Abstract:
BACKGROUND:Several small molecule corrector and potentiator drugs have recently been licensed for Cystic Fibrosis (CF) therapy. However, other aspects of the disease, especially inflammation, are less effectively treated by these drugs. We hypothesized that small molecule drugs could function either alone or as an adjuvant to licensed therapies to treat these aspects of the disease, perhaps emulating the effects of gene therapy in CF cells. The cardiac glycoside digitoxin, which has been shown to inhibit TNFα/NFκB signaling in CF lung epithelial cells, may serve as such a therapy. METHODS:IB3-1 CF lung epithelial cells were treated with different Vertex (VX) drugs, digitoxin, and various drug mixtures, and ELISA assays were used to assess suppression of baseline and TNFα-activated secretion of cytokines and chemokines. Transcriptional responses to these drugs were assessed by RNA-seq and compared with gene expression in AAV-[wildtype]CFTR-treated IB3-1 (S9) cells. We also compared in vitro gene expression signatures with in vivo data from biopsied nasal epithelial cells from digitoxin-treated CF patients. RESULTS:CF cells exposed to digitoxin exhibited significant suppression of both TNFα/NFκB signaling and downstream secretion of IL-8, IL-6 and GM-CSF, with or without co-treatment with VX drugs. No evidence of drug-drug interference was observed. RNA-seq analysis showed that gene therapy-treated CF lung cells induced changes in 3134 genes. Among these, 32.6% were altered by digitoxin treatment in the same direction. Shared functional gene ontology themes for genes suppressed by both digitoxin and gene therapy included inflammation (84 gene signature), and cell-cell interactions and fibrosis (49 gene signature), while genes elevated by both were enriched for epithelial differentiation (82 gene signature). A new analysis of mRNA data from digitoxin-treated CF patients showed consistent trends in expression for genes in these signatures. CONCLUSIONS:Adjuvant gene therapy-emulating activities of digitoxin may contribute to enhancing the efficacy of currently licensed correctors and potentiators in CF patients.
journal_name
Respir Resjournal_title
Respiratory researchauthors
Yang Q,Soltis AR,Sukumar G,Zhang X,Caohuy H,Freedy J,Dalgard CL,Wilkerson MD,Pollard HB,Pollard BSdoi
10.1186/s12931-019-1214-8subject
Has Abstractpub_date
2019-12-21 00:00:00pages
290issue
1eissn
1465-9921issn
1465-993Xpii
10.1186/s12931-019-1214-8journal_volume
20pub_type
杂志文章abstract:BACKGROUND:We have recently reported that protein phosphate 2A (PP2A) inactivation resulted in increased phosphorylation of the mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase 1 (JNK1) and glucocorticoid receptors (GR) at Ser(226), thereby reducing GR nuclear translocation and causing corticosteroid ins...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/s12931-016-0349-0
更新日期:2016-03-24 00:00:00
abstract:BACKGROUND:Although a large body of literature is available that describes the effects of smoking, asthma and COPD on lung function, most studies are restricted to a small age range and to one factor. As a consequence, available results are incomplete and often difficult to compare, also due to the ways the effects are...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/1465-9921-14-60
更新日期:2013-05-30 00:00:00
abstract:BACKGROUND:Generalized hypoxic pulmonary vasoconstriction (HPV) occurring during exposure to hypoxia is a detrimental process resulting in an increase in lung vascular resistance. Nebulization of sodium nitrite has been shown to inhibit HPV. The aim of this project was to investigate and compare the effects of nebuliza...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/1465-9921-11-81
更新日期:2010-06-21 00:00:00
abstract:BACKGROUND:Possible variation in bronchodilator response (BDR) according to age at the diagnosis of adult-onset asthma is unknown. Our aim was to assess if BDR in FEV1 is related to age at diagnosis of adult-onset asthma and how many subjects fulfill the 400 mL criterion of BDR, the suggested cut-off for asthma-like re...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/s12931-020-01441-w
更新日期:2020-07-13 00:00:00
abstract:BACKGROUND:Early life impairments leading to lower lung function by adulthood are considered as risk factors for chronic obstructive pulmonary disease (COPD). Recently, we compared the lung transcriptomic profile between two mouse strains with extreme total lung capacities to identify plausible pulmonary function deter...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/s12931-018-0795-y
更新日期:2018-06-06 00:00:00
abstract:BACKGROUND:Systemic sclerosis (SSc) is a rare connective tissue disease with a heterogeneous clinical course. Interstitial lung disease (ILD) is a common manifestation of SSc and a leading cause of death. MAIN BODY:All patients newly diagnosed with SSc should receive a comprehensive clinical evaluation, including asse...
journal_title:Respiratory research
pub_type: 杂志文章,评审
doi:10.1186/s12931-019-0980-7
更新日期:2019-01-18 00:00:00
abstract:BACKGROUND:Chronic respiratory diseases (CRDs) are leading causes of morbidity worldwide. However, the spatial and temporal trends in prevalence and incidence of CRDs have not been estimated. METHODS:Based on data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2017, we analyzed the prevalence and...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/s12931-020-1291-8
更新日期:2020-02-11 00:00:00
abstract:BACKGROUND:Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation (HSCT) is currently treated with systemic corticosteroids despite poor efficacy and side effects. This study investigated the therapeutic effect of budesonide/formoterol, montelukast and n-acetylcysteine, which a...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/s12931-016-0380-1
更新日期:2016-05-26 00:00:00
abstract::The airway epithelium forms a barrier against infection but also produces antimicrobial peptides (AMPs) and other inflammatory mediators to activate the immune system. It has been shown that in allergic disorders, Th2 cytokines may hamper the antimicrobial activity of the epithelium. However, the presence of Th2 cytok...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/1465-9921-12-59
更新日期:2011-05-02 00:00:00
abstract:BACKGROUND:Acute respiratory failure (ARF) and severe sepsis (SS) are possible complications in patients with community-acquired pneumonia (CAP). The aim of the study was to evaluate prevalence, characteristics, risk factors and impact on mortality of hospitalized patients with CAP according to the presence of ARF and ...
journal_title:Respiratory research
pub_type: 杂志文章,多中心研究
doi:10.1186/1465-9921-15-27
更新日期:2014-03-04 00:00:00
abstract::The interaction between viruses and dendritic cells (DCs) is varied and complex. DCs are key elements in the development of a host response to pathogens such as viruses, but viruses have developed survival tactics to either evade or diminish the immune system that functions to kill and eliminate these micro-organisms....
journal_title:Respiratory research
pub_type: 杂志文章,评审
doi:10.1186/rr63
更新日期:2001-01-01 00:00:00
abstract:BACKGROUND:Mutations in the DNAI1 gene, encoding a component of outer dynein arms of the ciliary apparatus, are the second most important genetic cause of primary ciliary dyskinesia (PCD), the genetically heterogeneous recessive disorder with the prevalence of ~1/20,000. The estimates of the DNAI1 involvement in PCD pa...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/1465-9921-11-174
更新日期:2010-12-08 00:00:00
abstract:BACKGROUND:Generally, structural destruction of lung parenchyma, such as pulmonary emphysema, is considered to be related to the low diagnostic yields and high complication rates of lung biopsies of peripheral lung lesions. Currently, little is known about the clinical outcomes of using endobronchial ultrasound with a ...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/s12931-019-1149-0
更新日期:2019-08-06 00:00:00
abstract:BACKGROUND:Obstructive sleep apnoea (OSA) and morbid obesity (MO), defined by a body mass index ≥35 kg/m2, are two closely related conditions. Recent studies suggest that circulating microRNA (miRNA) plays a potential role in the physiopathology of both conditions. To date, circulating miRNA expression has been studied...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/s12931-020-1302-9
更新日期:2020-02-04 00:00:00
abstract:BACKGROUND:The investigation of mesenchymal stromal cell (MSC)-conditioned medium or extracellular vesicles (exosomes or microvesicles) as a remedy for acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) has become a fast-growing field in recent years. Our purpose was to conduct a meta-analysis to inv...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/s12931-020-01574-y
更新日期:2020-11-20 00:00:00
abstract:BACKGROUND:Dual bronchodilator therapy is recommended for symptomatic patients with chronic obstructive pulmonary disease (COPD). There are limited data on effects of a combination of two long-acting bronchodilators on lung function including body plethysmography. METHODS:This multicentre, randomised, double-blind, si...
journal_title:Respiratory research
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1186/s12931-016-0498-1
更新日期:2017-01-11 00:00:00
abstract::The hygiene hypothesis states that childhood asthma develops as a result of decreased exposure to infectious agents during infancy and early childhood. This results in the persistence of the neonatal T helper lymphocyte 2 immunophenotype, thereby predisposing the child to atopic disease. While multiple studies support...
journal_title:Respiratory research
pub_type: 杂志文章,评审
doi:10.1186/rr81
更新日期:2001-01-01 00:00:00
abstract:BACKGROUND:Chronic obstructive pulmonary disease (COPD) is characterized by expiratory flow limitation, causing air trapping and lung hyperinflation. Hyperinflation leads to reduced exercise tolerance and poor quality of life in COPD patients. Total lung capacity (TLC) is an indicator of hyperinflation particularly in ...
journal_title:Respiratory research
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1186/s12931-014-0097-y
更新日期:2014-08-20 00:00:00
abstract:BACKGROUND:The aim of the study is to examine the effect of limited and prolonged hyperoxia on neonatal rat lung. This is done by examining the morphologic changes of apoptosis, the expression of ceramide, an important mediator of apoptosis, the expression of inflammatory mediators represented by IL-1beta and the expre...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/1465-9921-7-100
更新日期:2006-07-26 00:00:00
abstract::Idiopathic pulmonary fibrosis (IPF), the most prevalent idiopathic interstitial pneumonia, is associated with a poor prognosis. An accurate diagnosis of IPF is essential for optimal management. The recent ATS/ERS/JRS/ALAT recommendations on the diagnosis and management of IPF were developed from a systematic review of...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/1465-9921-14-S1-S2
更新日期:2013-01-01 00:00:00
abstract:BACKGROUND:Bronchiectasis (BE) is a chronic structural lung disease with frequent exacerbations, some of which require hospital admission though no clear associated factors have been identified. We aimed to evaluate factors associated with hospitalization due to exacerbations during a 1-year follow-up period. METHODS:...
journal_title:Respiratory research
pub_type: 杂志文章,多中心研究
doi:10.1186/s12931-017-0659-x
更新日期:2017-09-30 00:00:00
abstract:BACKGROUND:Macrolides reduce exacerbations in patients with COPD. Their effects on health status has not been assessed as primary outcome and is less clear. This study assessed the effects of prophylactic azithromycin on cough-specific health status in COPD-patients with chronic productive cough. METHODS:In this rando...
journal_title:Respiratory research
pub_type: 杂志文章,随机对照试验
doi:10.1186/1465-9921-14-125
更新日期:2013-11-14 00:00:00
abstract:BACKGROUND:Radiation pneumonitis (RP) is a frequent complication of concurrent chemoradiotherapy (CCRT) and is associated with severe symptoms that decrease quality of life and might result in pulmonary fibrosis or death. The aim of this study is to identify whether pulmonary function test (PFT) abnormalities may predi...
journal_title:Respiratory research
pub_type: 杂志文章,多中心研究
doi:10.1186/s12931-018-0775-2
更新日期:2018-04-24 00:00:00
abstract:BACKGROUND:Chitosan, a polymer derived from chitin, has been used for nasal drug delivery because of its biocompatibility, biodegradability and bioadhesiveness. Theophylline is a drug that reduces the inflammatory effects of allergic asthma but is difficult to administer at an appropriate dosage without causing adverse...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/1465-9921-7-112
更新日期:2006-08-24 00:00:00
abstract:BACKGROUND:Hepcidin serves as a major regulator of systemic iron metabolism and immune function. Airway epithelial cells have an extensive interface with the environment, and so must be able to respond locally to the presence of particulates, infection, and inflammation. Therefore, we hypothesized that hepcidin is expr...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/1465-9921-12-100
更新日期:2011-08-02 00:00:00
abstract:BACKGROUND:During 2007-2010, the National Health and Nutrition Examination Survey (NHANES) conducted a spirometry component which obtained pre-bronchodilator pulmonary lung function data on a nationally representative sample of US adults aged 6-79 years and post-bronchodilator pulmonary lung function data for the subse...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/1465-9921-14-103
更新日期:2013-10-09 00:00:00
abstract:BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease course. The recent advancement of antifibrotic therapy has increased the need for reliable and specific biomarkers. This study aimed to assess alveolar epithelial biomarkers as predictors for the efficacy of the anti...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/s12931-020-01582-y
更新日期:2020-11-30 00:00:00
abstract:BACKGROUND:Few longitudinal studies examine inflammation and lung function in asthma. We sought to determine the cytokines that reduce airflow, and the influence of respiratory viral infections on these relationships. METHODS:Children underwent home collections of nasal lavage during scheduled surveillance periods and...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/s12931-018-0922-9
更新日期:2018-11-21 00:00:00
abstract:BACKGROUND:This study assessed the cost-effectiveness of indacaterol/glycopyrronium (IND/GLY) versus salmeterol/fluticasone (SFC) in chronic obstructive pulmonary disease (COPD) patients with moderate to very severe airflow limitation and ≥1 exacerbation in the preceding year. METHODS:A previously published and valida...
journal_title:Respiratory research
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1186/s12931-017-0688-5
更新日期:2017-12-11 00:00:00
abstract:OBJECTIVE:We aimed to identify the prevalence and distribution patterns of allergens among Chinese children with asthma/asthma-like symptoms (ALS). METHODS:A total of 3479 children with asthma/ALS were enrolled. Skin prick test (SPT) was used to test the allergen-specific IgE. We analysed allergens prevalence and dist...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/s12931-020-1318-1
更新日期:2020-02-18 00:00:00