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• Sacubitril/valsartan (S/V) is a key treatment for heart failure. • Sleep-disordered breathing (SDB; obstructive and central) is a common co-morbidity. • SDB has an impact on the prognosis of patients with heart failure. • After only 3 months of treatment, S/V improved LV and RV function. • This was achieved via a significant increase in TAPSE and a reduction in sPAP. • The improvement in RV function was most evident in patients with central SDB. • To date, those with central SDB cannot benefit from any treatment other than drugs. Sacubitril/valsartan has been demonstrated to significantly improve left ventricular performance and remodelling in patients with heart failure. However, its effects on the right ventricle in patients with chronic heart failure and sleep-disordered breathing (SDB) have not been studied. To investigate the impact of sacubitril/valsartan treatment on right ventricular function in patients with SDB. This was a subanalysis of an observational prospective multicentre study involving 101 patients. At inclusion, patients were evaluated by echocardiography and nocturnal ventilatory polygraphy, which allowed patients to be divided into three groups: "central-SDB"; "obstructive-SDB"; and "no-SDB". After 3 months of sacubitril/valsartan therapy, a positive impact on right ventricular function was observed. In the general population, tricuspid annular plane systolic excursion increased by +1.32 ± 4.74 mm (P = 0.024) and systolic pulmonary artery pressure decreased by −3.1 ± 10.91 mmHg (P = 0.048). The central-SDB group experienced the greatest echocardiographic improvement, with a significant increase in tricuspid annular plane systolic excursion of +2.1 ± 4.9 mm (P = 0.045) and a significant reduction in systolic pulmonary artery pressure of −8.4 ± 9.7 mmHg (P = 0.001). Sacubitril/valsartan improved right ventricular function in patients with heart failure and SDB after only 3 months of treatment. The greatest improvement in right ventricular function was observed in the central-SDB group. [ABSTRACT FROM AUTHOR]

Abstract Primary Ciliary Dyskinesia (PCD) is a rare heterogeneous genetic disorder affecting motile cilia structure and function leading to lung disease. We generated induced pluripotent stem cells (iPSCs) from dermal fibroblasts of a female PCD patient carrying disease-causing variants in the CCDC40 gene. Reprogramming was performed with the human OSKM transcription factors using the Sendai-virus delivery system. The resulting transgene free iPSCs had normal karyotype, expressed pluripotency markers, could differentiate into the three germ layers in vivo and retained the disease-causing CCDC40 mutations. This iPSC line could be useful to model PCD disease and test gene therapy strategies. Resource Table Unlabelled Table Unique stem cell line identifier UHOMi001-A Alternative name(s) of stem cell line iPCD02.30 Institution Institute for Regenerative Medicine & Biotherapy (IRMB), Montpellier, FRANCE Contact information of distributor John De Vos john.devos@inserm.fr Type of cell line iPSC Origin human Additional origin info Age: 34 Sex: Female Cell Source Dermal fibroblasts Clonality Clonal Method of reprogramming hOCT4, hSOX2, hC-MYC, hKLF4 (CytoTune™-iPS 2.0 Sendai Reprogramming Kit - Invitrogen, Thermo Fisher Scientific Inc.) Genetic Modification YES Type of Modification Spontaneous mutation Associated disease Primary Ciliary Dyskinesia Gene/locus Compound Heterozygous mutations the Coiled-Coil Domain Containing 40 Gene (CCDC40): c.1116_1117delCT (Exon 7) and c.3180 + 1G > A (Intron 19) Method of modification N/A Name of transgene or resistance N/A Inducible/constitutive system N/A Date archived/stock date 2018-02-12 Cell line repository/bank N/A Ethical approval The study was approved by the regional scientific ethical committee (CPP Sud Med IV) under the number ID-RCB: 2013-A00892–43/CILIPS, Promoter University Hospital Of Montpellier) and informed consent was obtained from the patient. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is currently the third cause of death worldwide. Emphysema is an abnormal enlargement of air spaces in the lungs, with destruction of alveolar parishes. Cardiovascular disorders are the most frequent and serious comorbidities of COPD. Their interconnection is poorly understood but several hypotheses have been proposed, including hyperinflation, oxidative stress, and inflammation. In a rat model with exacerbated elastase (ELA)-induced emphysema that develops heart failure with preserved ejection fraction, our goal is to (1) describe the relationship between exacerbated emphysema and cardiovascular hemodynamic disorders, (2) characterize the inflammation status 24 h and 5 weeks after an exacerbation. The model includes a weekly intra-tracheal instillation of ELA, during four weeks with doses of 4, 6 or 10UI. At week 4, lipopolysaccharide (LPS) was instillated with ELA to mimic an exacerbation and approximate clinical conditions. Experiments were performed 24 hours after the last intra-tracheal instillation (ELA + LPS) and at week 9 just before sacrifice. In vivo, we did a cardiac stress test on metabolic treadmill, whole body plethysmography, echocardiography, arterial pressure, and collected blood samples. Ex vivo, we explanted the heart/lung block to assess pulmonary compliance and histology analyses. We identified a respiratory functional impairment proportional to the dose of elastase instilled. An exercise intolerance appeared after the exacerbation and persisted 5 weeks later. We observed a diastolic dysfunction after the exacerbation and at week 9, with a significantly dose dependent increased E/E' ratio, correlated with the extent of emphysema. A systolic and diastolic arterial hypertension appeared at week 9, especially in the 10UI elastase group. There was an increased lung compliance and decreased elastance. The characterization of inflammation is under investigation. This ELA-LPS animal model presents a chronic profile of heart failure with preserved ejection fraction linked in a dose-dependent manner to the intensity of the emphysema. Cardiopulmonary changes are accompanied by a reduction in exercise tolerance as well as arterial hypertension. This model seems useful to better understand the mechanisms of cardiac changes induced by emphysema. At length, we aim to develop an inhibition of T1 or T2 inflammation pathway, to determine the part played by this inflammation. [ABSTRACT FROM AUTHOR]

Background Cross-sectional severe asthma cluster analysis identified different phenotypes. We tested the hypothesis that these clusters will follow different courses. Objective We aimed to identify which asthma outcomes are specific and coherently associated with these different phenotypes in a prospective longitudinal cohort. Methods In a longitudinal cohort of 112 patients with severe asthma, the 5 Severe Asthma Research Program (SARP) clusters were identified by means of algorithm application. Because patients of the present cohort all had severe asthma compared with the SARP cohort, homemade clusters were identified and also tested. At the subsequent visit, we investigated several outcomes related to asthma control at 1 year (6-item Asthma Control Questionnaire [ACQ-6], lung function, and medication requirement) and then recorded the 3-year exacerbations rate and time to first exacerbation. Results The SARP algorithm discriminated the 5 clusters at entry for age, asthma duration, lung function, blood eosinophil measurement, ACQ-6 scores, and diabetes comorbidity. Four homemade clusters were mostly segregated by best ever achieved FEV 1 values and discriminated the groups by a few clinical characteristics. Nonetheless, all these clusters shared similar asthma outcomes related to asthma control as follows. The ACQ-6 score did not change in any cluster. Exacerbation rate and time to first exacerbation were similar, as were treatment requirements. Conclusion Severe asthma phenotypes identified by using a previously reported cluster analysis or newly homemade clusters do not behave differently concerning asthma control–related outcomes, which are used to assess the response to innovative therapies. This study demonstrates a potential limitation of the cluster analysis approach in the field of severe asthma. [ABSTRACT FROM AUTHOR]

Background: The management of occult lung lesions, particularly subsolid opacities, is a new challenge because they are difficult to localize during surgery and the number of lesions detected by computed tomography (CT) is increasing. Methods: Between February 2008 and December 2011, preoperative CT-guided marking with coils was systematically carried out to localize presumed impalpable nodules before video-assisted thoracoscopic surgery (VATS). The procedure feasibility, reliability, and safety as well as its impact on the resection volume and on the pathologic examination strategy were examined. Results: This preoperative marking procedure was used for 68 nodules in 60 consecutive patients. The mean procedural time was 25 minutes/patient and complications included minimal asymptomatic pneumothorax (42 cases, 70%) and hemorrhagic suffusion (21 patients, 35%). Patients with non-retrieved coils during VATS required larger resection volumes (94.88 mm3 vs 20.65 mm3; p = 0.008). The presence of a coil loop in the pleural space was not statistically associated with higher resected lung volume. Primary pulmonary adenocarcinoma was found in 42 patients (71.2%). Five nodules were associated with atypical adenomatous hyperplasia. Pathologic examination was considered to be improved by the presence of a coil next to the lesion but not within it. Coil placement modified the pathology practices for intraoperative analysis, as tissue sampling in the immediate vicinity of the coil was preferred to systematic sampling. Conclusions: Impalpable lung nodules can be safely marked with coils preoperatively to improve their surgical and pathologic management. [Copyright &y& Elsevier]

Summary: Background: Epidemics of asthma and overweight have been linked recently. They might be associated with systemic inflammation. In asthma hyperresponsiveness to adenosine (AMP) is more closely related to inflammation than to methacholine (MCh). The aim of the study was to determine responsiveness to AMP and MCh in overweight compared with normal weight asthmatics. Methods: Thirty women were enrolled (19 overweight) with mild controlled asthma according to GINA. A Body Mass Index (BMI) less than 25kg/m2 was considered as normal and a BMI above 25kg/m2 as overweight. We assessed the recent control of asthma (ACQ), pulmonary function tests, bronchial responsiveness to MCh and AMP (PC20 and O''Connor two-point dose–response slope), perception of symptoms (Borg scale), and blood inflammatory markers (leptin and hs-CRP by ELISA). Results: Overweight had a significant lower dose-response slope of the MCh challenge (p =0.009) as compared to normal weight patients, whereas no significant difference was observed for AMP challenge (p =0.27). Overweight patients had higher intercepts of the Borg scale measured before the MCh and AMP challenge tests (p =0.01 and p =0.03). Plasma leptin (p =0.001) and hs-CRP (p =0.05) concentrations were higher in overweight than normal weight patients. There was no correlation between challenges and inflammatory markers. Conclusions: Overweight asthmatic women have more pronounced systemic inflammation, but are less responsive to MCh. AMP responsiveness appeared to be comparable between both groups. Our findings suggest that overweight asthmatic women do not feature increased airway inflammation, but do represent a distinct phenotype as compared to normal weight patients. [Copyright &y& Elsevier]

Evidence highlights the concept of multiple trajectories leading to COPD. Early-life events (i.e., in utero lung development) may influence the maximally attained lung function and increase the risk to develop COPD. Human pluripotent stem cells (hiPSC) represent a unique opportunity to model lung development. We generated hiPSC lines from four highly characterized COPD patients with early onset and severe phenotype. Peripheral blood mononuclear cells (PBMCs) were reprogrammed using integration-free Sendai Virus. The cell lines had normal karyotype, expressed pluripotency hallmarks, and differentiated into the three primary germ layers. These lines offer a tool to study early-life origins of COPD. [ABSTRACT FROM AUTHOR]

Background: Reticular basement membrane (RBM) thickness is considered a hallmark for airway remodeling in airway diseases such as asthma. It is still unclear whether this measurement could be associated with disease severity or apply to chronic obstructive pulmonary disease (COPD). A wide range of results, at baseline or after therapeutic intervention, have been reported using different measurement methods. Objective: To determine whether increased RBM thickness could be associated specifically with severe asthma and in COPD in large samples. Methods: We blindly measured RBM thickness in endobronchial biopsies from 50 patients with severe asthma (mean age, 53 years; FEV1 66% predicted, inhaled steroids ≥1500 μg and 20 mg daily dose of oral corticosteroids, lifelong nonsmokers), 50 untreated patients with mild asthma (mean age, 33 years; FEV1 93%pred, lifelong nonsmokers), 50 patients with COPD (mean age, 57 years; FEV1 53%pred, all current smokers), and 18 control subjects using 2 different validated quantitative and computer-assisted methods (repeated multiple point-to-point vs area by length ratio). Results: Reticular basement membrane thickness was higher in severe asthma compared with mild asthma and COPD (P = .0053). On the basis of receiver operating characteristic curves, RBM thickness was effective in differentiating severe asthma from other groups (sensitivity and specificity, 98% and 95%, respectively, above a threshold of 5 μm vs control, 70% and 75% at 7 μm vs mild, 83% and 68% at 6 μm vs COPD). Conclusion: Increased RBM thickness was specifically associated with severe asthma, whereas surprisingly, COPD and mild asthma had similar remodeling features. Clinical implications: Reticular basement membrane thickness can be considered a hallmark of severe asthma. [Copyright &y& Elsevier]

Mepolizumab has demonstrated favorable safety and efficacy profiles in placebo-controlled trials of 12 months' duration or less; however, long-term data are lacking. We sought to evaluate the long-term safety and efficacy of mepolizumab in patients with severe eosinophilic asthma (SEA). COLUMBA (Open-label Long Term Extension Safety Study of Mepolizumab in Asthmatic Subjects, NCT01691859) was an open-label extension study in patients with SEA previously enrolled in DREAM (Dose Ranging Efficacy And Safety With Mepolizumab in Severe Asthma, NCT01000506). Patients received 100 mg of subcutaneous mepolizumab every 4 weeks plus standard of care until a protocol-defined stopping criterion was met. Safety end points included frequency of adverse events (AEs), serious AEs, and AEs of special interest. Efficacy end points included annualized exacerbation rates, changes from baseline in Asthma Control Questionnaire 5 scores, and blood eosinophil counts. Immunogenicity was also assessed. Overall, 347 patients were enrolled for an average of 3.5 years (maximum, 4.5 years; total exposure, 1201 patient-years). On-treatment AEs were reported in 94% of patients (exposure-adjusted rate, 3688 events/1000 patient-years). The most frequently reported on-treatment AEs were respiratory tract infection, headache, bronchitis, and asthma worsening. Seventy-nine (23%) patients experienced 1 or more on-treatment serious AEs; there were 6 deaths, none of which were assessed as related to mepolizumab. For patients with 156 weeks or greater enrollment, the exacerbation rate was 0.74 events/y (weeks 0–156), a 56% reduction from the off-treatment period between DREAM and COLUMBA. For all patients, at the first postbaseline assessment, the mean Asthma Control Questionnaire 5 score was reduced by 0.47 points, and blood eosinophil counts were reduced by 78%, with similar improvements maintained throughout the study. The immunogenicity profile (8% anti-drug antibodies) was consistent with previous studies. These data support the long-term safety and efficacy of mepolizumab in patients with SEA. [ABSTRACT FROM AUTHOR]

KIT is a receptor tyrosine kinase that after binding to its ligand stem cell factor activates signaling cascades linked to biological processes such as proliferation, differentiation, migration and cell survival. Based on studies performed on SCF and/or KIT mutant animals that presented anemia, sterility, and/or pigmentation disorders, KIT signaling was mainly considered to be involved in the regulation of hematopoiesis, gametogenesis, and melanogenesis. More recently, novel animal models and ameliorated cellular and molecular techniques have led to the discovery of a widen repertoire of tissue compartments and functions that are being modulated by KIT. This is the case for the lung, heart, nervous system, gastrointestinal tract, pancreas, kidney, liver, and bone. For this reason, the tyrosine kinase inhibitors that were originally developed for the treatment of hemato-oncological diseases are being currently investigated for the treatment of non-oncological disorders such as asthma, rheumatoid arthritis, and alzheimer's disease, among others. The beneficial effects of some of these tyrosine kinase inhibitors have been proven to depend on KIT inhibition. This review will focus on KIT expression and regulation in healthy and pathologic conditions other than cancer. Moreover, advances in the development of anti-KIT therapies, including tyrosine kinase inhibitors, and their application will be discussed. [ABSTRACT FROM AUTHOR]

Background: Structural changes to the airways are features of severe asthma. The bronchial epithelium facilitates this remodeling process. Learning about the changes that develop in the airway epithelium could improve our understanding of asthma pathogenesis and lead to new therapeutic approaches. Objective: We sought to determine the feasibility and relevance of air-liquid interface cultures of bronchial epithelium derived from endobronchial biopsy specimens of patients with different severities of asthma for studying the airway epithelium. Methods: Human bronchial epithelial cells derived from endobronchial biopsy specimens of patients with mild and severe asthma were maintained in culture for 21 days in an air-liquid interface to reproduce a fully differentiated airway epithelium. Initially, features of remodeling that included epithelial and subepithelial layers, as well as mucus production, were assessed in paraffin-embedded endobronchial biopsy specimens to evaluate morphologic characteristics of asthmatic patients’ epithelia. Ex vivo differentiated epithelia were then analyzed for morphology and function based on ultrastructural analysis, IL-8 release, lipoxin A4 generation, mucin production, and lipoxygenase gene expression. Results: Morphologic and inflammatory imbalances initially observed in endobronchial biopsy specimens obtained from patients with severe or mild asthma persisted in the air-liquid interface reconstituted epithelium throughout the differentiation process to 21 days. Epithelium from patients with severe asthma produced greater levels of mucin, released more IL-8, and produced lower levels of lipoxin A4 than that from patients with mild asthma. Expression of 15-lipoxygenase 2 was increased in epithelium from patients with severe asthma, whereas expression levels of MUC5AC, MUC5B, 5-lipoxygenase, and 15-lipoxygeanse 1 were similar to those of patients with mild asthma. Conclusion: Ex vivo cultures of fully differentiated bronchial epithelium from endobronchial biopsy specimens maintain inherent phenotypic differences specifically related to the severity of asthma. [Copyright &y& Elsevier]

Background: Right ventricular (RV) function has major prognostic implications for pulmonary arterial hypertension (PAH). RV function assessment by echocardiography is challenging in PAH patients. New techniques such as two-dimensional strain (2DS) and three dimension (3D) echocardiography may allow assessment of RV function. Objective: We sought to determine among echocardiographic techniques – those widely used, 2DS and 3D – which one was the best correlated to magnetic resonance imaging (MRI) measurements. Methods: Fourteen patients with PAH (mean age 58 +/- 17 yr, 7 women) were evaluated. RV fractional area change (RVFAC), Tei index, peak systolic velocity (S), Tricuspid Annular Plane Systolic Excursion (TAPSE) were measured. Global and segmental RV longitudinal deformations were recorded by 2DS echocardiography from 4 apical-chamber views using 6 segments RV model. Echocardiographic system designed for 3D was Tomtec. Results: TAPSE, peak S and RVFAC were lower in PAH patients than control and correlated to MRI (p<0.005). Global and free wall strain measured by 2DS and ejection fraction VD (FEVD) by MRI (r=0.73; p< 0.005) were inversely correlated. The 3D volume and 3D FEVD were strongly correlated to corresponding measurements obtained by MRI (volume: r=0.88; p<0.005) (FE: r=0.85; p<0.005). Conclusion: Both 2DS and 3D echocardiography techniques are strongly correlated to MRI. Simple and reliable 2DS could be preferred to 3D. [Copyright &y& Elsevier]

Summary: Asthma is the most frequently encountered allergic respiratory disease, and one that has a potentially serious impact on patients'' functioning and well-being. From a public health perspective, it is important to collect data on the prevalence, burden and management of asthma in order to improve understanding of the pathogenesis of asthma and to ensure that national healthcare policies are adapted and appropriate. In this respect, the different AIR surveys, which have collected standardised data on asthma in the general population of a large number of countries around the world, have made an important contribution. The latest of these surveys is the AIRMAG survey, performed in the three Maghreb countries of Algeria, Morocco and Tunisia. In these countries, the prevalence of asthma (3.4% to 3.9%) is in the low to moderate range. This is consistent with rates observed elsewhere in the Mediterranean basin. Nonetheless, the prevalence of asthma in the Maghreb may be expected to rise in the future as populations become more urbanised and adopt a more ‘Westernised’ lifestyle. Indeed the prevalence of asthma is already higher in the urban coastal regions of these countries than in the more rural mountainous and desert regions. Asthma control in the Maghreb is relatively poor compared to other regions evaluated in previous AIR studies, with control being unacceptable in around three-quarters of respondents. Although part of the explanation may reside in limited access to care, treatment rates for inhaled corticosteroids (26.1% of adults and 29.1% of children) were no worse than those reported in previous AIR studies. On the other hand, asthma monitoring through regular follow-up visits, home flow-meter use and preparation of individualised asthma management plans was in general unsatisfactory. In addition, awareness of asthma in the general population of the Maghreb countries was low. Education measures directed at the patient, together with programmes directed at the physician to ensure systematic monitoring and the use of a ‘treat to target’ approach to therapy, could do much to increase quality of life and minimise restrictions on activities in patients with asthma in the Maghreb. [Copyright &y& Elsevier]

Lungs have a complex structure composed of different cell types that form approximately 17 million airway branches of gas-delivering bronchioles connected to 500 million gas-exchanging alveoli. Airways and alveoli are lined by epithelial cells that display a low rate of turnover at steady-state, but can regenerate the epithelium in response to injuries. Here, we review the key points of lung development, homeostasis and epithelial cell plasticity in response to injury and disease, because this knowledge is required to develop new lung disease treatments. Of note, canonical signaling pathways that are essential for proper lung development during embryogenesis are also involved in the pathophysiology of most chronic airway diseases. Moreover, the perfect control of these interconnected pathways is needed for the successful differentiation of induced pluripotent stem cells (iPSC) into lung cells. Indeed, differentiation of iPSC into airway epithelium and alveoli is based on the use of biomimetics of normal embryonic and fetal lung development. In vitro iPSC-based models of lung diseases can help us to better understand the impaired lung repair capacity and to identify new therapeutic targets and new approaches, such as lung cell therapy. [ABSTRACT FROM AUTHOR]

Objective: Pulmonary arterial hypertension (PAH) is a rare and life-threatening disease well-marked by under diagnosis, delayed diagnosis and atypical treatments. Few data are available on the quality of life (QoL) and psychosocial characteristics of patients with PAH. Our aim is to describe the impact of psychological factors on the health-related quality of life (HRQoL) of treated PAH patients in a cross-sectional study.Methods: Consecutive patients presenting at our Competency Centre for PAH were recruited. The aetiology, New York Heart Association (NYHA) stage, haemodynamics, 6-min walk distance (6MWD), delta SPO2 (Pulse oximeter oxygen saturation; baseline lowest value during 6-min walk test (6MWT), current treatments and psychological history were recorded. HRQoL, anxiety, depression and coping strategies were explored using self-administered questionnaires (SF-36, HADS, STAI-Y, CHIP and WCC).Results: A total of 55 patients were included. The HRQoL of PAH patients was poor with altered results on several scales. Anxiety and depression were high and coping was focused on medical information strategies. Multivariate analysis indicated a positive relationship between 6MWD and the Physical Composite Score for QoL (p=0.004), as well as a negative relationship between delta SPO2 and the Mental Composite Score (p=0.02), irrespective of other known prognostic factors (such as haemodynamics at right heart catheterization). Depression and Trait-Anxiety were associated with a lower physical (p=0.001) and mental (p<0.001) QoL, respectively.Conclusions: Psychological factors impact the HRQoL of treated patients. A longitudinal and qualitative study should refine these results.Trial Registration: Clinical trial N°: NCT01380054. [ABSTRACT FROM AUTHOR]

The development of suitable Cystic Fibrosis (CF) models for preclinical bench tests of therapeutic candidates is challenging. Indeed, the validation of molecules to rescue the p.Phe508del-CFTR channel (encoded by the Cystic Fibrosis Transmembrane conductance Regulator gene carrying the p.Phe508del mutation) requires taking into account their overall effects on the epithelium. Suberoylanilide Hydroxamic Acid (SAHA), a histone deacetylase inhibitor (HDACi), was previously shown to be a CFTR corrector via proteostasis modulation in CFTR-deficient immortalized cells. Here, we tested SAHA effects on goblet cell metaplasia using an ex vivo model based on the air-liquid interface (ALI) culture of differentiated airway epithelial cells obtained by nasal scraping from CF patients and healthy controls. Ex vivo epithelium grew successfully in ALI cultures with significant rise in the expression of CFTR and of markers of airway epithelial differentiation compared to monolayer cell culture. SAHA decreased CFTR transcript and protein levels in CF and non-CF epithelia. Whereas SAHA induced lysine hyperacetylation, it did not change histone modifications at the CFTR promoter. SAHA reduced MUC5AC and MUC5 B expression and inhibited goblet epithelial cell differentiation. Similar effects were obtained in CF and non-CF epithelia. All the effects were fully reversible within five days from SAHA withdrawal. We conclude that, ex vivo, SAHA modulate the structure of airway epithelia without specific effect on CFTR gene and protein suggesting that HDACi cannot be useful for CF treatment. [ABSTRACT FROM AUTHOR]

Objectives: The current use of intravenous epoprostenol in patients with severe idiopathic, heritable or anorexigen-use associated pulmonary arterial hypertension (IHA-PAH) was investigated. Methods: This observational study evaluated newly diagnosed (≤1year) patients with IHA-PAH, enrolled in the French pulmonary hypertension (PH) registry between 2006 and 2010 and treated with epoprostenol. Among 209 consecutive patients receiving epoprostenol for the treatment of severe PH, 78 had IHA-PAH, including 43 patients naïve of previous PAH-specific treatment. Results: After 4months of epoprostenol therapy, improvement was observed for treatment naïve patients (n=43) and for patients who had received previous PAH-specific therapy (n=35): NYHA functional class improved in 79% and 44% of these patients, respectively, 6-minute walk distance increased by 146 (p<0.0001) and 41m (p=0.03), cardiac index increased by 1.2 (p<0.0001) and 0.5L·min−1·m−2 (p=0.006), and pulmonary vascular resistance decreased by 700 (p<0.0001) and 299dyn·s·cm−5 (p=0.009). In the treatment-naïve patient group, upfront combination of epoprostenol and oral PAH therapy tended to be more beneficial compared with epoprostenol monotherapy and was associated with improvement in cardiac index (p=0.03). The observed 1- and 3-year survival estimates from epoprostenol initiation were 84% and 69%, respectively. The highest survival rates were observed for treatment-naïve patients receiving upfront combination of epoprostenol and oral PAH therapy (92% and 88% at 1 and 3years, respectively). Conclusions: First-line therapy with epoprostenol, especially when combined with oral PAH treatment, was associated with a substantial improvement in clinical and hemodynamic status and favorable survival estimates in patients with severe IHA-PAH. [ABSTRACT FROM AUTHOR]

Abstract: Increasing evidence of a critical role played by the bronchial epithelium in airway homeostasis is opening new therapeutic avenues. Its unique situation at the interface with the environment suggests that the subtle regulation orchestrated by the epithelium between tolerance and specific immune response might be impaired in asthma. Airway mucus is acting as a physical and a biological fluid between the environment and the epithelium, synergistically moved by the cilia. In asthma, excessive mucus production is a hallmark of airway remodeling. Since many years we tried to therapeutically target mucus hypersecretion, but actually this option is still not achieved. The present review discusses the dynamic processes regulating airway mucus production. Airway inflammation is central in current asthma management. Understanding of how the airway epithelium influences the TH2 paradigm in response to deleterious agents is improving. The multiple receptors expressed by the airway epithelium are the transducers of the biological signals induced by various invasive agents to develop the most adapted response. Airway remodeling is observed in severe chronic airway diseases and may result from ongoing disturbance of signal transduction and epithelial renewal. Chronic airway diseases such as asthma will require assessment of these epithelial abnormalities to identify phenotypic characteristics associated with predicting a clinical benefit for epithelial-directed therapies. [Copyright &y& Elsevier]