Universities of Giessen and Marburg Lung Center

Gießen, Germany

Universities of Giessen and Marburg Lung Center

Gießen, Germany
Time filter
Source Type

Pepke-Zaba J.,Papworth Hospital | Ghofrani H.-A.,Universities of Giessen and Marburg Lung Center | Hoeper M.M.,Hannover Medical School
European Respiratory Review | Year: 2017

Chronic thromboembolic pulmonary hypertension (CTEPH) results from incomplete resolution of acute pulmonary emboli, organised into fibrotic material that obstructs large pulmonary arteries, and distal small-vessel arteriopathy. Pulmonary endarterectomy (PEA) is the treatment of choice for eligible patients with CTEPH; in expert centres, PEA has low in-hospital mortality rates and excellent long-term survival. Supportive medical therapy consists of lifelong anticoagulation plus diuretics and oxygen, as needed. An important recent advance in medical therapy for CTEPH is the arrival of medical therapies for patients with inoperable disease or persistent/recurrent pulmonary hypertension after PEA. The soluble guanylate cyclase stimulator riociguat is licensed for the treatment of CTEPH in patients with inoperable disease or with recurrent/persistent pulmonary hypertension after PEA. Clinical trials of this agent have shown improvements in patients’ haemodynamics and exercise capacity. Phosphodiesterase-5 inhibitors, endothelin receptor antagonists and prostanoids have been used in the treatment of CTEPH, but evidence of benefit is limited. Challenges in the future development of medical therapy for CTEPH include better understanding of the underlying pathology, end-points to monitor the condition’s progress, and the optimisation of pulmonary arterial hypertension therapies in relation to diverse patient characteristics and emerging options such as balloon pulmonary angioplasty. © ERS 2017.

Lang I.,Medical University of Vienna | Meyer B.C.,Hannover Medical School | Ogo T.,National Cerebral and Cardiovascular Center | Matsubara H.,National Hospital Organization | And 4 more authors.
European Respiratory Review | Year: 2017

Chronic thromboembolic pulmonary hypertension (CTEPH) is thought to result from incomplete resolution of pulmonary thromboemboli that undergo organisation into fibrous tissue within pulmonary arterial branches, filling pulmonary arterial lumina with collagenous obstructions. The treatment of choice is pulmonary endarterectomy (PEA) in CTEPH centres, which has low post-operative mortality and good long-term survival. For patients ineligible for PEA or who have recurrent or persistent pulmonary hypertension after surgery, medical treatment with riociguat is beneficial. In addition, percutaneous balloon pulmonary angioplasty (BPA) is an emerging option, and promises haemodynamic and functional benefits for inoperable patients. In contrast to conventional angioplasty, BPA with undersized balloons over guide wires exclusively breaks intraluminal webs and bands, without dissecting medial vessel layers, and repeat sessions are generally required. Observational studies report that BPA improves haemodynamics, symptoms and functional capacity in patients with CTEPH, but controlled trials with long-term follow-up are needed. Complications include haemoptysis, wire injury, vessel dissection, vessel rupture, reperfusion pulmonary oedema, pulmonary parenchymal bleeding and haemorrhagic pleural effusions. This review summarises the available evidence for BPA, patient selection, recent technical refinements and periprocedural imaging, and discusses the potential future role of BPA in the management of CTEPH. © ERS 2017.

Muhlbauer D.,Justus Liebig University | Dzieciolowski J.,Justus Liebig University | Hardt M.,Justus Liebig University | Hocke A.,Charité - Medical University of Berlin | And 10 more authors.
Journal of Virology | Year: 2015

Influenza A viruses (IAV) replicate their segmented RNA genome in the nucleus of infected cells and utilize caspase-dependent nucleocytoplasmic export mechanisms to transport newly formed ribonucleoprotein complexes (RNPs) to the site of infectious virion release at the plasma membrane. In this study, we obtained evidence that apoptotic caspase activation in IAV-infected cells is associated with the degradation of the nucleoporin Nup153, an integral subunit of the nuclear pore complex. Transmission electron microscopy studies revealed a distinct enlargement of nuclear pores in IAV-infected cells. Transient expression and subcellular accumulation studies of multimeric marker proteins in virus-infected cells provided additional evidence for increased nuclear pore diameters facilitating the translocation of large protein complexes across the nuclear membrane. Furthermore, caspase 3/7 inhibition data obtained in this study suggest that active, Crm1-dependent IAV RNP export mechanisms are increasingly complemented by passive, caspase-induced export mechanisms at later stages of infection. © 2015, American Society for Microbiology.

Galie N.,University of Bologna | Barbera J.A.,University of Barcelona | Frost A.E.,Baylor College of Medicine | Ghofrani H.-A.,Universities of Giessen and Marburg Lung Center | And 15 more authors.
New England Journal of Medicine | Year: 2015

Background Data on the effect of initial combination therapy with ambrisentan and tadalafil on long-term outcomes in patients with pulmonary arterial hypertension are scarce. Methods In this event-driven, double-blind study, we randomly assigned, in a 2:1:1 ratio, participants with World Health Organization functional class II or III symptoms of pulmonary arterial hypertension who had not previously received treatment to receive initial combination therapy with 10 mg of ambrisentan plus 40 mg of tadalafil (combination-therapy group), 10 mg of ambrisentan plus placebo (ambrisentanmonotherapy group), or 40 mg of tadalafil plus placebo (tadalafil-monotherapy group), all administered once daily. The primary end point in a time-to-event analysis was the first event of clinical failure, which was defined as the first occurrence of a composite of death, hospitalization for worsening pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response. RESULTS The primary analysis included 500 participants; 253 were assigned to the combination-therapy group, 126 to the ambrisentan-monotherapy group, and 121 to the tadalafil-monotherapy group. A primary end-point event occurred in 18%, 34%, and 28% of the participants in these groups, respectively, and in 31% of the pooledmonotherapy group (the two monotherapy groups combined). The hazard ratio for the primary end point in the combination-therapy group versus the pooled-monotherapy group was 0.50 (95% confidence interval [CI], 0.35 to 0.72; P<0.001). At week 24, the combination-therapy group had greater reductions from baseline in N-terminal pro-brain natriuretic peptide levels than did the pooled-monotherapy group (mean change,-67.2% vs.-50.4%; P<0.001), as well as a higher percentage of patients with a satisfactory clinical response (39% vs. 29%; odds ratio, 1.56 [95% CI, 1.05 to 2.32]; P = 0.03) and a greater improvement in the 6-minute walk distance (median change from baseline, 48.98 m vs. 23.80 m; P<0.001). The adverse events that occurred more frequently in the combination-therapy group than in either monotherapy group included peripheral edema, headache, nasal congestion, and anemia. Conclusions Among participants with pulmonary arterial hypertension who had not received previous treatment, initial combination therapy with ambrisentan and tadalafil resulted in a significantly lower risk of clinical-failure events than the risk with ambrisentan or tadalafil monotherapy. Copyright © 2015 Massachusetts Medical Society.

Sittka A.,Universities of Giessen and Marburg Lung Center | Vera J.,University of Rostock | Lai X.,Universities of Giessen and Marburg Lung Center | Lai X.,University of Rostock | And 2 more authors.
Pediatric Research | Year: 2013

Asthma has a high prevalence worldwide, and contributes significantly to the socioeconomic burden. According to a classical paradigm, asthma symptoms are attributable to an allergic, Th2-driven airway inflammation that causes airway hyperresponsiveness and results in reversible airway obstruction. Diagnosis and therapy are based mainly on these pathophysiologic concepts. However, these have increasingly been challenged by findings of recent studies, and the frequently observed failure in controlling asthma symptoms. Important recent findings are the protective "farm effect" in children, the possible prenatal mechanisms of this protection, the recognition of many different asthma phenotypes in children and adults, and the partly disappointing clinical effects of new targeted therapeutic approaches. Systems biology approaches may lead to a more comprehensive view of asthma pathophysiology and a higher success rate of new therapies. Systems biology integrates clinical and experimental data by means of bioinformatics and mathematical modeling. In general, the "-omics" approach, and the "mathematical modeling" approach can be described. Recently, several consortia have been attempting to bring together clinical and molecular data from large asthma cohorts, using novel experimental setups, biostatistics, bioinformatics, and mathematical modeling. This "systems medicine" approach to asthma will help address the different asthma phenotypes with adequate therapy and possibly preventive strategies. Copyright © 2013 International Pediatric Research Foundation, Inc.

Schmall A.,Max Planck Institute for Heart and Lung Research | Al-Tamari H.M.,Max Planck Institute for Heart and Lung Research | Herold S.,Universities of Giessen and Marburg Lung Center | Kampschulte M.,Universities of Giessen and Marburg Lung Center | And 10 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2015

Rationale: Recent studies indicate that tumor-associated macrophages (MΦ) with an M2 phenotype can influence cancer progression and metastasis, but the regulatory pathways remain poorly characterized. Objectives: This study investigated the role of tumor-associated MΦ in lung cancer. Methods: Coculturing of MΦ with mouse Lewis lung carcinoma (LLC1) and 10 different human lung cancer cell lines (adenocarcinoma, squamous cell carcinoma, and large cell carcinoma) caused up-regulation of CCR2/CCL2 and CX3CR1/ CX3CL1 in both the cancer cells and the MΦ. Measurements and Main Results: In the MΦ-tumor cell system, IL-10 drove CCR2 and CX3CR1 up-regulation, whereas CCL1, granulocyte colony-stimulating factor, and MIP1a were required for the up-regulation of CCL2 and CX3CL1. Downstream phenotypic effects included enhanced LLC1 proliferation and migration and MΦ M2 polarization. In vivo, MΦ depletion (clodronate,MΦFas-induced apoptosismice) and genetic ablation of CCR2 and CX3CR1 all inhibited LLC1 tumor growth and metastasis, shifted tumor-associated MΦ toward M1 polarization, suppressed tumor vessel growth, and enhanced survival (metastasis model). Furthermore, mice treated with CCR2 antagonist mimicked genetic ablation of CCR2, showing reduced tumor growth and metastasis. In human lung cancer samples, tumorMΦinfiltration and CCR2 expression correlatedwith tumor stage and metastasis. Conclusions: Tumor-associated MΦ play a central role in lung cancer growth and metastasis, with bidirectional cross-talk between MΦ and cancer cells via CCR2 and CX3CR1 signaling as a central underlying mechanism. These findings suggest that the therapeutic strategy of blocking CCR2 and CX3CR1 may prove beneficial for halting lung cancer progression. Copyright © 2015 by the American Thoracic Society.

Richter A.M.,Universities of Giessen and Marburg Lung Center | Walesch S.K.,Universities of Giessen and Marburg Lung Center | Wurl P.,Diakoniekrankenhaus Halle | Taubert H.,Friedrich - Alexander - University, Erlangen - Nuremberg | Dammann R.H.,Universities of Giessen and Marburg Lung Center
Oncogenesis | Year: 2012

The Ras association domain family (RASSF) comprises a group of tumor suppressors that are frequently epigenetically inactivated in various tumor entities and linked to apoptosis, cell cycle control and microtubule stability. In this work, we concentrated on the newly identified putative tumor suppressor RASSF10. Methylation analysis reveals RASSF10 promoter hypermethylation in lung cancer, head and neck (HN) cancer, sarcoma and pancreatic cancer. An increase in RASSF10 methylation from normal tissues, primary tumors to cancer cell lines was observed. Methylation was reversed by 5-aza-2'-deoxycytidine treatment leading to reexpression of RASSF10. We further show that overexpression of RASSF10 suppresses colony formation in cancer cell lines. In addition, RASSF10 is upregulated by cell-cell contact and regulated on promoter level as well as endogenously by forskolin, protein kinase A (PKA) and activator Protein 1 (AP-1), linking RASSF10 to the cAMP signaling pathway. Knockdown of the AP-1 member JunD interfered with contact inhibition induced RASSF10 expression. In summary, we found RASSF10 to be epigenetically inactivated by hypermethylation of its CpG island promoter in lung, HN, sarcoma and pancreatic cancer. Furthermore, our novel findings suggest that tumor suppressor RASSF10 is upregulated by PKA and JunD signaling upon contact inhibition and that RASSF10 suppresses growth of cancer cells. © 2012 Macmillan Publishers Limited. All rights reserved.

Veith C.,Universities of Giessen and Marburg Lung Center | Schermuly R.T.,Universities of Giessen and Marburg Lung Center | Brandes R.P.,Goethe University Frankfurt | Weissmann N.,Universities of Giessen and Marburg Lung Center
Journal of Physiology | Year: 2016

Oxygen (O2) is essential for the viability and function of most metazoan organisms and thus is closely monitored at both the organismal and the cellular levels. However, alveoli often encounter decreased O2 levels (hypoxia), leading to activation of physiological or pathophysiological responses in the pulmonary arteries. Such changes are achieved by activation of transcription factors. The hypoxia-inducible factors (HIFs) are the most prominent hypoxia-regulated transcription factors in this regard. HIFs bind to hypoxia-response elements (HREs) in the promoter region of target genes, whose expression and translation allows the organism, amongst other factors, to cope with decreased environmental O2 partial pressure (pO2). However, prolonged HIF activation can contribute to major structural alterations, especially in the lung, resulting in the development of pulmonary hypertension (PH). PH is characterized by a rise in pulmonary arterial pressure associated with pulmonary arterial remodelling, concomitant with a reduced intravascular lumen area. Patients with PH develop right heart hypertrophy and eventually die from right heart failure. Thus, understanding the molecular mechanisms of HIF regulation in PH is critical for the identification of novel therapeutic strategies. This review addresses the relationship of hypoxia and the HIF system with pulmonary arterial dysfunction in PH. We particularly focus on the cellular and molecular mechanisms underlying the HIF-driven pathophysiological processes. © 2016 The Physiological Society.

Janssen W.,Universities of Giessen and Marburg Lung Center | Schermuly R.T.,Universities of Giessen and Marburg Lung Center | Kojonazarov B.,Universities of Giessen and Marburg Lung Center
Experimental Physiology | Year: 2013

New findings: • What is the Topic of this review? The topic of the review is the physiological and molecular responses of the right ventricle to pressure overload and the role of the cGMP-phosphodiesterase 5 signalling pathway on right ventricular hypertrophy and function. • What advances does it highlight? Right ventricular dysfunction is a major determinant of prognosis in pulmonary arterial hypertension patients. In this review, we discuss the molecular physiological/ pathophysiological response of the right ventricle to high-pressure overload, with special emphasis on cGMP-phosphodiesterase 5 signalling. Pulmonary arterial hypertension (PAH) is a progressive disease that is associated with a poor prognosis and results in right heart dysfunction. While pulmonary vascular disease is the obvious primary pathological focus, right ventricular hypertrophy (RVH) and right ventricular (RV) dysfunction are major determinants of prognosis in PAH. Our knowledge about the molecular physiology and pathophysiology of RV hypertrophy and failure in response to pressure overload is still limited, and most data are derived from left heart research. However, the molecular mechanisms of left ventricular remodelling cannot be generalized to the RV, because the right and left ventricles differ greatly in their size, shape, architecture and function. Despite the recent advances in diagnosis and treatment of PAH, little is known about the molecular and cellular mechanisms that underlie the transition from compensatory to maladaptive RV remodelling. The cGMP-phosphodiesterase 5 (PDE5) pathway is one of the extensively studied pathways in PAH, but our knowledge about cGMP-PDE5 signalling in RV pathophysiology is still limited. For this purpose, there is need for animal models that can represent changes in the RV that closely mimic the human situation. The availability of an animal model of pressure-overload-induced RVH (e.g. pulmonary artery banding model) provides us with a valuable tool to understand the differences between adaptive and maladaptive RVH and to explore the direct effects of current PAH therapy on the heart. In this report, we discuss myocardial regulatory effects of cGMP-PDE5 signalling in preclinical models of RV pressure overload for understanding the physiological/pathophysiological mechanisms involved in maladaptive RVH. © 2013 The Physiological Society.

Veit F.,Universities of Giessen and Marburg Lung Center | Pak O.,Universities of Giessen and Marburg Lung Center | Brandes R.P.,Justus Liebig University | Weissmann N.,Universities of Giessen and Marburg Lung Center
Antioxidants and Redox Signaling | Year: 2015

Significance: An acute lack of oxygen in the lung causes hypoxic pulmonary vasoconstriction, which optimizes gas exchange. In contrast, chronic hypoxia triggers a pathological vascular remodeling causing pulmonary hypertension, and ischemia can cause vascular damage culminating in lung edema. Recent Advances: Regulation of ion channel expression and gating by cellular redox state is a widely accepted mechanism; however, it remains a matter of debate whether an increase or a decrease in reactive oxygen species (ROS) occurs under hypoxic conditions. Ion channel redox regulation has been described in detail for some ion channels, such as Kv channels or TRPC6. However, in general, information on ion channel redox regulation remains scant. Critical Issues and Future Directions: In addition to the debate of increased versus decreased ROS production during hypoxia, we aim here at describing and deciphering why different oxidants, under different conditions, can cause both activation and inhibition of channel activity. While the upstream pathways affecting channel gating are often well described, we need a better understanding of redox protein modifications to be able to determine the complexity of ion channel redox regulation. Against this background, we summarize the current knowledge on hypoxia-induced ROS-mediated ion channel signaling in the pulmonary circulation. Antioxid. Redox Signal. 22, 537-552 © Copyright 2015, Mary Ann Liebert, Inc. 2015.

Loading Universities of Giessen and Marburg Lung Center collaborators
Loading Universities of Giessen and Marburg Lung Center collaborators