Publications
1033 results found
Caramori G, Ruggeri P, Mumby S, et al., 2019, Molecular links between COPD and lung cancer: new targets for drug discovery?, Expert Opinion on Therapeutic Targets, Vol: 23, Pages: 539-553, ISSN: 1460-0412
Introduction: COPD and lung cancer are leading causes of morbidity and mortality worldwide, and they share a common environmental risk factor in cigarette smoke exposure and a genetic predisposition represented by their incidence in only a fraction of smokers. This reflects the ability of cigarette smoke to induce an inflammatory response in the airways of susceptible smokers. Moreover, COPD could be a driving factor in lung cancer, by increasing oxidative stress and the resulting DNA damage and repression of the DNA repair mechanisms, chronic exposure to pro-inflammatory cytokines, repression of innate immunity and increased cellular proliferation.Areas covered: We have focused our review on the potential pathogenic molecular links between tobacco smoking-related COPD and lung cancer and the potential molecular targets for new drug development by understanding the common signaling pathways involved in COPD and lung cancer.Expert commentary: Research in this field is mostly limited to animal models or small clinical trials. Large clinical trials are needed but mostly combined models of COPD and lung cancer are necessary to investigate the processes caused by chronic inflammation, including genetic and epigenetic alteration, and the expression of inflammatory mediators that link COPD and lung cancer, to identify new molecular therapeutic targets.
Xu M, Zhang Y, Wang M, et al., 2019, TRPV1 and TRPA1 in lung inflammation and airway hyperresponsiveness induced by fine particulate matter (PM2.5), Oxidative Medicine and Cellular Longevity, Vol: 2019, Pages: 1-15, ISSN: 1942-0900
Exposure to fine particulate matter (PM2.5) has been associated with lung inflammation and airway hyperresponsiveness (AHR). Transient receptor potential (TRP) vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) both may play important roles in lung inflammation and AHR. We investigated whether PM2.5-induced lung inflammation and AHR could be prevented by blocking TRPV1 and TRPA1 channels. Mice were injected intraperitoneally with AMG9810 (30 mg/kg, a TRPV1 antagonist) or A967079 (30 mg/kg, a TRPA1 antagonist) or their combination or vehicle (PBS) one hour before intranasal instillation of PM2.5 (7.8 mg/kg) or vehicle (PBS) for two consecutive days, and then the mice were studied 24 h later. All pretreatments inhibited PM2.5-induced AHR and inflammatory infiltration in the lung tissue and decreased inflammatory cytokine levels in the bronchoalveolar lavage fluid, together with oxidant levels in the lung. AMG9810 inhibited MFF expression and increased MFN2 expression while A967079 inhibited DRP1 expression and increased OPA1 expression; combined pretreatment reduced MFF and DPR1 expression and increased MFN2 and OPA1 expression. All pretreatments inhibited the activation of the TLR4/NF-κB pathway, while A967079 alone, and combined with AMG9810 also reduced the activation of the NLRP3/caspase-1 pathway. Both TRPV1 and TRPA1 channels play an important role in PM2.5-induced lung inflammation and AHR. However, inhibition of the TRPA1 channel or combined inhibition of TRPA1 and TRPV1 channels resulted in greater inhibitory effect on PM2.5-induced lung injury through regulating the mitochondrial fission/fusion proteins and inhibiting the TLR4/NF-κB and NLRP3/caspase-1 pathways.
Fiorentino F, Jaaly EA, Durham AL, et al., 2019, Low-frequency ventilation during cardiopulmonary bypass for lung protection: A randomized controlled trial, Journal of Cardiac Surgery, Vol: 34, Pages: 385-399, ISSN: 0886-0440
OBJECTIVE: Pulmonary dysfunction is a common complication in patients undergoing heart surgery. Current clinical practice does not include any specific strategy for lung protection. To compare the anti-inflammatory effects of low-frequency ventilation (LFV), as measured by nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) p65 pathway activation, for the entire cardiopulmonary bypass (CPB) vs both lungs left collapsed in patients undergoing coronary artery bypass grafting (CABG). METHODS: Two groups parallel randomized controlled trial. The primary outcome was inflammation measured by NF-κB p65 activation in pre- and post-CPB lung biopsies. Secondary outcomes were additional inflammatory markers in both biopsy tissue and blood. RESULTS: Thirty-seven patients were randomly allocated to LFV (18) and to both lungs left collapsed (19). The mean concentration of NF-κB p65 in the biopsies before chest closure (adjusted for pre-CPB concentration) was higher in the LFV group compared to both lungs left collapsed group but this was not significant (0.102, 95% confidence interval, -0.022 to 0.226, P = 0.104). There were no significant differences between groups in the other inflammatory markers measured in tissue and blood. CONCLUSIONS: In patients undergoing elective CABG, the use of LFV during CPB when compared to both lungs left collapsed does not seem to reduce inflammation in lung biopsies and blood.
Kuo C-HS, Pavlidis S, Zhu J, et al., 2019, Contribution of airway eosinophils in airway wall remodeling in asthma: role of MMP-10 and MET, Allergy, Vol: 74, Pages: 1102-1112, ISSN: 0105-4538
BackgroundEosinophils play an important role in the pathophysiology of asthma being implicated in airway epithelial damage and airway wall remodeling. We determined the genes associated with airway remodeling and eosinophilic inflammation in patients with asthma.MethodsWe analyzed the transcriptomic data from bronchial biopsies of 81 patients with moderate‐to‐severe asthma of the U‐BIOPRED cohort. Expression profiling was performed using Affymetrix arrays on total RNA. Transcription binding site analysis used the PRIMA algorithm. Localization of proteins was by immunohistochemistry.ResultsUsing stringent false discovery rate analysis, MMP‐10 and MET were significantly overexpressed in biopsies with high mucosal eosinophils (HE) compared to low mucosal eosinophil (LE) numbers. Immunohistochemical analysis confirmed increased expression of MMP‐10 and MET in bronchial epithelial cells and in subepithelial inflammatory and resident cells in asthmatic biopsies. Using less‐stringent conditions (raw P‐value < 0.05, log2 fold change > 0.5), we defined a 73‐gene set characteristic of the HE compared to the LE group. Thirty‐three of 73 genes drove the pathway annotation that included extracellular matrix (ECM) organization, mast cell activation, CC‐chemokine receptor binding, circulating immunoglobulin complex, serine protease inhibitors, and microtubule bundle formation pathways. Genes including MET and MMP10 involved in ECM organization correlated positively with submucosal thickness. Transcription factor binding site analysis identified two transcription factors, ETS‐1 and SOX family proteins, that showed positive correlation with MMP10 and MET expression.ConclusionPathways of airway remodeling and cellular inflammation are associated with submucosal eosinophilia. MET and MMP‐10 likely play an important role in these processes.
McGarvey L, Dupont L, Birring SS, et al., 2019, New understanding in the treatment of cough (NEUROCOUGH) ERS Clinical Research Collaboration: improving care and treatment for patients with cough, European Respiratory Journal, Vol: 53, ISSN: 0903-1936
Chronic cough is a common and troublesome clinical problem and currently there are no effective treatments [1]. While individual specialist cough clinics have been set up in some European countries, there is no formal mechanism to develop common management approaches. Furthermore, the vast majority of clinical trials of novel anti-tussive treatment have been conducted in a limited number of sites in the UK and USA, with little in the way of cough clinical trial infrastructure across Europe [2–7]. The NEw Understanding in the tReatment Of COUGH (NEUROCOUGH) Clinical Research Collaboration (CRC) seeks to address this through creating a platform allowing clinicians, together with researchers in academia and industrial partners across Europe and beyond, to exchange ideas and facilitate collaborations geared towards improved care and treatment for patients with cough. The core aims of NEUROCOUGH are to: 1) create a registry of Europe-wide specialist cough clinics operating according to agreed and standardised protocols; 2) establish a Europe-wide registry of “clinical trial ready” chronic cough patients suitable for multicentre experimental medicine studies and later phase precision medicine clinical trials; 3) seek public engagement to provide input into NEUROCOUGH based on the priorities and unmet needs of patients; and 4) encourage early career researchers and clinicians into the field of cough.In time, we envisage that NEUROCOUGH will bring clinicians, scientists, patients and industry together for larger-scale cough projects in a way that to date has not been possible. NEUROCOUGH will place Europe at the forefront of clinical improvements in chronic cough and provide a strong platform for attracting major clinical trials of anti-tussives, thus speeding up drug discovery with the ultimate aim of providing better treatments for patients with chronic cough.
Mortaz E, Azempour E, Mansouri D, et al., 2019, Common infections and target organs associated with chronic granulomatous disease in Iran, International Archives of Allergy and Immunology, Vol: 179, Pages: 62-73, ISSN: 1018-2438
Recurrent severe bacterial and fungal infections are characteristic features of the rare genetic immunodeficiency disorder chronic granulomatous disease (CGD). The disease usually manifests within the first years of life with an incidence of 1 in approximately 200,000 live births. The incidence is higher in Iran and Morocco where it reaches 1.5 per 100,000 live births. Mutations have been described in the 5 subunits of NADPH oxidase, mostly in gp91phox and p47phox, with fewer mutations reported in p67phox, p22phox, and p40phox. These mutations cause loss of superoxide production in phagocytic cells. CYBB, the gene encoding the large gp91phox subunit of the transmembrane component cytochrome b558 of the NADPH oxidase complex, is localized on the X-chromosome. Genetic defects in CYBB are responsible for the disease in the majority of male CGD patients. CGD is associated with the development of granulomatous reactions in the skin, lungs, bones, and lymph nodes, and chronic infections may be seen in the liver, gastrointestinal tract, brain, and eyes. There is usually a history of repeated infections, including inflammation of the lymph glands, skin infections, and pneumonia. There may also be a persistent runny nose, inflammation of the skin, and inflammation of the mucous membranes of the mouth. Gastrointestinal problems can also occur, including diarrhea, abdominal pain, and perianal abscesses. Infection of the bones, brain abscesses, obstruction of the genitourinary tract and/or gastrointestinal tract due to the formation of granulomatous tissue, and delayed growth are also symptomatic of CGD. The prevention of infectious complications in patients with CGD involves targeted prophylaxis against opportunistic microorganisms such as Staphylococcus aureus, Klebsiella spp., Salmonella spp. and Aspergillus spp. In this review, we provide an update on organ involvement and the association with specific isolated microorganisms in CGD patients.
Pavlidis S, Monast C, Loza MJ, et al., 2019, I_MDS: an inflammatory bowel disease molecular activity score to classify patients with differing disease-driving pathways and therapeutic response to anti-TNF treatment, PLoS Computational Biology, Vol: 15, ISSN: 1553-734X
Crohn's disease and ulcerative colitis are driven by both common and distinct underlying mechanisms of pathobiology. Both diseases, exhibit heterogeneity underscored by the variable clinical responses to therapeutic interventions. We aimed to identify disease-driving pathways and classify individuals into subpopulations that differ in their pathobiology and response to treatment. We applied hierarchical clustering of enrichment scores derived from gene set variation analysis of signatures representative of various immunological processes and activated cell types, to a colonic biopsy dataset that included healthy volunteers, Crohn's disease and ulcerative colitis patients. Patient stratification at baseline or after anti-TNF treatment in clinical responders and non-responders was queried. Signatures with significantly different enrichment scores were identified using a general linear model. Comparisons to healthy controls were made at baseline in all participants and then separately in responders and non-responders. Fifty-nine percent of the signatures were commonly enriched in both conditions at baseline, supporting the notion of a disease continuum within ulcerative colitis and Crohn's disease. Signatures included T cells, macrophages, neutrophil activation and poly:IC signatures, representing acute inflammation and a complex mix of potential disease-driving biology. Collectively, identification of significantly enriched signatures allowed establishment of an inflammatory bowel disease molecular activity score which uses biopsy transcriptomics as a surrogate marker to accurately track disease severity. This score separated diseased from healthy samples, enabled discrimination of clinical responders and non-responders at baseline with 100% specificity and 78.8% sensitivity, and was validated in an independent data set that showed comparable classification. Comparing responders and non-responders separately at baseline to controls, 43% and 70% of signatures were enri
Stock CJW, Michaeloudes C, Leoni P, et al., 2019, Bromodomain and extra-terminal (BET) protein inhibition restores redox balance and inhibits myofibroblast activation, BioMed Research International, Vol: 2019, ISSN: 2314-6133
Background and Objective. Progressive pulmonary fibrosis is the main cause of death in patients with systemic sclerosis (SSc) with interstitial lung disease (ILD) and in those with idiopathic pulmonary fibrosis (IPF). Transforming growth factor-β (TGF-β) and NADPH oxidase- (NOX-) derived reactive oxygen species (ROS) are drivers of lung fibrosis. We aimed to determine the role of the epigenetic readers, bromodomain and extraterminal (BET) proteins in the regulation of redox balance in activated myofibroblasts. Methods. In TGF-β-stimulated fibroblasts, we investigated the effect of the BET inhibitor JQ1 on the mRNA expression of the prooxidant gene NOX4 and the antioxidant gene superoxide dismutase (SOD2) by quantitative RT-PCR, the antioxidant transcription factor NF-E2-related factor 2 (Nrf2) activity by a reporter assay, and intracellular ROS levels by dichlorofluorescein staining. Myofibroblast activation was determined by α-smooth muscle actin immunocytochemistry. The role of specific BET protein isoforms in NOX4 gene regulation was studied by siRNA silencing and chromatin-immunoprecipitation. Results and Conclusions. Affymetrix gene array analysis revealed increased NOX4 and reduced SOD2 expression in SSc and IPF fibroblasts. SOD2 silencing in non-ILD control fibroblasts induced a profibrotic phenotype. TGF-β increased NOX4 and inhibited SOD2 expression, while increasing ROS production and myofibroblast differentiation. JQ1 reversed the TGF-β-mediated NOX4/SOD2 imbalance and Nrf2 inactivation and attenuated ROS production and myofibroblast differentiation. The BET proteins Brd3 and Brd4 were shown to bind to the NOX4 promoter and drive TGF-β-induced NOX4 expression. Our data indicate a critical role of BET proteins in promoting redox imbalance and pulmonary myofibroblast activation and support BET bromodomain inhibitors as a potential therapy for fibrotic lung disease.
Zhang JJ, Adcock IM, Bai Z, et al., 2019, Health effects of air pollution: What we need to know and to do in the next decade, Journal of thoracic disease, Vol: 11, Pages: 1727-1730, ISSN: 2077-6624
Tariq K, Schofield JPR, Nicholas BL, et al., 2019, Sputum proteomic signature of gastro-oesophageal reflux in patients with severe asthma, Respiratory Medicine, Vol: 150, Pages: 66-73, ISSN: 0954-6111
Gastro-oesophageal reflux disease (GORD) has long been associated with poor asthma control without an established cause-effect relationship. 610 asthmatics (421 severe/88 mild-moderate) and 101 healthy controls were assessed clinically and a subset of 154 severe asthmatics underwent proteomic analysis of induced sputum using untargeted mass spectrometry, LC-IMS-MS E . Univariate and multiple logistic regression analyses (MLR) were conducted to identify proteins associated with GORD in this cohort. When compared to mild/moderate asthmatics and healthy individuals, respectively, GORD was three- and ten-fold more prevalent in severe asthmatics and was associated with increased asthma symptoms and oral corticosteroid use, poorer quality of life, depression/anxiety, obesity and symptoms of sino-nasal disease. Comparison of sputum proteomes in severe asthmatics with and without active GORD showed five differentially abundant proteins with described roles in anti-microbial defences, systemic inflammation and epithelial integrity. Three of these were associated with active GORD by multiple linear regression analysis: Ig lambda variable 1–47 (p = 0·017) and plasma protease C1 inhibitor (p = 0·043), both in lower concentrations, and lipocalin-1 (p = 0·034) in higher concentrations in active GORD. This study provides evidence which suggests that reflux can cause subtle perturbation of proteins detectable in the airways lining fluid and that severe asthmatics with GORD may represent a distinct phenotype of asthma.
Wang M, Zhang Y, Xu M, et al., 2019, Roles of TRPA1 and TRPV1 in cigarette smoke -induced airway epithelial cell injury model, Free Radical Biology and Medicine, Vol: 134, Pages: 229-238, ISSN: 0891-5849
Transient receptor potential protein (TRP) ion channels TRPA1 and TRPV1 may be important in mediating airway tissue injury and inflammation. This study was designed to clarify the role of TRPA1 and TRPV1 channels in cigarette smoke extract (CSE)-induced damage to bronchial and alveolar epithelial cells. Alveolar epithelial (A549) cells and bronchial epithelial (Beas-2B) cells were treated with CSE in the presence and absence of a TRPA1 inhibitor (100 μM, A967079), a TRPV1 inhibitor (100 μM, AMG9810) or both. DCFH-DA and MitoSOX Red probes were used to assay intracellular and mitochondrial oxidative stress, respectively. The mRNA levels of inflammatory mediators (IL-1β, IL-8, IL-18, IL-33) and antioxidants (HO-1, NQO1, MnSOD, catalase) and the protein expression levels of mitochondrial and inflammasome factors (MFN2, OPA1, DRP1, MFF, NLRP3,caspase-1) were respectively detected by RT-PCR and Western Blot. The results were validated in TRPA1 shRNA and TRPV1 shRNA cells. In both cell types, 10% CSE increased intracellular and mitochondrial oxidative stress, induced Ca2+ influx, increased inflammatory gene expression, reduced antioxidant gene expression and inhibited the activities of mitochondrial respiratory chain (MRC) complexes. 10% CSE increased the expression of mitochondrial fission proteins (MFF and DRP1), Caspase-1 and NLRP3 protein expression and decreased that of mitochondrial fusion proteins (MFN2 and OPA1). Both inhibitors and gene-knockout of TRPA1 and TRPV1 reduced oxidative stress, blocked Ca2+ influx, and inhibited inflammatory and increased antioxidant gene expression. They also prevented the changes in mitochondrial fission and fusion proteins and in MRC complexes activities induced by CSE. Both TRPA1 and TRPV1 mediate CSE-induced damage of bronchial and alveolar epithelial cells via modulation of oxidative stress, inflammation and mitochondrial damage and their inhibition should be considered as potential therapy for COPD.
Ravanetti L, Dijkhuis A, Dekker T, et al., 2019, IL-33 drives influenza-induced asthma exacerbations by halting innate and adaptive anti-viral immunity, Journal of Allergy and Clinical Immunology, Vol: 143, Pages: 1355-1370, ISSN: 0091-6749
BACKGROUND: Influenza virus triggers severe exacerbations of asthma for which no adequate treatment is available. It is known that IL-33 levels correlate with exacerbation severity, but its role in the immune-pathogenesis of exacerbations has remained elusive. OBJECTIVE: We hypothesized that IL-33 is necessary to drive asthma exacerbations. We intervened with the IL-33 cascade and sought to dissect its role, also in synergy with TSLP, in airway inflammation, anti-viral activity and lung function. We aimed to unveil the major source of IL-33 in the airways and IL-33-dependent mechanisms that underlie severe asthma exacerbation. METHODS: Mild asthmatic patients were experimentally infected with rhinovirus. Mice were chronically exposed to house dust mite (HDM) extract and then infected with influenza to resemble key features of exacerbations in humans. Interventions included anti-IL-33-receptor ST2 and/or anti-TSLP. RESULTS: We identified bronchial ciliated cells and Type-II alveolar cells as a major local source of IL-33 during virus-driven exacerbation in humans and mice, respectively. By blocking ST2 we demonstrated that IL-33 and not TSLP was necessary to drive exacerbations. IL-33 enhanced AHR and airway inflammation by suppressing innate and adaptive anti-viral responses and by instructing epithelial cells and dendritic cells (DCs) of HDM-sensitized mice to dampen IFN-β expression and prevent the Th1-promoting DCs phenotype. IL-33 also boosted luminal NETosis and halted cytolytic anti-viral activities, but did not affect the Th2-response. CONCLUSION: Interventions targeting the IL-33/ST2 axis could prove an effective acute, short-term therapy for virus-induced asthma exacerbation.
Piquereau J, Boet A, Pechoux C, et al., 2019, The BET bromodomain inhibitor I-BET-151 induces structural and functional alterations of the heart mitochondria in healthy male mice and rats, International Journal of Molecular Sciences, Vol: 20, Pages: 1-16, ISSN: 1422-0067
The bromodomain and extra-terminal domain family inhibitors (BETi) are a promising new class of anticancer agents. Since numerous anticancer drugs have been correlated to cardiomyopathy, and since BETi can affect non-cancerous tissues, we aimed to investigate in healthy animals any ultrastructural BETi-induced alterations of the heart as compared to skeletal muscle. Male Wistar rats were either treated during 3 weeks with I-BET-151 (2 or 10 mg/kg/day) (W3) or treated for 3 weeks then allowed to recover for another 3 weeks (W6) (3-weeks drug washout). Male C57Bl/6J mice were only treated during 5 days (50 mg/kg/day). We demonstrated the occurrence of ultrastructural alterations and progressive destruction of cardiomyocyte mitochondria after I-BET-151 exposure. Those mitochondrial alterations were cardiac muscle-specific, since the skeletal muscles of exposed animals were similar in ultrastructure presentation to the non-exposed animals. I-BET-151 decreased the respiration rate of heart mitochondria in a dose-dependent manner. At the higher dose, it also decreased mitochondrial mass, as evidenced by reduced right ventricular citrate synthase content. I-BET-151 reduced the right and left ventricular fractional shortening. The concomitant decrease in the velocity-time-integral in both the aorta and the pulmonary artery is also suggestive of an impaired heart function. The possible context-dependent cardiac side effects of these drugs have to be appreciated. Future studies should focus on the basic mechanisms of potential cardiovascular toxicities induced by BETi and strategies to minimize these unexpected complications.
Chung KF, Adcock IM, 2019, Precision medicine for the discovery of treatable mechanisms in severe asthma, Allergy, Vol: 74, Pages: 1649-1659, ISSN: 0105-4538
Although the complex disease of asthma has been defined as being heterogeneous, the extent of its endophenotypes remain unclear. The pharmacological approach to initiating treatment has, until recently, been based on disease control and severity. The introduction of antibody therapies targeting the Type2 inflammation pathway for patients with severe asthma has resulted in the recognition of an allergic and an eosinophilic phenotype, which are not mutually exclusive. Concomitantly, molecular phenotyping based on a transcriptomic analysis of bronchial epithelial and sputum cells has identified a Type-2-high inflammation cluster characterised by eosinophilia and recurrent exacerbations, as well as Type-2-low clusters linked with IL-6 trans-signalling, interferon pathways, inflammasome activation and mitochondrial oxidative phosphorylation pathways. Systems biology approaches are establishing the links between these pathways or mechanisms, and clinical and physiologic features. Validation of these pathways contributes to defining endotypes and treatable mechanisms. Precision medicine approaches are necessary to link treatable mechanisms with treatable traits and biomarkers derived from clinical, physiologic and inflammatory features of clinical phenotypes. The deep molecular phenotyping of airway samples along with non-invasive biomarkers linked to bioinformatic and machine learning techniques will enable the rapid detection of molecular mechanisms that transgresses beyond the concept of treatable traits. This article is protected by copyright. All rights reserved.
Agusti A, Faner R, Donaldson G, et al., 2019, Chronic Airway Diseases Early Stratification (CADSET): a new ERS Clinical Research Collaboration, European Respiratory Journal, Vol: 53, ISSN: 0903-1936
A recent editorial in the European Respiratory Journal highlighted the strategic importance of the Clinical Research Collaborations (CRCs) launched in 2013 by the European Respiratory Society (ERS) [1]. These have the aim of 1) promoting the exchange of research ideas among clinicians and affiliated scientists in Europe and/or globally; 2) building an infrastructure for prospective clinical research; 3) securing additional funding through national and European Union funding streams; and 4) facilitating the planning, implementation, evaluation and publication of clinical and translational studies at pan-European level and beyond. So far, there are currently 17 ongoing CRCs that cover eight major respiratory disease domains (airway diseases, interstitial lung diseases, pulmonary vascular diseases, sleep and breathing disorders, respiratory critical care, paediatric respiratory diseases, respiratory infections and thoracic oncology), all of them linked to one or more ERS assemblies [2–12]. CADSET, an acronym that stands for “Chronic Airway Diseases Early Stratification”, is the latest addition to the list of ongoing CRCs (www.ersnet.org/research/clinical-research-collaborations). This editorial presents the rationale, goals and research strategy for CADSET.
Roth-Walter F, Adcock IM, Benito-Villalvilla C, et al., 2019, Comparing biologicals and small molecule drug therapies for chronic respiratory diseases, Allergy, Vol: 74, Pages: 432-448, ISSN: 0105-4538
Chronic airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), together with their comorbidities, bear a significant burden on public health. Increased appreciation of molecular networks underlying inflammatory airway disease needs to be translated into new therapies for distinct phenotypes not controlled by current treatment regimens. On the other hand, development of new safe and effective therapies for such respiratory diseases is an arduous and expensive process. Antibody-based (biological) therapies are successful in treating certain respiratory conditions not controlled by standard therapies such as severe allergic and refractory eosinophilic severe asthma, while in other inflammatory respiratory diseases, such as COPD, biologicals are having a more limited impact. Small molecule drug (SMD)-based therapies represent an active field in pharmaceutical research and development. SMDs expand biologicals' therapeutic targets by reaching the intracellular compartment by delivery as either an oral or topically-based formulation, offering both convenience and lower costs. Aim of this review is to compare and contrast the distinct pharmacological properties and clinical applications of SMDs- and antibody-based treatment strategies, their limitations and challenges, in order to highlight how they should be integrated for their optimal utilization and to fill the critical gaps in current treatment for chronic inflammatory respiratory diseases. This article is protected by copyright. All rights reserved.
Sanchez S, Pavlidis S, Adcock I, et al., 2019, TRANSCRIPTOMIC GENE SIGNATURES IN ADULTS WITH SEVERE ASTHMA: AN ANALYSIS OF U-BIOPRED STUDY AND PRC HEALTHY LUNGS MIAD STUDY, Publisher: WILEY, Pages: 62-62, ISSN: 1323-7799
Zakarya R, Adcock I, Oliver BG, 2019, Epigenetic impacts of maternal tobacco and e-vapour exposure on the offspring lung, Clinical Epigenetics, Vol: 11, ISSN: 1868-7083
In utero exposure to tobacco products, whether maternal or environmental, have harmful effects on first neonatal and later adult respiratory outcomes. These effects have been shown to persist across subsequent generations, regardless of the offsprings' smoking habits. Established epigenetic modifications induced by in utero exposure are postulated as the mechanism underlying the inherited poor respiratory outcomes. As e-cigarette use is on the rise, their potential to induce similar functional respiratory deficits underpinned by an alteration in the foetal epigenome needs to be explored. This review will focus on the functional and epigenetic impact of in utero exposure to maternal cigarette smoke, maternal environmental tobacco smoke, environmental tobacco smoke and e-cigarette vapour on foetal respiratory outcomes.
Jia M, Yan X, Jiang X, et al., 2019, Ezrin, a membrane cytoskeleton cross-linker protein, as a marker of epithelial damage in asthma, American Journal of Respiratory and Critical Care Medicine, Vol: 199, Pages: 496-507, ISSN: 1073-449X
RATIONALE: Bronchial epithelial cell damage occurs in patients with bronchial asthma. Ezrin, a membrane-cytoskeleton protein, maintains cellular morphology and intercellular adhesion and protects the barrier function of epithelial cells. OBJECTIVES: To study the role of ezrin in bronchial epithelial cells injury and correlate its expression with asthma severity. METHODS: Levels of ezrin were measured in exhaled breath condensate (EBC) and serum in asthma patients and bronchoalveolar lavage fluid (BALF) from a mouse model of asthma by ELISA. The regulation of IL-13 on ezrin protein levels was studied in primary bronchial epithelial cells (PBECs). Ezrin knockdown using shRNA was studied in human bronchial epithelial 16HBE cells. RESULTS: Ezrin levels were decreased in asthmatic EBC (392.7±34.99 vs 150.5±10.22 pg/ml, p<0.0001) and serum (700.7±55.59 vs 279.2±25.83pg/ml, p<0.0001) compared to normal subjects. Levels were much lower in uncontrolled (p<0.001) and partly-controlled patients (p<0.01) compared to well-controlled subjects. EBC and serum ezrin levels correlated with lung function in asthma patients and serum ezrin levels were negatively correlated with serum IL-13 and periostin. IL-13-induced down-regulation of ezrin expression in PBECs was significantly attenuated by the JAK2 (Janus tyrosine kinase 2) inhibitor TG101348. Ezrin knockdown changed 16HBE cell morphology, enlarged intercellular spaces and increased their permeability. Ezrin expression was decreased in the lung tissue and BALF of 'asthmatic' mice and negatively correlated with BALF IL-13 level. CONCLUSIONS: Ezrin down-regulation is associated with IL-13-induced epithelial damage and might be a potential biomarker of asthma control.
Alipoor SD, Tabarsi P, Varahram M, et al., 2019, Serum exosomal miRNAs are associated with active pulmonary tuberculosis, Disease Markers, Vol: 2019, ISSN: 0278-0240
Introduction. Tuberculosis (TB) remains a major threat to human health. Due to the limited accuracy of the current TB diagnostictests, it is critical to determine novel biomarkers for this disease. Circulating exosomes have been used as diagnostic biomarkers invarious diseases. Objective of the Study. In this pilot study, we examined the expression of miRNAs as biomarker candidates for thediagnosis of TB infection. Methods. Serum-derived exosomes were isolated from TB patients and matched control subjects. Theexpression of miR-484, miR-425, and miR-96 was examined by RT-PCR methods. Results. The expression of miR-484, miR-425,and miR-96 were significantly increased in serum of TB patients which correlated with the TB infection level. A receiveroperating characteristic (ROC) curve analysis showed the diagnostic potency of each individual serum exosomal miRNA withan area under the curve AUC = 0 72 for miR-484 (p < 0 05), 0.66 for miR-425 (p < 0 05), and 0.62 for miR-96 (p < 0 05).Conclusion. These results demonstrate that exosomal miRNAs have diagnostic potential in active tuberculosis. The diagnosticpower may be improved when combined with conventional diagnostic markers.
Jevnikar Z, Östling J, Ax E, et al., 2019, Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation, Journal of Allergy and Clinical Immunology, Vol: 143, Pages: 577-590, ISSN: 0091-6749
BACKGROUND: Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) with asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthma is unclear. OBJECTIVE: To explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthma. METHODS: An IL-6TS gene signature, obtained from air-liquid interface (ALI) cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R, was used to stratify lung epithelium transcriptomic data (U-BIOPRED cohorts) by hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis and immunohistochemical analysis of bronchial biopsies. RESULTS: Activation of IL-6TS in ALI cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of IL-6TS High asthma patients with increased epithelial expression of IL-6TS inducible genes in absence of systemic inflammation. The IL-6TS High subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings, TLR pathway genes were up-regulated while the expression of tight junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, MMP3, MIP-1β, IL-8 and IL-1β. CONCLUSIONS: Local lung epithelial IL-6TS activation in absence of type 2 airway inflammation defines a novel subset of asthmatics and may drive airway inflammation and epithelial dysfunction in these patients.
Wang H, FitzPatrick M, Wilson NJ, et al., 2019, CSF3R/CD114 mediates infection-dependent transition to severe asthma, Journal of Allergy and Clinical Immunology, Vol: 143, Pages: 785-788.e6, ISSN: 0091-6749
Schleich F, Bikov A, Mathioudakis AG, et al., 2019, Research highlights from the 2018 European Respiratory Society International Congress: airway disease., ERJ Open Research, Vol: 5, ISSN: 2312-0541
The annual European Respiratory Society (ERS) International Congress (held in Paris in 2018) was once again a platform for discussion of the highest-quality scientific research, cutting-edge techniques and innovative new therapies within the respiratory field. This article discusses only some of the high-quality research studies presented at this year's Congress, with a particular focus on airway diseases including asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis and cough, as presented through Assembly 5 of the ERS (Airway Diseases: Asthma and COPD). The authors establish the key take-home messages of these studies, compare their findings and place them in the context of current understanding.
Bozier J, Rutting S, Xenaki D, et al., 2019, Heightened response to e-cigarettes in COPD, ERJ Open Research, Vol: 5, ISSN: 2312-0541
E-cigarettes induce greater inflammatory mediators from COPD lung cells; therefore, the risks of e-cigarette use in COPD might be greater than in people without COPD http://ow.ly/xmnN30nzDhX.
Simpson AJ, Hekking P-P, Shaw DE, et al., 2019, Treatable traits in the European U-BIOPRED adult asthma cohorts, Allergy, Vol: 74, Pages: 406-411, ISSN: 0105-4538
Xu M, Li F, Wang M, et al., 2019, Protective effects of VGX-1027 in PM2.5-induced airway inflammation and bronchial hyperresponsiveness, European Journal of Clinical Pharmacology, Vol: 842, Pages: 373-383, ISSN: 0031-6970
Fine particulate matter (PM2.5) can penetrate into alveolar spaces and induce airway inflammation. Recent evidence suggests that the activation of Toll-like receptor 4 (TLR4) signaling may participate in PM2.5-induced acute lung injury. We investigated the effect of VGX-1027, a TLR4 blocker, on PM2.5-induced airway inflammation and bronchial hyperresponsiveness (BHR) in a murine model in vivo and on inflammatory mechanisms in vitro in human airway epithelial cells. Mice were injected intraperitoneally with vehicle (PBS) or VGX-1027 (25 mg/kg) one hour before intranasal instillation of vehicle (PBS) or PM2.5 (7.8 mg/kg) for two consecutive days and inflammatory events and BHR studied 24 h later. Human airway epithelial Beas-2b cells were pretreated with vehicle or VGX-1027 (50 μM) in vitro one hour before incubation with vehicle or PM2.5 (150 ng/ml) for 24 h and effects on inflammatory mediators and mechanisms studied. VGX-1027 pretreatment attenuated PM2.5-induced BHR and elevated total and neutrophils, macrophages, lymphocytes and eosinophils numbers in bronchoalveolar lavage (BAL) fluid in vivo. PM2.5-induced BAL fluid inflammatory mediator levels including TNF-α, chemokine (C-X-C motif) ligand1, IL-1β, IL-6 and IL-18 were reduced by VGX-1027. PM2.5-induced increases in TNF-α, IL-1β, IL-6 and IL-18 mRNA levels in Beas-2b cells were also reduced by VGX-1027. Mechanistically, VGX-1027 inhibited PM2.5-induced activation of the TLR4-NF-κB-p38 MAPK and NLRP3-caspase-1 pathways as well as the dysregulation of mitochondrial fusion/fission proteins in vivo and in vitro. VGX-1027 may be a potential prophylactic treatment for PM2.5-induced acute lung injury that has airway inflammation, BHR and mitochondrial damage.
Caramori G, Mumby S, Girbino G, et al., 2019, Corticosteroids, Nijkamp and Parnham’s Principles of Immunopharmacology: Fourth revised and extended edition, Pages: 661-688, ISBN: 9783030108090
CORTISOL secretion by the cortex of e adrenal glands (Fig. 32. 1) increases in response to any stress in the body, whether physical (such as illness, trauma, surgery or temperature extremes) or psychological. However, this hormone is more than a simple marker of stress levels—it is necessary for the correct functioning of almost every part of the body. Excesses or deficiencies of this crucial hormone also lead to various physical symptoms and disease states [1]. Although cortisol is not essential for life per se, it helps an organism to cope more efficiently with its environment with particular metabolic actions on glucose production and protein and fat catabolism. Nevertheless, loss or profound diminishment of cortisol secretion leads to a state of abnormal metabolism and an inability to deal with stressors, which, if untreated, may be fatal [1, 2].
Hersh CP, Adcock IM, Celedon JC, et al., 2019, High-throughput sequencing in respiratory, critical care, and sleep medicine research. An Official American Thoracic Society Workshop Report, Annals of the American Thoracic Society, Vol: 16, Pages: 1-16, ISSN: 2329-6933
High-throughput, “next-generation” sequencing methods are now being broadly applied across all fields of biomedical research, including respiratory disease, critical care, and sleep medicine. Although there are numerous review articles and best practice guidelines related to sequencing methods and data analysis, there are fewer resources summarizing issues related to study design and interpretation, especially as applied to common, complex, nonmalignant diseases. To address these gaps, a single-day workshop was held at the American Thoracic Society meeting in May 2017, led by the American Thoracic Society Section on Genetics and Genomics. The aim of this workshop was to review the design, analysis, interpretation, and functional follow-up of high-throughput sequencing studies in respiratory, critical care, and sleep medicine research. This workshop brought together experts in multiple fields, including genetic epidemiology, biobanking, bioinformatics, and research ethics, along with physician-scientists with expertise in a range of relevant diseases. The workshop focused on application of DNA and RNA sequencing research in common chronic diseases and did not cover sequencing studies in lung cancer, monogenic diseases (e.g., cystic fibrosis), or microbiome sequencing. Participants reviewed and discussed study design, data analysis and presentation, interpretation, functional follow-up, and reporting of results. This report summarizes the main conclusions of the workshop, specifically addressing the application of these methods in respiratory, critical care, and sleep medicine research. This workshop report may serve as a resource for our research community as well as for journal editors and reviewers of sequencing-based manuscript submissions in our research field.
Pavlidis S, Takahashi K, Kwong FNK, et al., 2019, "T2-high" in severe asthma related to blood eosinophil, exhaled nitric oxide and serum periostin, European Respiratory Journal, Vol: 53, ISSN: 0903-1936
BACKGROUND: Type-2 (T2) immune responses in airway epithelial cells (AECs) classifies mild-moderate asthma into a T2-high phenotype. We examined whether currently-available clinical biomarkers can predict AEC-defined T2-high phenotype within U-BIOPRED cohort. METHODS: The transcriptomic profile of AECs obtained from brushings of 103 patients with asthma and 44 healthy controls was obtained and gene set variation analysis used to determine the relative expression score of T2 asthma using a signature from IL-13-exposed AECs. RESULTS: 37% of asthmatics (45% non-smoking severe asthma, n=49, 33% of smoking or ex-smoking severe asthma, n=18 and 28% mild-moderate asthma, n=36) were T2-high using AEC gene expression. They were more symptomatic with higher levels of nitric oxide in exhaled breath (FeNO) and of blood and sputum eosinophils but not of serum IgE or periostin. Sputum eosinophilia correlated best with the T2-high signature. FeNO (≥30 ppb) and blood eosinophils (≥300/µL) gave a moderate prediction of T2-high asthma. Sputum IL-4, IL-5 and IL-13 protein levels did not correlate with gene expression. CONCLUSION: T2-high severe asthma can be predicted to some extent from raised levels of FeNO, blood and sputum eosinophil counts, but serum IgE or serum periostin were poor predictors. Better bedside biomarkers are needed to detect T2-high.
Shrine N, Portelli MA, John C, et al., 2019, Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study, Lancet Respiratory Medicine, Vol: 7, Pages: 20-34, ISSN: 2213-2600
BACKGROUND: Few genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma. METHODS: In this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10-6 in stage 1. We set genome-wide significance at p less than 5 × 10-8. For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls. FINDINGS: We included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive im
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