F Grimminger

Publications (243)1102.48 Total impact

• Article: Surfactant-Therapie für das akute Lungenversagen (ARDS)

  D. Walmrath, A. Günther, F. Grimminger, W. Seeger
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  ABSTRACT: Ausgedehnte inflammatorische Prozesse im mikrovaskulären, interstitiellen und alveolären Kompartiment der Lunge charakterisieren das akute Atemnotsyndrom (ARDS). Dies führt zu vasomotorischen Veränderungen der pulmonalen Strombahn, Extravasation von Plasmaproteinen, Zellschädigung und schweren Gasaustauschstörungen. Ursächlich werden seit langem auch Veränderungen des alveolären Surfactant-Systems in der pathogenetischen Sequenz dieses lebensbedrohlichen Syndroms diskutiert. Diese Hypothese wird nicht zuletzt durch den ähnlichen Verlauf der respiratorischen Insuffizienz beim ARDS und bei Frühgeborenen (Infant Respiratory Distress Syndrome [IRDS]), bei denen ein primärer Surfactant-Mangel zugrunde liegt, unterstützt. Die Surfactant-Veränderungen beim ARDS äußern sich als Mangel an oberflächenaktiven Substanzen, Veränderungen in der Surfactant-Komposition, Störungen in der relativen Surfactant-Subtypenverteilung, Inhibition der Surfactant-Funktion durch extravadierte Plasmaproteine sowie Inhibition oder Veränderung der Surfactant-Komponenten durch inflammatorische Mediatoren.¶   Diese Veränderungen der alveolären Surfactant-Funktion tragen zu den verschiedenen pathophysiologischen Merkmalen beim ARDS bei. Zentrale Bedeutung nehmen dabei der Verlust der Lungencompliance, Ventilations-Perfusions-Verteilungsstörungen einschließlich intrapulmonalem Shunt-Fluss aufgrund einer gestörten Ventilationsverteilung (Atelektasen, partieller Alveolarkollaps, Kollaps der kleinen Atemwege) und Lungenödembildung ein. Darüber hinaus scheinen persistierende Atelektasen, begünstigt durch Surfactant-Mangel und eine alveoläre Fibrinbeladung, Schlüsselreize für die Fibroblastenproliferation und die Ausbildung der Fibrose in der späten Phase des ARDS (Kollaps-Induration) zu sein.¶   Zusammenfassend scheinen die gegenwärtig verfügbaren Daten zu den Störungen der alveolären Surfactant-Funktion beim ARDS therapeutische Studien zur transbronchialen Surfactant-Applikation zu rechtfertigen. In zwei klinischen Untersuchungen, deren Ziel die Überprüfung der sicheren und effizienten Anwendbarkeit einer hohen Dosis transbronchial applizierten Surfactants bei ARDS-Patienten war, konnte eine akute Verbesserung des Gasaustausches nachgewiesen werden. Darüber hinaus wurde tendenziell in der Therapiegruppe eine niedrigere Letalität beobachtet. Eine kontrollierte Studie prüft derzeit an einem größeren Patientenkollektiv mit ARDS den Einfluss einer transbronchialen Surfactant-Applikation auf die Letalität dieses Erkrankungsbildes. Adult Respiratory Distress Syndrome (ARDS) is characterized by extended inflammatory processes in the lung microvascular, interstitial and alveolar compartments, resulting in vasomotor disturbances, plasma leakage, cell injury and complex gas exchange disturbances. Abnormalities of the alveolar surfactant system have long since been implicated in the pathogenetic sequelae of this life-threatening syndrome. This hypothesis is supported by similarities in pulmonary failure between patients with ARDS and preterm babies with Infant Respiratory Distress Syndrome (IRDS), which is known to be triggered primarily by a lack of surfactant material. Mechanisms of surfactant alterations in ARDS include lack of surface-active compounds, changes in the relative composition of the surfactant constituents, alteration of the extracellular surfactant subtype distribution, inhibition of surfactant function by plasma protein leakage, and damage/inhibition of surfactant compounds by inflammatory mediators.¶   Alterations in alveolar surfactant function may well contribute to a variety of pathophysiological key events encountered in ARDS. These include decrease in compliance, ventilation-perfusion mismatch including shunt-flow due to altered gas flow distribution (atelectasis, partial alveolar collapse, small airway collapse) and lung edema formation. Persistent atelectasis of surfactant-deficient and, in particular, fibrin-loaded alveoli may represent a key event to trigger fibroblast proliferation and fibrosis in late ARDS (collapse induration).¶   Overall, the presently available data on surfactant abnormalities in ARDS lend credit to therapeutic trials with transbronchial surfactant application. Accordingly, acute improvement of gas exchange was encountered in two recently performed pilot studies addressing the safety and efficacy of a transbronchial application of large quantities of exogenous surfactant material. Although not the primarily goal in these pilot studies, a tendency towards lower mortality in the surfactant treatment groups was noted. At present, a controlled study enrolling higher patient numbers is being performed to probe the impact of a transbronchial surfactant administration on the outcome of ARDS patients.
  Intensivmedizin + Notfallmedizin 05/2012; 38(6):514-523.
• Article: Aktuelle Therapie der pulmonal-arteriellen Hypertonie

  H.-A. Ghofrani, R. Voswinckel, F. Reichenberger, H. Gall, W. Seeger, F. Grimminger
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  ABSTRACT: Noch Mitte der 1990-er Jahre war die pulmonal-arterielle Hypertonie (PAH) eine Erkrankung mit sehr schlechter Prognose, deren Therapie auf Antikoagulation, supportiven Maßnahmen und ggf. (Herz)-Lungen-Transplantation basierte. Die Erforschung der pathophysiologischen Vorgänge in der pulmonalen Strombahn führte zur Entwicklung pulmonal-vasodilativer Therapien mit Prostanoiden, Endothelinrezeptorantagonisten, und Phosphodiesterase-5-Inhibitoren, die für die Behandlung der PAH in Studien geprüft und klinisch etabliert sind. Dies hat die PAH zu einer behandelbaren, oftmals langfristig beherrschbaren Erkrankung gemacht und wesentlich zur Besserung der Prognose dieser Patienten beigetragen. Auf der Basis neuer pathobiologischer Erkenntnisse werden derzeit spezifische, primär antiproliferativ wirkende Substanzen in mehreren klinischen Studien evaluiert. Trotz dieser Fortschritte sind wir von der Vision einer Heilung der Erkrankung jedoch noch weit entfernt. As recently as the mid 1990s, pulmonary arterial hypotension (PAH) was still a disease with a very poor prognosis. Its treatment was based on anticoagulation, supportive measures and, where indicated, heart and lung transplant. Research into the pathophysiological processes in the pulmonary vascular system lead to the development of pulmonary vasodilator therapy using prostanoids, endothelin-receptor antagonists and phosphodiesterase-5 inhibitors, which have been tested and clinically established for the treatment of PAH in studies. As a result, PAH has become a treatable disease which can often be controlled in the long term, leading to a better prognosis in these patients. On the basis of new pathobiological findings, specific substances with a primarily antiproliferative effect are currently being evaluated in several clinical studies. In spite of this progress, we still remain a long way from realizing our vision of a cure for this disease. SchlüsselwörterPulmonal-arterieller Mitteldruck-Prostanoide-Endothelininhibitor-Kombinationstherapie-Verlaufskontrolle KeywordsMean pulmonary arterial pressure-Prostanoids-Endothelin inhibitor-Combination therapy-Follow-up
  Der Pneumologe 04/2012; 7(3):192-199.
• Article: Inhalative Strategien zur Verbesserung der pulmonalen Hämodynamik und des Gasaustausches bei Sepsis und schwerer pulmonaler Hypertonie

  F. Grimminger, F. Rose, H. A. Ghofrani, R. T. Schermuly, N. Weissmann, H. Olschewski, D. Walmrath, W. Seeger
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  ABSTRACT: Die chronische pulmonale Hypertonie und das septische Lungenversagen (ARDS) sind Krankheiten mit völlig unterschiedlichen Auslösern, die zu einer Störung der transpulmonalen Blutströmung führen. Die Beeinträchtigung der Hämodynamik im kleinen Kreislauf beruht auf einer pathologischen Gefäßverengung, die sowohl eine Überlastung des rechten Ventrikels als auch eine gravierende Störung des Gasaustausches durch Perfusionsfehlverteilungen verursachen kann. Die unterschiedlichen auf die Vaskularisation einwirkenden Schädigungsmechanismen können dabei sowohl eine irreversible als auch eine reversible Verengung der Lungengefäße bewirken. Prinzipiell bestehen drei Möglichkeiten durch pharmakologische Intervention die Widerstandserhöhung zu beeinflussen: • Aufhebung eines dauerhaft erhöhten Vasotonus durch Relaxation der glatten Gefäßmuskulatur (Angriffspunkt der Vasodilatatoren). • Beeinflussung einer thrombusbedingten Obliteration der Lungenstrombahn (Embolie, in situ Thrombose) durch Antikoagulanzien oder Fibrinolitika (nur im Akutstadium). • Beeinflussung des strukturellen Gefäßumbaus (vaskuläres Remodelling) durch Einsatz von antiinflammatorischen und antiproliferativen Agenzien bei der chronischen pulmonalen Hypertonie. Die systemische (intravenöse, oder orale) Gabe von vasodilatativen Agenzien ist sowohl bei der Sepsis als auch bei der chronischen pulmonalen Hypertonie mit erheblichen Nachteilen behaftet: • Antagonisierung der hypoxischen pulmonalen Vaskonstriktion und damit Zunahme der Ventilations-Perfusions-Verteilungsstörung (Abfall der arteriellen Oxygenierung). • Unerwünschte systemische Effekte der Vasodilatatoren (Verstärkung der meist vorbestehenden systemischen Hypotension). Der wesentliche Vorteil des inhalativen Applikationsmodus ist die pulmonale Anreicherung der Agenzien (pulmonale Selektivität) mit bevorzugter Deposition gerade in den gut belüfteten Alveolarbezirken (intrapulmonale Selektivität). Die erwünschte Abnahme des pulmonal-vaskulären Widerstandes ist so gleichzeitig mit einer Optimierung der intrapulmonalen Perfusionsverteilung und einer Verbesserung des Gasaustausches verbunden. Erste positive Erfahrungen mit dieser Vorgehensweise wurden bei beatmeten Patienten mit septischem Lungenversagen unter Einsatz von inhaliertem NO und aerosoliertem Prostazyklin gewonnen. Der Einsatz des stabilen Prostazyklinanalogons Iloprost (Ilomedin) ermöglichte aufgrund der längeren Halbwertszeit der Substanz einen intermittierenden Inhalationsmodus und so eine ambulante Selbstbehandlung von Patienten mit chronischer pulmonaler Hypertonie. Chronic pulmonary hypertension and septic lung failure display different clinical features resulting in severe disturbances in the pulmonary circulation. In these diseases, the pulmonary bloodflow is impaired by a pathologic constriction of blood vessels that may lead to right ventricular overloading as well as serious worsening of gas exchange mainly caused by ventilation/perfusion mismatch. Various mechanisms deteriorating the vascular function may induce both an irreversible and a reversible contraction of pulmonary vessels, respectively. Two pharmacological approaches exist to reduce the vascular resistance: • Reduction of the increased vascular tone by relaxation of vascular smooth muscle cells (effect of vasodilators). • Inhibition of thrombus-mediated obliteration of the lung perfusion by use of anti-coagulatory and fibrinolytic drugs. • Prevention of the structural reorganization of pulmonary vessels (vascular remodeling) by use of vasodilators with anti-inflammatory and anti-proliferative potency such as prostanoids. The systemic (intravenous or oral) application of vasodilative agents in sepsis and chronic pulmonary hypertension has, however, important side effects: • Antagonism of the hypoxic pulmonary vasoconstriction aggravates the ventilation/perfusion mismatch (decrease in arterial oxygenation). • Side effects of these vasodilators (systemic hypotension). The inhalative route of application is superior because of the pulmonary enrichment of the applied agent (pulmonary selectivity). Furthermore, a preferential deposition in the well-ventilated areas of the lung is achieved (intrapulmonary selectivity). Thus, the decrease in pulmonary-vascular resistance is paralleled by both optimized ventilation-perfusion matching and subsequently improved gas exchange. First clinical studies with inhaled nitric oxide and aerosolized prostacyclin have been performed in intubated and mechanically ventilated patients with septic lung failure. At present, the use of the long-acting prostacyclin analogue ilomedin for ambulant treatment of patients with chronic pulmonary hypertension is under investigation. Schlüsselwörter Acute/adult respiratory distress syndrome–Pulmonale Hypertonie–inhalative Therapie–Sepsis-Stickstoffmonoxid–Prostazyklin–ARDS und pulmonale Hypertonie–Neue Aspekte der inhalativen TherapieKey words Acute/adult respiratory distress syndrome–pulmonary hypertension–inhalative therapy–sepsis-nitric oxide–prostacyclin–ARDS and pulmonary hypertension–new aspects of the inhalative therapy
  Zeitschrift für Kardiologie 04/2012; 89(6):477-484. · 0.97 Impact Factor
• Article: Phosphodiesterase-4 promotes proliferation and angiogenesis of lung cancer by crosstalk with HIF.

  S S Pullamsetti, G A Banat, A Schmall, M Szibor, D Pomagruk, J Hänze, E Kolosionek, J Wilhelm, T Braun, F Grimminger, W Seeger, R T Schermuly, R Savai
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  ABSTRACT: Lung cancer is the leading cause of cancer death worldwide. Recent data suggest that cyclic nucleotide phosphodiesterases (PDEs) are relevant in various cancer pathologies. Pathophysiological role of phosphodiesterase 4 (PDE4) with possible therapeutic prospects in lung cancer was investigated. We exposed 10 different lung cancer cell lines (adenocarcinoma, squamous and large cell carcinoma) to hypoxia and assessed expression and activity of PDE4 by real-time PCR, immunocytochemistry, western blotting and PDE activity assays. Expression and activity of distinct PDE4 isoforms (PDE4A and PDE4D) increased in response to hypoxia in eight of the studied cell lines. Furthermore, we analyzed various in silico predicted hypoxia-responsive elements (p-HREs) found in in PDE4A and PDE4D genes. Performing mutation analysis of the p-HRE in luciferase reporter constructs, we identified four functional HRE sites in the PDE4A gene and two functional HRE sites in the PDE4D gene that mediated hypoxic induction of the reporter. Silencing of hypoxia-inducible factor subunits (HIF1α and HIF2α) by small interfering RNA reduced hypoxic induction of PDE4A and PDE4D. Vice versa, using a PDE4 inhibitor (PDE4i) as a cyclic adenosine monophosphate (cAMP) -elevating agent, cAMP analogs or protein kinase A (PKA)-modulating drugs and an exchange protein directly activated by cAMP (EPAC) activator, we demonstrated that PDE4-cAMP-PKA/EPAC axis enhanced HIF signaling as measured by HRE reporter gene assay, HIF and HIF target genes expression ((lactate dehydrogenase A), LDHA, (pyruvate dehydrogenase kinase 1) PDK1 and (vascular endothelial growth factor A) VEGFA). Notably, inhibition of PDE4 by PDE4i or silencing of PDE4A and PDE4D reduced human lung tumor cell proliferation and colony formation. On the other hand, overexpression of PDE4A or PDE4D increased human lung cancer proliferation. Moreover, PDE4i treatment reduced hypoxia-induced VEGF secretion in human cells. In vivo, PDE4i inhibited tumor xenograft growth in nude mice by attenuating proliferation and angiogenesis. Our findings suggest that PDE4 is expressed in lung cancer, crosstalks with HIF signaling and promotes lung cancer progression. Thus, PDE4 may represent a therapeutic target for lung cancer therapy.Oncogene advance online publication, 23 April 2012; doi:10.1038/onc.2012.136.
  Oncogene 04/2012; · 6.37 Impact Factor
• Article: Therapie der pulmonalarteriellen Hypertonie

  R. Voswinckel, F. Reichenberger, H. Gall, W. Seeger, F. Grimminger, H.A. Ghofrani
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  ABSTRACT: Zur Behandlung der pulmonalarteriellen Hypertonie (PAH) liegen aktuelle internationale Leitlinien der European Society of Cardiology sowie des American College of Chest Physicians vor. Die Klassifikation der pulmonalen Hypertonie sowie Leitlinien zur Diagnostik und Therapie wurden zuletzt auf dem 4.Weltkongress zur PAH in Dana Point (Kalifornien) im Jahr 2008 angepasst. Basierend auf diesen Leitlinien erfolgt ein Überblick über die aktuellen Therapieempfehlungen für Patienten mit PAH, entsprechend der Gruppe1 der diagnostischen WHO-Klassifikation der pulmonalen Hypertonie. Demnach wird empfohlen, die Diagnostik und Therapie in einem Expertenzentrum durchzuführen. Wir teilen die Therapieformen der PAH in Basistherapien (z.B. orale Antikoagulanzien, Diuretika, Sauerstofftherapie) und spezifische Therapien (z.B. Phosphodiesterase-5-Hemmstoffe, Endothelinrezeptorantagonisten, Prostanoide) ein. Zuletzt werden noch einige neue Substanzen dargestellt, die sich bereits verhältnismäßig weit in der klinischen Entwicklung befinden. Current international guidelines on the treatment of pulmonary arterial hypertension (PAH) are compiled by the European Society of Cardiology and the American College of Chest Physicians. The classification of pulmonary hypertension and guidelines on diagnosis and therapy were last adopted at the 4th World Congress of PAH in Dana Point (California) in the year 2008. Based on these guidelines this article presents an overview of the current therapy recommendations for patients with PAH corresponding to group 1 of the diagnostic WHO classification of pulmonary hypertension. Here it is recommended that diagnostic and therapy should be carried out in an expert centre. The therapy forms for PAH can be classified into basic therapy (e.g. oral anticoagulants, diuretics and oxygen therapy) and specific therapy (e.g. phosphodiesterase-5 inhibitors, endothelin receptor antagonists and prostanoids). Finally, some new substances will be presented which have already progressed relatively far in the clinical development.
  Der Internist 04/2012; 50(9):1101-1110. · 0.30 Impact Factor
• Chapter: Alteration of Pulmonary Surfactant in Ards - Pathogenetic Role and Therapeutic Perspectives

  A. Günther, D. Walmrath, F. Grimminger, W. Seeger
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  ABSTRACT: The adult respiratory distress syndrome (ARDS) characterizes different states o acute impairment of pulmonary gas exchange. Underlying noxious events may directly affect lung parenchyma from the alveolar side (e.g. gastric acid aspiration), or - more classically - the lung vasculature may be the primary target site of circulating humoral or cellular mediators activated under conditions of systemic inflammatory events such a: sepsis or severe polytrauma. Key pathophysiological features of the initial “exsudative” phase of ARDS include an increase in capillary endothelial and alveolar epithelial permeability, leakage of protein rich edema fluid into interstitial and alveolar spaces, increase in pulmonary vascular resistance with maldistribution of pulmonary perfusion, alveolar instability with formation of atelectases and ventilatory inhomogeneities as well as severe disturbances of gas exchange characterized by ventilation-perfusion mismatch and extensive shunt flow.
  07/2011: pages 97-105;
• Article: Terguride ameliorates monocrotaline-induced pulmonary hypertension in rats.

  R Dumitrascu, C Kulcke, M Königshoff, F Kouri, X Yang, N Morrell, H A Ghofrani, N Weissmann, R Reiter, W Seeger, F Grimminger, O Eickelberg, R T Schermuly, S S Pullamsetti
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  ABSTRACT: Pulmonary arterial hypertension (PAH) is a life-threatening disease characterised by vasoconstriction and remodelling of the pulmonary vasculature. The serotonin (5-hydroxytryptamine (5-HT)) pathway has been shown to play a major role in the pathogenesis of PAH, but pharmacological modulation of this pathway for treatment of PAH is, to date, at a pre-clinical level. Terguride is a 5-HT receptor (5-HTR) antagonist that is well tolerated and clinically approved for ovulation disorders. Immunohistochemistry against 5-HTR(₂A/B) on human lungs revealed their localisation to the vascular smooth muscle layer and quantitative RT-PCR showed 5-HTR(₂B) upregulation in pulmonary artery smooth muscle cells (PASMC) isolated from PAH patients. Proliferation and migration of cultured primary human PASMC were dose-dependently blocked by terguride. Therapeutic 5-HT signalling inhibition was 1) demonstrated in isolated, ventilated and perfused rat lungs and 2) by chronic terguride treatment of rats with monocrotaline (MCT)-induced pulmonary hypertension in a preventive or curative approach. Terguride inhibited proliferation of PASMCs and abolished 5-HT-induced pulmonary vasoconstriction. Chronic terguride treatment prevented dose-dependently the development and progression of MCT-induced PAH in rats. Thus, terguride represents a valuable novel therapeutic approach in PAH.
  European Respiratory Journal 05/2011; 37(5):1104-18. · 5.89 Impact Factor
• Article: Inflammation, immunological reaction and role of infection in pulmonary hypertension.

  S S Pullamsetti, R Savai, W Janssen, B K Dahal, W Seeger, F Grimminger, H A Ghofrani, N Weissmann, R T Schermuly
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  ABSTRACT: Inflammation underlies a wide variety of physiological and pathological processes. Acute inflammation is the initial response of the body to harmful stimuli. Chronic inflammation, by contrast, is a prolonged, dysregulated and maladaptive response that involves active inflammation, tissue destruction and attempts at tissue repair. Over the past few years, such persistent inflammation has been shown to be associated with pulmonary hypertension (PH). Substantial advances in basic and experimental science have illuminated the role of inflammation and the underlying cellular and molecular mechanisms that contribute to PH. This review summarizes the experimental and clinical evidence for inflammation in various types of PH. In addition, it assesses the current state of knowledge regarding the inducers/triggers of chronic inflammation and infection, as well as the inflammatory mediators and cells that are involved in PH. Infiltration of inflammatory cells, such as dendritic cells, macrophages, mast cells, T-lymphocytes and B-lymphocytes, in the vascular lesions and an elevation of serum/tissue concentrations of proinflammatory cytokines and chemokines and their contribution to pulmonary vascular remodelling are reported in detail. We review the data supporting the use of inflammatory markers as prognostic and predictive factors in PH. Finally, we consider how new insights into inflammation in PH may identify innovative therapeutic strategies.
  Clinical Microbiology and Infection 01/2011; 17(1):7-14. · 4.54 Impact Factor
• Article: Mitochondrial cytochrome redox states and respiration in acute pulmonary oxygen sensing.

  N Sommer, O Pak, S Schörner, T Derfuss, A Krug, E Gnaiger, H A Ghofrani, R T Schermuly, C Huckstorf, W Seeger, F Grimminger, N Weissmann
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  ABSTRACT: Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism to optimise lung gas exchange. We aimed to decipher the proposed oxygen sensing mechanism of mitochondria in HPV. Cytochrome redox state was assessed by remission spectrophotometry in intact lungs and isolated pulmonary artery smooth muscle cells (PASMC). Mitochondrial respiration was quantified by high-resolution respirometry. Alterations were compared with HPV and hypoxia-induced functional and molecular readouts on the cellular level. Aortic and renal arterial smooth muscle cells (ASMC and RASMC, respectively) served as controls. The hypoxia-induced decrease of mitochondrial respiration paralleled HPV in isolated lungs. In PASMC, reduction of respiration and mitochondrial cytochrome c and aa3 (complex IV), but not of cytochrome b (complex III) matched an increase in matrix superoxide levels as well as mitochondrial membrane hyperpolarisation with subsequent cytosolic calcium increase. In contrast to PASMC, RASMC displayed a lower decrease in respiration and no rise in superoxide, membrane potential or intracellular calcium. Pharmacological inhibition of mitochondria revealed analogous kinetics of cytochrome redox state and strength of HPV. Our data suggest inhibition of complex IV as an essential step in mitochondrial oxygen sensing of HPV. Concomitantly, increased superoxide release from complex III and mitochondrial membrane hyperpolarisation may initiate the cytosolic calcium increase underlying HPV.
  European Respiratory Journal 11/2010; 36(5):1056-66. · 5.89 Impact Factor
• Article: Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension.

  B K Dahal, D Kosanovic, P K Pamarthi, A Sydykov, Y-J Lai, R Kast, H Schirok, J-P Stasch, H A Ghofrani, N Weissmann, F Grimminger, W Seeger, R T Schermuly
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  ABSTRACT: An accumulating body of evidence incriminates Rho kinase (ROCK) in the pathogenesis of pulmonary hypertension (PH). The therapeutic efficacy of azaindole-1, a novel highly selective and orally active ROCK inhibitor, has not yet been investigated in PH. This study aimed to investigate the effects of azaindole-1 on 1) acute hypoxic pulmonary vasoconstriction (HPV), 2) proliferation of pulmonary arterial smooth muscle cells (PASMCs) and 3) animal models of PH. Azaindole-1 significantly inhibited HPV in isolated, ventilated and buffer-perfused murine lungs and proliferation of primary rat PASMCs in vitro. Azaindole-1 was administered orally from 21 to 35 days after monocrotaline (MCT) injection in rats and hypoxic exposure in mice. Azaindole-1 (10 and 30 mg per kg body weight per day in rats and mice, respectively) significantly improved haemodynamics and right ventricular hypertrophy. Moreover, the medial wall thickness and muscularisation of peripheral pulmonary arteries were ameliorated. Azaindole-1 treatment resulted in a decreased immunoreactivity for phospho-myosin phosphatase target subunit 1 and proliferating cell nuclear antigen in pulmonary vessels of MCT-injected rats, suggesting an impaired ROCK activity and reduced proliferating cells. Azaindole-1 provided therapeutic benefit in experimental PH, and this may be attributable to its potent vasorelaxant and antiproliferative effects. Azaindole-1 may offer a useful approach for treatment of PH.
  European Respiratory Journal 10/2010; 36(4):808-18. · 5.89 Impact Factor
• Article: Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study.

  H A Ghofrani, M M Hoeper, M Halank, F J Meyer, G Staehler, J Behr, R Ewert, G Weimann, F Grimminger
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  ABSTRACT: We assessed the therapeutic potential of riociguat, a novel soluble guanylate cyclase stimulator, in adults with chronic thromboembolic pulmonary hypertension (CTEPH; n = 42) or pulmonary arterial hypertension (PAH; n = 33) in World Health Organization (WHO) functional class II/III. In this 12-week, multicentre, open-label, uncontrolled phase II study, patients received oral riociguat 1.0-2.5 mg t.i.d. titrated according to systemic systolic blood pressure (SBP). Primary end-points were safety and tolerability; pharmacodynamic changes were secondary end-points. Riociguat was generally well tolerated. Asymptomatic hypotension (SBP <90 mmHg) occurred in 11 patients, but blood pressure normalised without dose alteration in nine and after dose reduction in two. Median 6-min walking distance increased in patients with CTEPH (55.0 m from baseline (390 m); p<0.0001) and PAH (57.0 m from baseline (337 m); p<0.0001); patients in functional class II or III and bosentan pre-treated patients showed similar improvements. Pulmonary vascular resistance was significantly reduced by 215 dyn·s·cm(-5) from baseline (709 dyn·s·cm(-5); p<0.0001). 42 (56%) patients were considered to have experienced drug-related adverse events (AEs; 96% mild or moderate). Dyspepsia, headache and hypotension were the most frequent AEs. Study discontinuation because of AEs was 4%. These preliminary data show that riociguat has a favourable safety profile and improves exercise capacity, symptoms and pulmonary haemodynamics in CTEPH and PAH. Randomised controlled trials are underway.
  European Respiratory Journal 10/2010; 36(4):792-9. · 5.89 Impact Factor
• Article: c-ANCA-induced neutrophil-mediated lung injury: a model of acute Wegener's granulomatosis.

  K Hattar, S Oppermann, C Ankele, N Weissmann, R T Schermuly, R M Bohle, R Moritz, B Krögel, W Seeger, F Grimminger, U Sibelius, U Grandel
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  ABSTRACT: Anti-neutrophil cytoplasmic antibodies (c-ANCA) targeting proteinase 3 (PR3) are implicated in the pathogenesis of Wegener's granulomatosis (WG). Fulminant disease can present as acute lung injury (ALI). In this study, a model of ALI in WG was developed using isolated rat lungs. Isolated human polymorphonuclear leukocytes (PMNs) were primed with tumour necrosis factor (TNF) to induce surface expression of PR3. Co-perfusion of TNF-primed neutrophils and monoclonal anti-PR3 antibodies induced a massive weight gain in isolated lungs. This effect was not observed when control immunoglobulin G was co-perfused with TNF-primed PMNs. The c-ANCA-induced oedema formation was paralleled by an increase in the capillary filtration coefficient as a marker of increased pulmonary endothelial permeability. In contrast, pulmonary artery pressure was not affected. In the presence of the oxygen radical scavenger superoxide dismutase and a NADPH oxidase inhibitor, c-ANCA-induced lung oedema could be prevented. Inhibition of neutrophil elastase was equally effective in preventing c-ANCA-induced lung injury. In conclusion, anti-PR3 antibodies induced neutrophil mediated, elastase- and oxygen radical-dependent ALI in the isolated lung. This experimental model supports the hypothesis of a pathogenic role for c-ANCA in WG and offers the possibility of the development of therapeutic strategies for the treatment of lung injury in fulminant WG.
  European Respiratory Journal 07/2010; 36(1):187-95. · 5.89 Impact Factor
• Article: Epoxyeicosatrienoates are the dominant eicosanoids in human lungs upon microbial challenge.

  L Kiss, H Schütte, W Padberg, N Weissmann, K Mayer, T Gessler, R Voswinckel, W Seeger, F Grimminger
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  ABSTRACT: Lipoxygenase, cyclo-oxygenase and cytochrome P450 (CYP) products of arachidonic acid (AA) are implicated in pulmonary vasoregulation. The CYP-mediated epoxyeicosatrienoates (EETs) have been described previously as the predominant eicosanoids in human lungs upon stimulation with the Ca(2+) ionophore A23187. In this study, we challenged perfused human lungs with two microbial agents: Escherichia coli haemolysin (ECH) and formyl-methionyl-leucyl-phenylalanine (fMLP). Both stimuli elicited pronounced generation of leukotrienes (LTs), hydroxyeicosatetraenoic acids (HETEs), prostanoids (PTs) and EETs/dihydroxyeicosatrienoic acids (DHETs), as assessed by liquid chromatography-mass spectrometry, paralleled by pulmonary artery pressor response and lung oedema formation. The maximum buffer concentrations of EETs/DHETs surpassed those of LTs plus HETEs and PTs by a factor of four (ECH) or three (AA/fMLP). Dual 5-lipoxygenase/cyclo-oxygenase inhibition caused pronounced reduction of AA/fMLP-induced LT/PT synthesis and oedema formation but only limited attenuation of pulmonary vasoconstriction, while inhibition of CYP epoxygenase clearly attenuated AA/fMLP-induced EET/DHET synthesis and vasoconstriction but not oedema formation, suggesting a major contribution of LTs/PTs to vascular leakage and of EETs/DHETs to pressor response. Consequently, generation of EETs/DHETs is greater than that of LTs plus HETEs and PTs in ex vivo perfused human lungs upon microbial challenge suggesting a substantial contribution of these mediators to inflammatory-infectious pulmonary injury.
  European Respiratory Journal 04/2010; 36(5):1088-98. · 5.89 Impact Factor
• Article: Burden of pulmonary arterial hypertension in Germany.

  H Wilkens, F Grimminger, M Hoeper, G Stähler, B Ehlken, C Plesnila-Frank, K Berger, A Resch, A Ghofrani
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  ABSTRACT: This study aimed to describe health care provision, resource consumption and related costs, as well as treatment patterns and quality of life in adult patients with pulmonary arterial hypertension (PAH) in Germany. Data for this retrospective and prospective cost-of-illness-study were derived from hospitals, general practitioners and patients. Costs were evaluated from the perspective of third party payer and patient. Quality of life data were collected by using three validated instruments. A total of 167 patients were enrolled at 10 hospitals. Time period from first occurrence of symptoms to confirmed diagnosis of PAH was 2.3 years on average. Mean number of GP visits was 1.5 per patient per month, and within 15 months, inpatient stays were reported for 50% of patients. The ratio of combination therapy to single-drug therapy for endothelin receptor antagonists, phosphodiesterase-5-inhibitor and prostacyclin analogues increased significantly during 15 months. Treatment costs were, on average, euro47,400 per patient per year, arising mainly from drugs. Compared to the general population, quality of life of PAH patients was considerably impaired. This is the first study which evaluated aspects of the medical and economic consequences of PAH based on a large cohort of PAH patients in Germany.
  Respiratory medicine 02/2010; 104(6):902-10. · 2.33 Impact Factor
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  Available from: Alexander Dietrich

  Article: The role of classical transient receptor potential channels in the regulation of hypoxic pulmonary vasoconstriction.

  B Fuchs, A Dietrich, T Gudermann, H Kalwa, F Grimminger, N Weissmann
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  ABSTRACT: Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism of the lung matching blood perfusion to ventilation during local alveolar hypoxia. HPV thus optimizes pulmonary gas exchange. In contrast chronic and generalized hypoxia leads to pulmonary vascular remodeling with subsequent pulmonary hypertension and right heart hypertrophy. Among other non-selective cation channels, the family of classical transient receptor potential channels (TRPC) has been shown to be expressed in pulmonary arterial smooth muscle cells. Among this family, TRPC6 is essential for the regulation of acute HPV in mice. Against this background, in this chapter we give an overview about the TRPC family and their role in HPV.
  Advances in experimental medicine and biology 01/2010; 661:187-200. · 1.09 Impact Factor
• Article: Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension

  B.K. Dahal, D. Kosanovic, P.K. Pamarthi, A. Sydykov, Y-J. Lai, R. Kast, H. Schirok, J-P. Stasch, H.A. Ghofrani, N. Weissmann, F. Grimminger, W. Seeger, R.T. Schermuly
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  ABSTRACT: Accumulating body of evidence incriminate Rho-kinase (ROCK) in the pathogenesis of pulmonary hypertension (PH). Therapeutic efficacy of azaindole-1, a novel highly selective and orally active ROCK inhibitor, has not yet been investigated in PH. This study aimed to investigate the effects of azaindole-1 on 1) acute hypoxic pulmonary vasoconstriction (HPV), 2) proliferation of pulmonary arterial smooth muscle cells (PASMCs) and 3) animal models of PH. Azaindole-1 significantly inhibited HPV in isolated, ventilated and buffer-perfused murine lungs and proliferation of primary rat PASMCs in vitro. Azaindole-1 was administered orally from 21 to 35 days after monocrotaline injection in rats (MCT-rats) and hypoxic exposure in mice. Azaindole-1 (10 and 30 mg·kg–1 body weight·day–1 in rats and mice, respectively) significantly improved hemodynamics and right ventricular hypertrophy. Moreover, the medial wall thickness and muscularization of peripheral pulmonary arteries were ameliorated. Azaindole-1 treatment resulted in a decreased immunoreactivity for phospho-myosin phosphatase target subunit 1 (p-MYPT1) and proliferating cell nuclear antigen (PCNA) in pulmonary vessels of MCT-rats, suggesting an impaired ROCK activity and reduced proliferating cells. Azaindole-1 provided therapeutic benefit in experimental PH, and this may be attributable to its potent vasorelaxant and antiproliferative effects. Azaindole-1 may offer a useful approach for treatment of PH.
  Eur Respir J 2010, doi:10.1183/09031936.00140309. 01/2010;
• Article: [Update: Current clinical developments in pulmonary hypertension].

  D Dumitrescu, H A Ghofrani, F Grimminger, M M Hoeper, S Rosenkranz
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  ABSTRACT: During the last years, therapeutic options for the treatment of pulmonary arterial hypertension (PAH) have significantly improved. However, the therapeutic concept depends on the etiology of the disease, so that an exact classification is mandatory. Currently, three substance classes are approved for the treatment of PAH (Group I of the Venice Classification): Endothelin receptor antagonists, phosphodiesterase type-5 inhibitors, and prostanoids. After the World Conference in Dana Point (2008), recent changes in therapeutic strategies comprise the early treatment of the disease, as well as the increased importance of an early use of combination therapy if treatment goals are not met. Several new substances are currently evaluated in clinical trials. The soluble guanylate cyclase (sGC) stimulators achieve potent, NO-independent vasodilation. Another promising pathophysiological approach is currently evaluated by the use of tyrosine kinase inhibitors - anti-proliferative drugs which inhibit or even may reverse the pulmonary vascular remodeling process. Serotonin receptor antagonists are also reported to have anti-proliferative, anti-thrombotic and anti-fibrotic effects. Other forms of pulmonary hypertension (Groups II-V) are strictly separated from PAH. Evidence on treatment with PAH specific agents is strongly needed for these groups. Patients with non-PAH pulmonary hypertension should be referred to PAH expert centers, and preferably treated in controlled studies.
  DMW - Deutsche Medizinische Wochenschrift 09/2009; 134 Suppl 5:S160-3. · 0.53 Impact Factor
• Article: [Pulmonary hypertension in COPD and interstitial lung diseases].

  P Markart, H A Ghofrani, F Grimminger, A Günther
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  ABSTRACT: Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD) and of interstitial lung diseases (ILD) such as idiopathic pulmonary fibrosis and sarcoidosis. When present in these patients, PH is usually mild to moderate. When severe PH is diagnosed in COPD and ILD patients, other potentially better treatable underlying causes should be ruled out. In COPD patients, PH is associated with an increased risk of severe exacerbations and a reduced life expectancy. Similarly, in patients with ILD, the presence of PH correlates with a poor prognosis. Doppler echocardiography is the best non-invasive method for the diagnosis of PH, but is frequently inaccurate in patients with advanced lung diseases. Thus, when clinical suspicion remains high, right heart catheterization in a reference center is required to ultimately confirm the presence of PH. Treatment of PH in COPD and ILD is primarily based on long term oxygen therapy. Drugs approved for pulmonary arterial hypertension, such as prostanoids, phosphodiesterase inhibitors, and endothelin receptor antagonists, may represent promising options for COPD and ILD patients, however, their use may be hampered by potentially deleterious effects on gas exchange and their efficacy yet remains to be proven in appropriately designed and controlled clinical trials. Lung transplantation may be considered in all patients with an advanced disease.
  DMW - Deutsche Medizinische Wochenschrift 09/2009; 134 Suppl 5:S164-6. · 0.53 Impact Factor
• Article: [Therapy of pulmonary arterial hypertension].

  R Voswinckel, F Reichenberger, H Gall, W Seeger, F Grimminger, H A Ghofrani
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  ABSTRACT: Current international guidelines on the treatment of pulmonary arterial hypertension (PAH) are compiled by the European Society of Cardiology and the American College of Chest Physicians. The classification of pulmonary hypertension and guidelines on diagnosis and therapy were last adopted at the 4th World Congress of PAH in Dana Point (California) in the year 2008. Based on these guidelines this article presents an overview of the current therapy recommendations for patients with PAH corresponding to group 1 of the diagnostic WHO classification of pulmonary hypertension. Here it is recommended that diagnostic and therapy should be carried out in an expert centre. The therapy forms for PAH can be classified into basic therapy (e. g. oral anticoagulants, diuretics and oxygen therapy) and specific therapy (e. g. phosphodiesterase-5 inhibitors, endothelin receptor antagonists and prostanoids). Finally, some new substances will be presented which have already progressed relatively far in the clinical development.
  Der Internist 09/2009; 50(9):1101-2, 1104-9. · 0.30 Impact Factor
• Article: Reproducible effects of intravenously administered fish oil in acute relapsing psoriasis

  P Mayser, F Grimminger, C Papavassilis, E Schlotzer, W Seeger
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  ABSTRACT: In several studies, dietary fish oil has been found to be beneficial in psoriasis, although the results have been controversial. To overcome the slow kinetics and limited availability of oral supplementation, a patient with acute relapsing psoriasis received an ω-3 fatty acid-based lipid emulsion (100 ml/day containing 2.1 g eicosapentaenoic acid (EPA) and 2.1 g docosahexaenoic acid) for 10 days. Clinical symptoms were assessed using the PASI. The PASI score dropped from 18.4 to 4.2. In addition leukotriene generation of ionophore-stimulated neutrophils showed a more than tenfold increase in EPA-derived lipoxygenase product formation. Because of a renewed exacerbation 1 year later, a second trial was started with double the previous dose over a period of 15 days. Probably because of a worse clinical condition, the patient responded more slowly than during the first trial, and the increase in EPA-derived metabolites was more retarded. Modulation of eicosanoid metabolism by intravenous ω-3 fatty acid supplementation appears to have a rapid and reproducible beneficial effect on inflammatory skin lesions in acute relapsing psoriasis.
  07/2009; 7(4):211-214.