source dogs were ...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
doi:10.1164/ajrccm.151.5.7735610
更新日期:1995-05-01 00:00:00
abstract::Mechanical ventilation may promote overdistension-induced pulmonary lesions in patients with acute respiratory distress syndrome (ARDS). The static pressure-volume (P-V) curve of the respiratory system can be used to determine the lung volume and corresponding static airway pressure at which lung compliance begins to ...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
doi:10.1164/ajrccm.152.1.7599810
更新日期:1995-07-01 00:00:00
abstract::Genes for the chemokine receptors CCR5 and CCR2 are characterized by polymorphisms resulting in a nonfunctional receptor expression. Ligands for CCR2 and CCR5 (chemokines monocyte chemotactic protein-1 [MCP-1] and RANTES) are implicated in the pathogenesis of sarcoidosis. We have, therefore, analyzed polymorphisms of ...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
doi:10.1164/ajrccm.162.3.2001022
更新日期:2000-09-01 00:00:00
abstract:KEYWORDS:Children as young as 6 years old can perform spirometry, yet the relationship between current asthma, lung function, and bronchial responsiveness has not been described at this age; 2,537 children from a community-based birth cohort were assessed at 6 years of age, with history (n = 2,141), physical examinatio...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
doi:10.1164/rccm.200304-556OC
更新日期:2004-04-01 00:00:00
abstract:RATIONALE:Low blood levels of 25-hydroxyvitamin D (25[OH]D) have been associated with a higher risk of respiratory infections in general populations and higher risk of exacerbations of lung disease in people with asthma. We hypothesized that low blood levels of 25(OH)D in patients with chronic obstructive pulmonary dis...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章,随机对照试验
doi:10.1164/rccm.201109-1644OC
更新日期:2012-02-01 00:00:00
abstract::We prospectively investigated the lower airway response in boilermakers overhauling an oil-powered boiler. We studied 26 male boilermakers with a mean age (SD) of 43.3 (8.6) yr. Pre-exposure spirometry and methacholine challenge tests were performed before beginning the boiler overhaul; postexposure tests were perform...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
doi:10.1164/ajrccm.152.5.7582280
更新日期:1995-11-01 00:00:00
abstract::Infection of the cystic fibrosis (CF) airways elicits an exaggerated, interleukin-8 (IL-8) mediated, neutrophil inflammatory response. Necrosing neutrophils release DNA and actin into the airways, increasing the viscoelasticity of airway secretions. Mucolytics aim to improve airway clearance by reducing this viscoelas...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
doi:10.1164/ajrccm.162.5.9908107
更新日期:2000-11-01 00:00:00
abstract::The last century experienced remarkable advances in the classification, diagnosis, and understanding of the pathogenesis of the interstitial lung diseases. Technological advances, particularly physiologic testing, lung imaging studies, bronchoalveolar lavage, surgical lung biopsy, and histopathologic assessment, impro...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章,评审
doi:10.1164/rccm.200503-483OE
更新日期:2005-08-01 00:00:00
abstract::To investigate whether the language of dyspnea provides relevant clinical information in addition to that provided by ratings of overall dyspnea intensity when assessing subjective response to therapy, we conducted a prospective study in a cohort of 25 patients with acute asthma presenting to the emergency department ...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
doi:10.1164/ajrccm.158.3.9707088
更新日期:1998-09-01 00:00:00
abstract:RATIONALE:Severe asthma (SA) remains poorly understood. Mast cells (MC) are implicated in asthma pathogenesis, but it remains unknown how their phenotype, location, and activation relate to asthma severity. OBJECTIVES:To compare MC-related markers measured in bronchoscopically obtained samples with clinically relevant...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
doi:10.1164/rccm.201002-0295OC
更新日期:2011-02-01 00:00:00
abstract::The present study was undertaken to determine if a synthetic peptide, KLLLLKLLLLKLLLLKLLLLK (KL4), in which K = lysine and L = leucine, in an aqueous dispersion of phospholipids (DPPC and POPG), would expand pulmonary alveoli and improve gas exchange in premature human infants with respiratory distress syndrome (RDS)....
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
doi:10.1164/ajrccm.153.1.8542150
更新日期:1996-01-01 00:00:00