Pulido T.,Ignacio Chavez National Heart Institute |
Adzerikho I.,Republican Scientific Practical Center Cardiology |
Channick R.N.,Massachusetts General Hospital |
Delcroix M.,Gasthuisberg University Hospital |
And 19 more authors.
New England Journal of Medicine | Year: 2013
BACKGROUND: Current therapies for pulmonary arterial hypertension have been adopted on the basis of short-term trials with exercise capacity as the primary end point. We assessed the efficacy of macitentan, a new dual endothelin-receptor antagonist, using a primary end point of morbidity and mortality in a long-term trial. METHODS: We randomly assigned patients with symptomatic pulmonary arterial hypertension to receive placebo once daily, macitentan at a once-daily dose of 3 mg, or macitentan at a once-daily dose of 10 mg. Stable use of oral or inhaled therapy for pulmonary arterial hypertension, other than endothelin-receptor antagonists, was allowed at study entry. The primary end point was the time from the initiation of treatment to the first occurrence of a composite end point of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of pulmonary arterial hypertension. RESULTS: A total of 250 patients were randomly assigned to placebo, 250 to the 3-mg macitentan dose, and 242 to the 10-mg macitentan dose. The primary end point occurred in 46.4%, 38.0%, and 31.4% of the patients in these groups, respectively. The hazard ratio for the 3-mg macitentan dose as compared with placebo was 0.70 (97.5% confidence interval [CI], 0.52 to 0.96; P = 0.01), and the hazard ratio for the 10-mg macitentan dose as compared with placebo was 0.55 (97.5% CI, 0.39 to 0.76; P<0.001). Worsening of pulmonary arterial hypertension was the most frequent primary end-point event. The effect of macitentan on this end point was observed regardless of whether the patient was receiving therapy for pulmonary arterial hypertension at baseline. Adverse events more frequently associated with macitentan than with placebo were headache, nasopharyngitis, and anemia. CONCLUSIONS: Macitentan significantly reduced morbidity and mortality among patients with pulmonary arterial hypertension in this event-driven study. Copyright © 2013 Massachusetts Medical Society.
News Article | March 2, 2017
Smoke from cigarettes blocks self-healing processes in the lungs and consequently can lead to chronic obstructive pulmonary disease (COPD). Researchers at the Helmholtz Zentrum München, partner in the German Center for Lung Research (DZL), and their international colleagues have reported this in the American Journal of Respiratory and Critical Care Medicine. Cough, bronchitis and breathing difficulties -- these are the typical manifestations of COPD. Exact figures are not available, but estimates assume that ten to twelve percent of the adults over 40 years of age in Germany suffer from the disease. Experts estimate the national economic costs of the disease at almost six billion euros annually.* Scientists around the world are attempting to discover how the disease develops and what biological adjustments can be made to stop it. One approach involves the lung's natural self-healing, which no longer takes place in COPD. "In healthy patients, the so-called WNT/beta-catenin signaling pathway is responsible for the lung's homeostasis. Until now, it was not clear why it was silenced in patients with COPD," explains Dr. Dr. Melanie Königshoff, head of the Lung Repair and Regeneration (LRR) Research Unit of the Comprehensive Pneumology Center (CPC) at Helmholtz Zentrum München. She and her team spent the last few years tackling this question in the framework of an ERC Starting Grant and discovered that one of the Frizzled molecules- Frizzled 4 -plays an important role. "Frizzled 4 is a receptor molecule that sits on the surface of lung cells, where it regulates their self-renewal via WNT/beta-catenin," explains first author Wioletta Skronska-Wasek, doctoral candidate at the LRR. "However if the cells are exposed to cigarette smoke, Frizzled 4 disappears from the surface and cell growth comes to a halt." The starting point for the current study was the team's observation that in the lung tissue of COPD patients, and especially that of smokers, there were significantly fewer Frizzled 4 receptors than in non-smokers. "In the next step, we were able to prove in cell culture and model systems that inhibition of Frizzled 4 signaling on the cells led to decreased WNT/beta-catenin activity and consequently to reduced wound healing and repair capacity," described Dr. Ali Önder Yildirim, an expert on the effects of cigarette smoke in the lung. He is a group leader at the Institute of Lung Biology of the CPC at the Helmholtz Zentrum München and also participated in the study. The authors additionally recognized that without the receptor, there was a loss of certain proteins that are important for the structure of lung tissue (including elastin, fibulin and IGF1) and the lung's elasticity, allowing patients to breathe. To confirm their results, the scientists artificially increased Frizzled 4 levels in a cell culture test to stimulate its production. The increase in Frizzled 4 reactivated the blocked repair process and led to the production of many of the previously reduced proteins. "The activation of the Frizzled 4 receptor can restore the WNT/beta-catenin signaling pathway and consequently lead to repair in the lung," explains Melanie Königshoff. This is an exciting starting point for further research which might develop new therapies for COPD patients.** The name "Frizzled" stems from its discovery in genetically modified fruit flies: animals that lacked Frizzled showed a hair malposition, so that it looked "frizzled". Just recently, Melanie Königshoff and her team were able to elucidate another mechanism that prevents the lungs in COPD patients from healing themselves. https:/ The WNT/beta-catenin pathway is also defective in this case. Investigations by the Königshoff team also show the key role that this signal chain has in the lung, where it also plays a role in pulmonary fibrosis. https:/ Skronska-Wasek, W. et al. (2017): Reduced Frizzled receptor 4 expression prevents WNT/β-catenin-driven alveolar lung repair in COPD. American Journal of Respiratory and Critical Care Medicine, doi: 10.1164/rccm.201605-0904OC http://www. The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. http://www. The Lung Repair and Regeneration Research Unit is part of the Comprehensive Pneumology Center (CPC), which is a joint undertaking of the Helmholtz Zentrum München, Ludwig Maximilian University Munich with its University Hospital, and the Asklepios Specialist Clinics Munich-Gauting. The CPC's objective is to conduct research on chronic lung diseases in order to develop new diagnostic tools and therapies. The LRR Research Unit examines new mechanisms and repair processes in the lungs for a better understanding that will allow the development of new therapeutic approaches. The unit also focuses on developing new methods in order to reduce the gap between pre-clinical research and its application on patients. The CPC is a facility of the German Center for Lung Research (Deutsches Zentrum für Lungenforschung - DZL). http://www. The German Center for Lung Research (DZL) pools German expertise in the field of pulmonology research and clinical pulmonology. The association's head office is in Giessen. The aim of the DZL is to find answers to open questions in research into lung diseases by adopting an innovative, integrated approach and thus to make a sizeable contribution to improving the prevention, diagnosis and individualized treatment of lung disease and to ensure optimum patient care. http://www.
Raedler D.,Ludwig Maximilians University of Munich |
Raedler D.,German Center for Lung Research |
Schaub B.,Ludwig Maximilians University of Munich |
Schaub B.,German Center for Lung Research
The Lancet Respiratory Medicine | Year: 2014
Early life influences are crucial for the development of distinct childhood asthma phenotypes, which are currently included under the term asthma syndrome. Improved characterisation of different childhood asthma phenotypes will help to elucidate specific underlying immune mechanisms-namely, endotypes. Besides genetics, epigenetics and environmental factors have an effect on innate and adaptive immune regulatory networks. Crucial determining factors for complex immune regulation and barrier function include family history of atopy, respiratory infections, microbiome, and nutrition. Recent diagnostic approaches, including biomarkers, might offer a unique opportunity to improve definitions of asthma sub-phenotypes, prediction of outcome, and treatment options, by referring to the underlying pathophysiology. For prevention and patient-individualised medicine, a multifactorial approach incorporating deep phenotyping and mathematical models for analysis to extend our present knowledge is needed. © 2014 Elsevier Ltd.
Reck M.,German Center for Lung Research |
Heigener D.,German Center for Lung Research |
Reinmuth N.,German Center for Lung Research
Expert Review of Clinical Pharmacology | Year: 2014
An unmet need remains for effective, well-tolerated treatment options in advanced non-small-cell lung cancer that can alleviate the disease burden for a broad selection of patients. Nintedanib (Vargatef) is a potent, oral, triple angiokinase inhibitor of three distinct pro-angiogenic pathways. A recent Phase III trial of second-line nintedanib plus docetaxel met the primary end point of progression-free survival and demonstrated significant benefit in the key secondary end point of overall survival, with median overall survival greater than 1 year for patients with adenocarcinoma histology. This article summarizes preclinical and clinical experience with nintedanib in non-small-cell lung cancer to date and discusses how it may be used in the future, including prospects for individualizing treatment by tumor proliferation dynamics and molecular biomarkers of response. © 2014 Informa UK, Ltd.
Saul V.V.,Justus Liebig University |
Schmitz M.L.,Justus Liebig University |
Schmitz M.L.,German Center for Lung Research
Journal of Molecular Medicine | Year: 2013
The serine/threonine kinase homeodomain-interacting protein kinase (HIPK2) is a tumor suppressor and functions as an evolutionary conserved regulator of signaling and gene expression. This kinase regulates a surprisingly vast array of biological processes that range from the DNA damage response and apoptosis to hypoxia signaling and cell proliferation. Recent studies show the tight control of HIPK2 by hierarchically occurring posttranslational modifications such as phosphorylation, small ubiquitin-like modifier modification, acetylation, and ubiquitination. The physiological function of HIPK2 as a regulator of cell proliferation and survival has a downside: proliferative diseases. Dysregulation of HIPK2 can result in increased proliferation of cell populations as it occurs in cancer or fibrosis. We discuss various models that could explain how inappropriate expression, modification, or localization of HIPK2 can be a driver for these proliferative diseases. © 2013 Springer-Verlag Berlin Heidelberg.
Reck M.,Lung Clinic Grosshansdorf |
Reck M.,German Center for Lung Research |
Kaiser R.,Boehringer Ingelheim |
Mellemgaard A.,Herlev University Hospital |
And 11 more authors.
The Lancet Oncology | Year: 2014
Background: The phase 3 LUME-Lung 1 study assessed the efficacy and safety of docetaxel plus nintedanib as second-line therapy for non-small-cell lung cancer (NSCLC). Methods: Patients from 211 centres in 27 countries with stage IIIB/IV recurrent NSCLC progressing after first-line chemotherapy, stratified by ECOG performance status, previous bevacizumab treatment, histology, and presence of brain metastases, were allocated (by computer-generated sequence through an interactive third-party system, in 1:1 ratio), to receive docetaxel 75 mg/m2 by intravenous infusion on day 1 plus either nintedanib 200 mg orally twice daily or matching placebo on days 2-21, every 3 weeks until unacceptable adverse events or disease progression. Investigators and patients were masked to assignment. The primary endpoint was progression-free survival (PFS) by independent central review, analysed by intention to treat after 714 events in all patients. The key secondary endpoint was overall survival, analysed by intention to treat after 1121 events had occurred, in a prespecified stepwise order: first in patients with adenocarcinoma who progressed within 9 months after start of first-line therapy, then in all patients with adenocarcinoma, then in all patients. This trial is registered with ClinicalTrials.gov, number NCT00805194. Findings: Between Dec 23, 2008, and Feb 9, 2011, 655 patients were randomly assigned to receive docetaxel plus nintedanib and 659 to receive docetaxel plus placebo. The primary analysis was done after a median follow-up of 7·1 months (IQR 3·8-11·0). PFS was significantly improved in the docetaxel plus nintedanib group compared with the docetaxel plus placebo group (median 3·4 months [95% CI 2·9-3·9] vs 2·7 months [2·6-2·8]; hazard ratio [HR] 0·79 [95% CI 0·68-0·92], p=0·0019). After a median follow-up of 31·7 months (IQR 27·8-36·1), overall survival was significantly improved for patients with adenocarcinoma histology who progressed within 9 months after start of first-line treatment in the docetaxel plus nintedanib group (206 patients) compared with those in the docetaxel plus placebo group (199 patients; median 10·9 months [95% CI 8·5-12·6] vs 7·9 months [6·7-9·1]; HR 0·75 [95% CI 0·60-0·92], p=0·0073). Similar results were noted for all patients with adenocarcinoma histology (322 patients in the docetaxel plus nintedanib group and 336 in the docetaxel plus placebo group; median overall survival 12·6 months [95% CI 10·6-15·1] vs 10·3 months [95% CI 8·6-12·2]; HR 0·83 [95% CI 0·70-0·99], p=0·0359), but not in the total study population (median 10·1 months [95% CI 8·8-11·2] vs 9·1 months [8·4-10·4]; HR 0·94, 95% CI 0·83-1·05, p=0·2720). Grade 3 or worse adverse events that were more common in the docetaxel plus nintedanib group than in the docetaxel plus placebo group were diarrhoea (43 [6·6%] of 652 vs 17 [2·6%] of 655), reversible increases in alanine aminotransferase (51 [7·8%] vs six [0·9%]), and reversible increases in aspartate aminotransferase (22 [3·4%] vs three [0·5%]). 35 patients in the docetaxel plus nintedanib group and 25 in the docetaxel plus placebo group died of adverse events possibly unrelated to disease progression; the most common of these events were sepsis (five with docetaxel plus nintedanib vs one with docetaxel plus placebo), pneumonia (two vs seven), respiratory failure (four vs none), and pulmonary embolism (none vs three). Interpretation: Nintedanib in combination with docetaxel is an effective second-line option for patients with advanced NSCLC previously treated with one line of platinum-based therapy, especially for patients with adenocarcinoma. Funding: Boehringer Ingelheim. © 2014 Elsevier Ltd.
Meiners S.,Ludwig Maximilians University of Munich |
Meiners S.,German Center for Lung Research |
Eickelberg O.,Ludwig Maximilians University of Munich |
Eickelberg O.,German Center for Lung Research |
And 2 more authors.
European Respiratory Journal | Year: 2015
Ageing is the main risk factor for major non-communicable chronic lung diseases, including chronic obstructive pulmonary disease, most forms of lung cancer and idiopathic pulmonary fibrosis. While the prevalence of these diseases continually increases with age, their respective incidence peaks at different times during the lifespan, suggesting specific effects of ageing on the onset and/or pathogenesis of chronic obstructive pulmonary disease, lung cancer and idiopathic pulmonary fibrosis. Recently, the nine hallmarks of ageing have been defined as cell-autonomous and non-autonomous pathways involved in ageing. Here, we review the available evidence for the involvement of each of these hallmarks in the pathogenesis of chronic obstructive pulmonary disease, lung cancer, or idiopathic pulmonary fibrosis. Importantly, we propose an additional hallmark, "dysregulation of the extracellular matrix", which we argue acts as a crucial modifier of cell-autonomous changes and functions, and as a key feature of the above-mentioned lung diseases. Copyright ©ERS 2015.
Schmitz M.L.,Justus Liebig University |
Schmitz M.L.,German Center for Lung Research |
De La Vega L.,University of Dundee
Antioxidants and Redox Signaling | Year: 2015
Significance: The expression and/or activity of histone deacetylases (HDACs) can be regulated by a variety of environmental conditions, including inflammation and oxidative stress. These events result in diminished or exaggerated protein acetylation, both of which can be causative for many ailments. While the anti-inflammatory activity of HDAC inhibitors (HDACis) is well known, recent studies started unraveling details of the molecular mechanisms underlying the pro-inflammatory function of HDACs. Recent Advances: Recent evidence shows that HDACs are found in association with transcribed regions and ensure proper transcription by maintaining acetylation homeostasis. We also discuss current insights in the molecular mechanisms mediating acetylation-dependent inhibition of pro-inflammatory transcription factors of the NF-κB, HIF-1, IRF, and STAT families. Critical Issues: The high number of acetylations and the complexity of the regulatory consequences make it difficult to assign biological effects directly to a single acetylation event. The vast majority of acetylated proteins are nonhistone proteins, and it remains to be shown whether the therapeutic effects of HDACis are attributable to altered histone acetylation. Future Directions: In the traditional view, only exaggerated acetylation is harmful and causative for diseases. Recent data show the relevance of acetylation homeostasis and suggest that both diminished and inflated acetylation can enable the development of ailments. Since acetylation of nonhistone proteins is essential for the induction of a substantial part of the inflammatory gene expression program, HDACis are more than "epigenetic drugs." The identification of substrates for individual HDACs will be the prerequisite for the adequate use of highly specific HDACis. © Copyright 2015, Mary Ann Liebert, Inc.
Bruske I.,Helmholtz Center for Environmental Research |
Flexeder C.,Helmholtz Center for Environmental Research |
Heinrich J.,Helmholtz Center for Environmental Research |
Heinrich J.,German Center for Lung Research
Current Opinion in Allergy and Clinical Immunology | Year: 2014
PURPOSE OF REVIEW: When evaluating the causal link between obesity and the development of asthma in children, prospective cohort studies are essential. The results of the most recently published birth cohort studies from Sweden, Germany, Brazil, Belarus, and California, USA, as well as from a joint analysis of eight European birth cohorts of the Global Allergy and Asthma European Network are evaluated. Moreover, the results of two meta-analyses are presented. RECENT FINDINGS: Most recent prospective cohort studies found a dose-response association between overweight or obesity and asthma. The evidence of effect modification by sex, ethnicity, and age was inconsistent. Both meta-analyses also showed that overweight children were at an increased risk of incident asthma compared with nonoverweight children and that the relationship was further elevated for obesity. SUMMARY: Prospective cohort studies and two recently published meta-analyses found an association between overweight (and especially obesity) and asthma in the appropriate temporal sequence and in a dose-response manner. Children with a pronounced weight gain slope in early life were particularly at risk for asthma within the first 6 years of life. The gain in BMI over time during infancy may be an even more important predictor for asthma in childhood than excess weight at any specific age. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
News Article | December 16, 2016
In chronic obstructive pulmonary disease (COPD), the patients' lungs lose their ability to repair damages on their own. Scientists at the Helmholtz Zentrum München, partner in the German Center for Lung Research (DZL) now have a new idea as to why this might be so. In the Journal of Experimental Medicine, they blame the molecule Wnt5a for this problem. The first indication of COPD is usually a chronic cough. As the disease progresses, the airways narrow and often pulmonary emphysema develops. This indicates irreversible expansion and damage to the alveoli, or air sacks. "The body is no longer able to repair the destroyed structures," explains Dr. Dr. Melanie Königshoff, head of the Research Unit Lung Repair and Regeneration (LRR) at the Comprehensive Pneumology Center (CPC) of Helmholtz Zentrum München. She and her team have made it their job to understand how this happens. "In our current work we have been able to show that COPD results in a change in the messengers that lung cells use to communicate with one another," Königshoff continues. Specifically, the scientists discovered increased production of the Wnt5a molecule, which disrupts the classic (or canonical, as the experts call it) Wnt/beta-catenin signaling pathway* that is responsible for such repairs. "Our working hypothesis was that the relationship between different Wnt messengers is no longer balanced in COPD," reports Dr. Hoeke Baarsma, LRR scientist and the study's first author. The team correspondingly searched for possible interference signals. "In both the pre-clinical model and the tissue samples from patients, we found that in COPD tissue particularly the non-canonical Wnt5a molecule is increased and occurs in a modified form." According to the authors, stimuli that typically cause a reaction in COPD, such as cigarette smoke, additionally lead to increased production of Wnt5a and consequently to impaired lung regeneration. In the next step, the researchers were able to show where the misdirected signal originates: "It is produced by certain cells in the connective tissue, the so-called fibroblasts," Baarsma says. When pulmonary epithelial cells were treated with the Wnt5a derived from the fibroblasts, the cells lost their healing ability. The scientists were also able to use antibodies directed against Wnt5a in two different experimental models to slow down the lung destruction and better maintain the lung function. "Our results show that the classic Wnt/beta-catenin signal cascade is disrupted by the Wnt5a ligand. This is a completely new mechanism in association with COPD and could lead to new therapeutic approaches, which are urgently needed for treatment," study leader Königshoff explains the importance of the results. * The Wnt signaling pathway is one of many pathways for forwarding signals in order to allow cells to respond to external changes. The signaling pathway is named after its main player "Wnt", a signaling protein that takes on a key function in the development of various animal cells as a local mediator. Numerous proteins are involved in the canonical (classic) forwarding of the signals, including beta-catenin as the central cellular messenger. A pathway in which Wnt acts through other messengers, as described here, is called a non-canonical signaling pathway; this can have a negative impact on the canonical signaling. Background: Melanie Königshoff's department is a part of the German Center for Lung Research (Deutsches Zentrum für Lungenforschung - DZL). Dr. Hoeke Baarsma works as a post-doctoral scientist in the framework of the PFP program, which is sponsored by the Helmholtz Association. Original publication: Baarsma, HA et al. (2016): Non-canonical WNT-5A signaling impairs 1 endogenous lung repair in COPD. Journal of Experimental Medicine, doi: 10.1084/jem.20160675 The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. http://www. The Lung Repair and Regeneration Research Unit is part of the Comprehensive Pneumology Center (CPC), which is a joint undertaking of the Helmholtz Zentrum München, Ludwig Maximilian University Munich with its University Hospital, and the Asklepios Specialist Clinics Munich-Gauting. The CPC's objective is to conduct research on chronic lung diseases in order to develop new diagnostic tools and therapies. The LRR Research Unit examines new mechanisms and repair processes in the lungs for a better understanding that will allow the development of new therapeutic approaches. The unit also focuses on developing new methods in order to reduce the gap between pre-clinical research and its application on patients. The CPC is a facility of the German Center for Lung Research (Deutsches Zentrum für Lungenforschung - DZL). http://www. The German Center for Lung Research (DZL) pools German expertise in the field of pulmonology research and clinical pulmonology. The association's head office is in Giessen. The aim of the DZL is to find answers to open questions in research into lung diseases by adopting an innovative, integrated approach and thus to make a sizeable contribution to improving the prevention, diagnosis and individualized treatment of lung disease and to ensure optimum patient care. http://www. Contact for the media: Department of Communication, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg - Tel. +49 89 3187 2238 - Fax: +49 89 3187 3324 - E-mail: firstname.lastname@example.org