60 results on '"Sommer, Natascha"'
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2. Mitochondrial Respiration in Peripheral Blood Mononuclear Cells Negatively Correlates with Disease Severity in Pulmonary Arterial Hypertension.
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Sommer, Natascha, Theine, Finn Fabian, Pak, Oleg, Tello, Khodr, Richter, Manuel, Gall, Henning, Wilhelm, Jochen, Savai, Rajkumar, Weissmann, Norbert, Seeger, Werner, Ghofrani, Hossein A., and Hecker, Matthias
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MONONUCLEAR leukocytes , *PULMONARY arterial hypertension , *RESPIRATION , *VASCULAR resistance , *MITOCHONDRIA , *PULMONARY hypertension - Abstract
Mitochondrial and immune cell dysfunction contributes to the development of pulmonary arterial hypertension (PAH). We thus aimed to investigate mitochondrial respiration and mitochondrial gene expression patterns in the peripheral blood mononuclear cells (PBMC) of patients with idiopathic and hereditary PAH and their correlation to disease parameters. Mitochondrial respiration determined using high-resolution respirometry was not significantly different in PBMC when comparing an outpatient cohort of PAH patients with healthy controls. However, when directly comparing mitochondrial respiration to the hemodynamic parameters of an inpatient PAH cohort, mitochondrial respiration negatively correlated with pulmonary vascular resistance (PVR) and positively correlated with the cardiac index (CI). Furthermore, microarray analysis shows upregulation of mitochondrial erythroid-specific 5-aminolevulinate synthase 2 (ALAS2), as well as the regulation of genes involved in iron and heme metabolism, in the PBMC of patients with PAH, with ALAS2 upregulation in PAH patients being confirmed on the protein level. Multiple regression analysis with age and gender as confounders showed that both PVR and hemoglobin content negatively correlated with maximal respiration. Therefore, we conclude that mitochondrial function in the PBMC of PAH patients is affected by disease severity. However, further studies to investigate cell-type-specific alterations and functional consequences are necessary. [ABSTRACT FROM AUTHOR]
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- 2022
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3. Metabolic Reprogramming in Congenital Cyanotic Heart Disease: Another Fight in Puberty?
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Sommer, Natascha, Weissmann, Norbert, and Ghofrani, Hossein-Ardeschir
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CONGENITAL heart disease , *TYPE 2 diabetes , *PRECOCIOUS puberty , *PUBERTY , *SODIUM-glucose cotransporters , *PYRUVATE dehydrogenase kinase , *CARDIOVASCULAR diseases , *RESEARCH , *RESEARCH methodology , *MEDICAL cooperation , *EVALUATION research , *COMPARATIVE studies , *CYANOSIS - Abstract
Congenital heart disease, hypoxia, metabolism, puberty, pulmonary heart disease, pulmonary hypertension HIF-1 indicates hypoxia-inducible factor-1 ; HOX, hypoxia; incl., including; LV, left ventricle; and RV, right ventricle. Keywords: congenital heart disease; hypoxia; metabolism; puberty; pulmonary heart disease; pulmonary hypertension EN congenital heart disease hypoxia metabolism puberty pulmonary heart disease pulmonary hypertension 2273 2276 4 06/10/21 20210608 NES 210608 B Article, see p 2254 b Congenital heart diseases are complex anatomic malformations that lead to molecular and structural adaptations to compensate for the resulting hemodynamic disturbances. [Extracted from the article]
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- 2021
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4. Current and future treatments of pulmonary arterial hypertension.
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Sommer, Natascha, Ghofrani, Hossein A., Pak, Oleg, Bonnet, Sebastien, Provencher, Steve, Sitbon, Olivier, Rosenkranz, Stephan, Hoeper, Marius M., and Kiely, David G.
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PULMONARY hypertension , *VASCULAR remodeling , *ENDOTHELIN receptors , *BONE morphogenetic protein receptors , *TRANSCRIPTION factors , *ANIMAL models in research , *APOPTOSIS - Abstract
Therapeutic options for pulmonary arterial hypertension (PAH) have increased over the last decades. The advent of pharmacological therapies targeting the prostacyclin, endothelin, and NO pathways has significantly improved outcomes. However, for the vast majority of patients, PAH remains a life‐limiting illness with no prospect of cure. PAH is characterised by pulmonary vascular remodelling. Current research focusses on targeting the underlying pathways of aberrant proliferation, migration, and apoptosis. Despite success in preclinical models, using a plethora of novel approaches targeting cellular GPCRs, ion channels, metabolism, epigenetics, growth factor receptors, transcription factors, and inflammation, successful transfer to human disease with positive outcomes in clinical trials is limited. This review provides an overview of novel targets addressed by clinical trials and gives an outlook on novel preclinical perspectives in PAH. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc [ABSTRACT FROM AUTHOR]
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- 2021
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5. Bypassing mitochondrial complex III using alternative oxidase inhibits acute pulmonary oxygen sensing.
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Sommer, Natascha, Alebrahimdehkordi, Nasim, Pak, Oleg, Knoepp, Fenja, Strielkov, Ievgen, Scheibe, Susan, Dufour, Eric, Andjelkovic, Ana, Sydykov, Akylbek, Saraji, Alireza, Petrovic, Aleksandar, Quanz, Karin, Hecker, Matthias, Kumar, Manish, Wahl, Joel, Kraut, Simone, Seeger, Werner, Schermuly, Ralph T., Ghofrani, Hossein A., and Ramser, Kerstin
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CIGARETTE smoke , *ADULT respiratory distress syndrome , *VASCULAR remodeling , *REACTIVE oxygen species , *PERSISTENT fetal circulation syndrome , *TRP channels - Published
- 2020
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6. Resolvin E1 and its precursor 18R-HEPE restore mitochondrial function in inflammation.
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Hecker, Matthias, Sommer, Natascha, Foch, Sebastian, Hecker, Andreas, Hackstein, Holger, Witzenrath, Martin, Weissmann, Norbert, Seeger, Werner, and Mayer, Konstantin
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MITOCHONDRIAL pathology , *IMMUNOLOGY of inflammation , *ARACHIDONIC acid , *INFLAMMATORY mediators , *MEMBRANE potential - Abstract
Inflammatory disorders such as sepsis are a major cause of morbidity and mortality. Mitochondrial dysfunction is considered a key factor in the pathogenesis of severe inflammation. In the present study, we aimed to investigate the impact of arachidonic acid, omega-3 ( n -3) fatty acids, and n -3-derived lipid mediators 18 R -HEPE and resolvin (Rv) E1 on mitochondrial function in experimental inflammation. The results revealed that, in contrast to n -6 and n -3 fatty acids, both 18 R -HEPE and RvE1 possess anti-inflammatory and anti-apoptotic properties. Both mediators are able to restore inflammation-induced mitochondrial dysfunction, which is characterized by a decrease in mitochondrial respiration and membrane potential, as well as an imbalance of mitochondrial fission and fusion. Furthermore, inhibition of mitochondrial fission by Mdivi-1 and Dynasore reduces levels of the pro-inflammatory cytokines IL-6 and IL-8. These results suggest a novel functional mechanism for the beneficial effects of RvE1 in inflammatory reactions. [ABSTRACT FROM AUTHOR]
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- 2018
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7. Correction: Sommer et al. Decreased Thymic Output Contributes to Immune Defects in Septic Patients. J. Clin. Med. 2020, 9 , 2695.
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Sommer, Natascha, Noack, Steffen, Hecker, Andreas, Hackstein, Holger, Bein, Gregor, Weissmann, Norbert, Seeger, Werner, Mayer, Konstantin, and Hecker, Matthias
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PATIENTS , *APOLOGIZING - Abstract
Reference 1 Sommer N., Noack S., Hecker A., Hackstein H., Bein G., Weissmann N., Seeger W., Mayer K., Hecker M. Decreased Thymic Output Contributes to Immune Defects in Septic Patients. From Graph to Graph Footnotes 1 B Publisher's Note: b MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Decreased Thymic Output Contributes to Immune Defects in Septic Patients. [Extracted from the article]
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- 2022
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8. The prognostic impact of thyroid function in pulmonary hypertension.
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Richter, Manuel J., Sommer, Natascha, Schermuly, Ralph, Grimminger, Birk, Seeger, Werner, Tello, Khodr, Ghofrani, Hossein A., and Gall, Henning
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PULMONARY hypertension treatment , *THYROID diseases , *TRIIODOTHYRONINE , *THROMBOEMBOLISM , *DEATH rate - Abstract
Background Thyroid disease is common in patients with pulmonary hypertension (PH), but its effect on long-term survival remains unknown. We examined the prognostic significance of thyroid hormone levels of free triiodothyronine (fT3) and free thyroxine and thyroid-stimulating hormone (TSH), and thyroid hormone replacement (THR) therapy in PH. Methods We conducted a retrospective analysis of 1,756 patients enrolled in the Giessen PH Registry in 1999 to 2013 with baseline thyroid function data; of these, 355, 533, 498, and 370 had pulmonary arterial hypertension (PAH); including 192 with idiopathic PAH (iPAH), PH due to left heart disease, PH due to lung diseases, and chronic thromboembolic PH (CTEPH), respectively. Thyroid function parameters associated with mortality were identified using Cox regression and Kaplan-Meier analyses. Results Transplant-free survival at 1, 3, and 5 years was 86.7%, 65.6%, and 53.0%, respectively. Absence of THR therapy was an independent predictor of death in iPAH (multivariate hazard ratio [HR], 2.50; 95% confidence interval [CI], 1.06–5.75). In patients without THR therapy, TSH levels in the lowest and highest quartiles (compared with the middle 2 quartiles) independently predicted death in iPAH (HR, 1.98; 95% CI, 1.07–3.67), whereas reduced fT3 levels were independently associated with increased death in PAH (HR, 8.30; 95% CI, 2.50–25.00) and CTEPH (HR, 1.79; 95% CI, 1.14–4.20). Conclusions Thyroid hormone levels and THR therapy are prognostic factors in iPAH, PAH, and CTEPH. Prospective studies are warranted to verify the prognostic significance of thyroid function and the effect of THR therapy in PH. [ABSTRACT FROM AUTHOR]
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- 2016
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9. Mitochondrial reactive oxygen species in acute oxygen sensing of the pulmonary vasculature.
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Sommer, Natascha
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BLOOD vessels , *MITOCHONDRIA , *REACTIVE oxygen species - Published
- 2022
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10. Pulmonary Hemodynamic Response to Exercise in Chronic Thromboembolic Pulmonary Hypertension before and after Pulmonary Endarterectomy.
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Richter, Manuel Jonas, Sommer, Natascha, Gall, Henning, Voswinckel, Robert, Seeger, Werner, Mayer, Eckhard, Wiedenroth, Christoph B., Rieth, Andreas, Grimminger, Friedrich, Guth, Stefan, and Ghofrani, Hossein A.
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CARDIAC catheterization , *CARDIOPULMONARY system , *ECHOCARDIOGRAPHY , *ENDARTERECTOMY , *EXERCISE tests , *HEMODYNAMICS , *LIFE skills , *PULMONARY hypertension , *STATISTICS , *T-test (Statistics) , *THROMBOEMBOLISM , *DATA analysis , *TREATMENT effectiveness , *RETROSPECTIVE studies , *DATA analysis software , *DESCRIPTIVE statistics , *MANN Whitney U Test - Abstract
Background: Pulmonary endarterectomy (PEA) is the treatment of choice in surgically accessible chronic thromboembolic pulmonary hypertension (CTEPH). An important predictor of outcome is postsurgical residual pulmonary hypertension. Objective: We aimed to use the hemodynamic response during exercise before PEA as a measurement for the hemodynamic outcome 1 year after PEA. Methods: Between January 2011 and December 2013, 299 patients underwent PEA in our center. A total of 16 patients who were assessed by means of invasive hemodynamic measurements during exercise both at baseline and 1 year after PEA were retrospectively analyzed. Results: Pre-PEA mean pulmonary arterial pressure (mPAP) increased during exercise from 35.8 ± 7.6 to 53.8 ± 5.1 mm Hg, diastolic pulmonary arterial pressure (dPAP) from 21.5 ± 5.6 to 30.3 ± 9.6 mm Hg, cardiac output (CO) from 4.4 ± 0.8 to 6.5 ± 1.9 l/min and diastolic pulmonary gradient (DPG) from 14.6 ± 4.9 to 20.7 ± 12.7 mm Hg. Post-PEA mPAP increased from 23.7 ± 6.6 at rest to 43.2 ± 7.1 mm Hg, while CO increased to a higher extent from 5.1 ± 0.9 to 8.4 ± 1.9 l/min. There were significant correlations between pre-PEA DPG/CO and dPAP/CO slopes with the pulmonary vascular resistance (Spearman r = 0.578, p = 0.019, and r = 0.547, p = 0.028) and mPAP at rest after PEA (Spearman r = 0.581, p = 0.018, and r = 0.546, p = 0.028). Conclusions: In CTEPH, the presurgical dynamic DPG/CO and dPAP/CO slopes during submaximal exercise are associated with the hemodynamic outcome 1 year after PEA. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]
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- 2015
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11. Redox signaling and reactive oxygen species in hypoxic pulmonary vasoconstriction
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Fuchs, Beate, Sommer, Natascha, Dietrich, Alexander, Schermuly, Ralph Theo, Ghofrani, Hossein Ardeschir, Grimminger, Friedrich, Seeger, Werner, Gudermann, Thomas, and Weissmann, Norbert
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OXIDATIVE stress , *PULMONARY blood vessels , *CELLULAR signal transduction , *REACTIVE oxygen species , *HYPOXEMIA , *VASOCONSTRICTION , *MOLECULAR biology , *SMOOTH muscle , *MITOCHONDRIA - Abstract
Abstract: Hypoxic pulmonary vasoconstriction (HPV) is an essential physiological mechanism of the lung that matches blood perfusion with alveolar ventilation to optimize gas exchange. Perturbations of HPV, as may occur in pneumonia or adult respiratory distress syndrome, can cause life-threatening hypoxemia. Despite intensive research for decades, the molecular mechanisms of HPV have not been fully elucidated. Reactive oxygen species (ROS) and changes in the cellular redox state are proposed to link O2 sensing and pulmonary arterial smooth muscle cell contraction underlying HPV. In this regard, mitochondria and NAD(P)H oxidases are discussed as sources of ROS. However, there is controversy whether ROS levels decrease or increase during hypoxia. With this background we summarize the current knowledge on the role of ROS and redox state in HPV. [ABSTRACT FROM AUTHOR]
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- 2010
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12. Oxygen sensors in hypoxic pulmonary vasoconstriction
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Weissmann, Norbert, Sommer, Natascha, Schermuly, Ralph Theo, Ghofrani, Hossein Ardeschir, Seeger, Werner, and Grimminger, Friedrich
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HYPOXEMIA , *LIVER diseases , *BLOOD pressure , *LUNG diseases - Abstract
Abstract: Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism adapting lung perfusion to regional ventilation. Perturbations to HPV, such as those occurring in pneumonia, acute respiratory distress syndrome and liver failure, can result in arterial hypoxemia. Under conditions of general hypoxia, HPV increases pulmonary vascular resistance and thus causes acute pulmonary hypertension. Despite intensive research, the underlying mechanisms of HPV have not been fully elucidated. Deciphering signalling pathways that result in HPV could suggest novel approaches to address a failure of HPV, as well as for the treatment of pulmonary hypertension associated with HPV. Within this context, this review focuses on current concepts in the oxygen sensing mechanisms that underlie HPV. [Copyright &y& Elsevier]
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- 2006
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13. Interaction of ambrisentan and phenprocoumon in patients with pulmonary hypertension.
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Sommer, Natascha, Grimminger, Jan, Ghofrani, Hossein A., and Tiede, Henning
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- 2014
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14. Decreased Thymic Output Contributes to Immune Defects in Septic Patients.
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Sommer, Natascha, Noack, Steffen, Hecker, Andreas, Hackstein, Holger, Bein, Gregor, Weissmann, Norbert, Seeger, Werner, Mayer, Konstantin, and Hecker, Matthias
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T cells , *APOPTOSIS , *CELLULAR aging , *LYMPHOPENIA - Abstract
Background: Prolonged immunosuppression and hypoinflammation, termed compensatory anti-inflammatory response syndrome (CARS), contribute to high morbidity and mortality in the late phase of sepsis. Although apoptosis is a well-known cause of lymphopenia in sepsis, the contribution of thymic output to immune alterations in sepsis and potential compensatory mechanisms are largely unknown. Methods: We investigate the release of CD4+ T cells from the thymus and their peripheral proliferation by evaluating T-cell receptor excision circles (TREC) and the expression of CD31 as markers for recent thymic emigrants (RTE) and their proliferative offspring in septic patients with relevant lymphopenia in the CARS phase. Moreover, we determine the aging of T cells by measuring telomere characteristics. Results: In septic patients, we found decreased CD4+ T-helper cell numbers, while CD8+ T cell numbers were unchanged. As a possible cause, we detected increased apoptosis of CD4+ T-helper cells and decreased levels of IL-7, which promotes the maturation of T cells in the thymus. Accordingly, the relative number of mature CD4+ T cells, TREC-containing CD4+ T cells, and CD31+ RTEs (characteristic of thymic output) was decreased, while the relative number of CD31-T cells (peripherally expanded naïve T cells) was increased. Furthermore, the telomere length decreased, although telomerase activity and markers for the shelterin complex were increased specifically in CD4+ but not in CD8+ T cells. Conclusion: We thus conclude that, in addition to T-cell apoptosis, decreased thymic output and increased aging of CD4+ T cells may contribute to lymphopenia and immunosuppression in sepsis. Increased proliferation of peripheral T cells cannot compensate for these effects. [ABSTRACT FROM AUTHOR]
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- 2020
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15. Association of cardiorespiratory fitness level with vascular function and subclinical atherosclerosis in the elderly.
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Größer, Vincent, Weyh, Christopher, Böttrich, Tim, Frech, Torsten, Nolte, Svenja, Sommer, Natascha, Huber, Magdalena, Eder, Klaus, Dörr, Oliver, Hoelscher, Sophie, Weber, Rebecca, Akdogan, Ebru, Nef, Holger, Most, Astrid, Hamm, Christian W., Krüger, Karsten, and Bauer, Pascal
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CARDIOPULMONARY fitness , *OLDER people , *PULSE wave analysis , *ATHEROSCLEROSIS , *CARDIOVASCULAR diseases risk factors - Abstract
Purpose: Physical exercise is crucial for healthy aging and plays a decisive role in the prevention of atherosclerotic cardiovascular disease (ASCVD). A higher level of cardiorespiratory fitness (CRF) in the elderly is associated with lower cardiovascular and all-cause mortality. This study investigated the association of CRF level with vascular function and cardiovascular risk factors in the elderly. Methods: We examined 79 apparently healthy and physically active subjects aged > 55 years (64 ± 4 years). Cardiovascular functional parameters assessed included brachial and central blood pressure (BP), pulse wave velocity (PWV), augmentation index (Aix), and ankle-brachial index. Sonography of the common carotid artery was performed. CRF level was determined by a cardiopulmonary exercise test, and everyday activity was quantified with an accelerometer. Results: All participants had a higher CRF level than the reported age-specific normative values. Twenty-nine subjects had subclinical atherosclerosis of the common carotid artery. Compared with participants without atherosclerosis, they were older (p = 0.007), displayed higher brachial systolic BP (p = 0.006), and higher central systolic BP (p = 0.014). Lower brachial (p = 0.036) and central (p = 0.003) systolic BP, lower PWV (p = 0.004), lower Aix (p < 0.001), lower body fat percentage (< 0.001), and lower LDL cholesterol (p = 0.005) were associated with a higher CRF level. Conclusions: In this cohort of healthy and physically active individuals, subjects with subclinical atherosclerosis displayed higher systolic brachial and central BP. A higher CRF level was associated with enhanced vascular function, consistent with an influence of CRF on both BP and vascular function in the elderly. [ABSTRACT FROM AUTHOR]
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- 2024
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16. The Role of the Redox Enzyme p66Shc in Biological Aging of the Lung.
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Castro, Claudia F. Garcia, Nardiello, Claudio, Hadzic, Stefan, Kojonazarov, Baktybek, Kraut, Simone, Gierhardt, Mareike, Schäffer, Julia, Bednorz, Mariola, Quanz, Karin, Heger, Jacqueline, Korfei, Martina, Wilhelm, Jochen, Hecker, Matthias, Bartkuhn, Marek, Arnhold, Stefan, Guenther, Andreas, Seeger, Werner, Schulz, Rainer, Weissmann, Norbert, and Sommer, Natascha
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PULMONARY circulation , *ECHOCARDIOGRAPHY - Abstract
The mitochondrial adaptor protein p66Shc has been suggested to control life span in mice via the release of hydrogen peroxide. However, the role of p66Shc in lung aging remains unsolved. Thus, we investigated the effects of p66Shc-/- on the aging of the lung and pulmonary circulation. In vivo lung and cardiac characteristics were investigated in p66Shc-/- and wild type (WT) mice at 3, 12, and 24 months of age by lung function measurements, micro-computed tomography (μCT), and echocardiography. Alveolar number and muscularization of small pulmonary arteries were measured by stereology and vascular morphometry, respectively. Protein and mRNA levels of senescent markers were measured by western blot and PCR, respectively. Lung function declined similarly in WT and p66Shc-/- mice during aging. However, μCT analyses and stereology showed slightly enhanced signs of agingrelated parameters in p66Shc-/- mice, such as a decline of alveolar density. Accordingly, p66Shc-/- mice showed higher protein expression of the senescence marker p21 in lung homogenate compared to WT mice of the corresponding age. Pulmonary vascular remodeling was increased during aging, but aged p66Shc-/- mice showed similar muscularization of pulmonary vessels and hemodynamics like WT mice. In the heart, p66Shc-/- prevented the deterioration of right ventricular (RV) function but promoted the decline of left ventricular (LV) function during aging. p66Shc-/- affects the aging process of the lung and the heart differently. While p66Shc-/- slightly accelerates lung aging and deteriorates LV function in aged mice, it seems to exert protective effects on RV function during aging. [ABSTRACT FROM AUTHOR]
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- 2024
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17. n-3 Polyunsaturated Fatty Acids Modulate LPS-Induced ARDS and the Lung–Brain Axis of Communication in Wild-Type versus Fat-1 Mice Genetically Modified for Leukotriene B4 Receptor 1 or Chemerin Receptor 23 Knockout.
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Hernandez, Jessica, Schäffer, Julia, Herden, Christiane, Pflieger, Fabian Johannes, Reiche, Sylvia, Körber, Svenja, Kitagawa, Hiromu, Welter, Joelle, Michels, Susanne, Culmsee, Carsten, Bier, Jens, Sommer, Natascha, Kang, Jing X., Mayer, Konstantin, Hecker, Matthias, and Rummel, Christoph
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CHEMERIN , *OMEGA-3 fatty acids , *ADULT respiratory distress syndrome , *OMEGA-6 fatty acids , *UNSATURATED fatty acids , *PNEUMONIA , *LUNG diseases , *IMMUNOSTAINING - Abstract
Specialized pro-resolving mediators (SPMs) and especially Resolvin E1 (RvE1) can actively terminate inflammation and promote healing during lung diseases such as acute respiratory distress syndrome (ARDS). Although ARDS primarily affects the lung, many ARDS patients also develop neurocognitive impairments. To investigate the connection between the lung and brain during ARDS and the therapeutic potential of SPMs and its derivatives, fat-1 mice were crossbred with RvE1 receptor knockout mice. ARDS was induced in these mice by intratracheal application of lipopolysaccharide (LPS, 10 µg). Mice were sacrificed at 0 h, 4 h, 24 h, 72 h, and 120 h post inflammation, and effects on the lung, liver, and brain were assessed by RT-PCR, multiplex, immunohistochemistry, Western blot, and LC-MS/MS. Protein and mRNA analyses of the lung, liver, and hypothalamus revealed LPS-induced lung inflammation increased inflammatory signaling in the hypothalamus despite low signaling in the periphery. Neutrophil recruitment in different brain structures was determined by immunohistochemical staining. Overall, we showed that immune cell trafficking to the brain contributed to immune-to-brain communication during ARDS rather than cytokines. Deficiency in RvE1 receptors and enhanced omega-3 polyunsaturated fatty acid levels (fat-1 mice) affect lung–brain interaction during ARDS by altering profiles of several inflammatory and lipid mediators and glial activity markers. [ABSTRACT FROM AUTHOR]
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- 2023
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18. Hypoxic pulmonary vasoconstriction in isolated mouse pulmonary arterial vessels.
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Strielkov, Ievgen, Krause, Nicole Catherine, Sommer, Natascha, Schermuly, Ralph Theo, Ghofrani, Hossein Ardeschir, Grimminger, Friedrich, Gudermann, Thomas, Dietrich, Alexander, and Weissmann, Norbert
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VASOCONSTRICTION , *VASCULAR remodeling , *PERFUSION , *VENTILATION , *DEPOLARIZATION (Cytology) - Abstract
New Findings: What is the central question of this study? Hypoxic pulmonary vasoconstriction has never been characterized in isolated mouse pulmonary arteries of different generations in detail. What is the main finding and its importance? We found that only small intrapulmonary arteries (80–200 μm in diameter) exhibit hypoxic pulmonary vasoconstriction. The observed response was sustained, significantly potentiated by depolarization‐induced preconstriction and not dependent on the endothelium or TRPC6 channels. Abstract: Hypoxic pulmonary vasoconstriction (HPV) is a physiological response of pulmonary arteries, which adapts lung perfusion to regional ventilation. The properties of HPV vary significantly between animal species. Despite extensive use of mouse models in studies of HPV, this physiological response has never been characterized in isolated mouse pulmonary arteries in detail. Using wire myography, we investigated the effect of 80 min exposure to hypoxia on the tone in mouse pulmonary arteries of different generations in the presence and absence of preconstriction. Hypoxia induced a sustained relaxation in non‐preconstricted extrapulmonary arteries (500–700 μm in diameter), but not in the presence of KCl‐induced preconstriction. Large intrapulmonary arteries (450–650 μm in diameter) did not exhibit a significant response to the hypoxic challenge. In contrast, in small intrapulmonary arteries (80–200 μm in diameter), hypoxia elicited a slowly developing sustained constriction, which was independent of the endothelium. The response was significantly potentiated in arteries preconstricted with KCl, but not with U46619. Hypoxic pulmonary vasoconstriction was not altered in pulmonary arteries of TRPC6‐deficient mice, which suggests that this response corresponds to the sustained phase of biphasic HPV observed earlier in isolated, buffer‐perfused and ventilated mouse lungs. In conclusion, we have established a protocol that allows the study of sustained HPV in isolated mouse pulmonary arteries. The data obtained might be useful for future studies of the mechanisms of HPV in mice. [ABSTRACT FROM AUTHOR]
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- 2018
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19. Circulating Angiopoietin-1 Is Not a Biomarker of Disease Severity or Prognosis in Pulmonary Hypertension.
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Richter, Manuel Jonas, Tiede, Svenja Lena, Sommer, Natascha, Schmidt, Thomas, Seeger, Werner, Ghofrani, Hossein Ardeschir, Schermuly, Ralph, and Gall, Henning
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PULMONARY hypertension diagnosis , *PULMONARY hypertension , *ANGIOPOIETIN-1 , *SEVERITY of illness index , *BIOMARKERS , *LONGITUDINAL method , *PROGNOSIS - Abstract
Background: Circulating angiopoietin-1 (Ang-1) has been linked to pulmonary hypertension (PH) in experimental studies. However, the clinical relevance of Ang-1 as a biomarker in PH remains unknown. We aimed to investigate the prognostic and clinical significance of Ang-1 in PH using data from the prospectively recruiting Giessen PH Registry. Methods: Patients with suspected PH (without previous specific pulmonary arterial hypertension [PAH] therapy) who underwent initial right heart catheterization (RHC) in our national referral center between July 2003 and May 2012 and who agreed to optional biomarker analysis were included if they were diagnosed with idiopathic PAH, connective tissue disease-associated PAH (CTD-PAH), PH due to left heart disease (PH-LHD), or chronic thromboembolic PH (CTEPH), or if PH was excluded by RHC (non-PH controls). The association of Ang-1 levels with disease severity (6-minute walk distance and pulmonary hemodynamics) was assessed using linear regression, and the impact of Ang-1 levels on transplant-free survival (primary endpoint) and clinical worsening was assessed using Kaplan—Meier curves, receiver operating characteristic (ROC) analyses, and Cox regression. Results: 151 patients (39, 39, 32, and 41 with idiopathic PAH, CTD-PAH, PH-LHD, and CTEPH, respectively) and 41 non-PH controls were included. Ang-1 levels showed no significant difference between groups (p = 0.8), and no significant associations with disease severity in PH subgroups (p ≥ 0.07). In Kaplan—Meier analyses, Ang-1 levels (stratified by quartile) had no significant impact on transplant-free survival (p ≥ 0.27) or clinical worsening (p ≥ 0.51) in PH subgroups. Regression models found no significant association between Ang-1 levels and outcomes (p ≥ 0.31). ROC analyses found no significant cut-off that would maximize sensitivity and specificity. Conclusions: Despite a strong pathophysiological association in experimental studies, this first comprehensive analysis of Ang-1 in PH subgroups suggests that Ang-1 is not a predictive and clinically relevant biomarker in PH. [ABSTRACT FROM AUTHOR]
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- 2016
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20. iNOS Deletion in Alveolar Epithelium Cannot Reverse the Elastase-Induced Emphysema in Mice.
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Gredic, Marija, Sharma, Vinita, Hadzic, Stefan, Wu, Cheng-Yu, Pak, Oleg, Kojonazarov, Baktybek, Duerr, Julia, Mall, Marcus A., Guenther, Andreas, Schermuly, Ralph T., Grimminger, Friedrich, Seeger, Werner, Kraut, Simone, Sommer, Natascha, and Weissmann, Norbert
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LUNGS , *CHRONIC obstructive pulmonary disease , *NITRIC-oxide synthases , *SYSTOLIC blood pressure , *PULMONARY hypertension , *CHRONIC bronchitis - Abstract
Background: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. In addition to chronic bronchitis and emphysema, patients often develop at least mild pulmonary hypertension (PH). We previously demonstrated that inhibition of inducible nitric oxide synthase (iNOS) prevents and reverses emphysema and PH in mice. Interestingly, strong iNOS upregulation was found in alveolar epithelial type II cells (AECII) in emphysematous murine lungs, and peroxynitrite, which can be formed from iNOS-derived NO, was shown to induce AECII apoptosis in vitro. However, the specific cell type(s) that drive(s) iNOS-dependent lung regeneration in emphysema/PH has (have) not been identified yet. Aim: we tested whether iNOS knockout in AECII affects established elastase-induced emphysema in mice. Methods: four weeks after a single intratracheal instillation of porcine pancreatic elastase for the induction of emphysema and PH, we induced iNOS knockout in AECII in mice, and gave an additional twelve weeks for the potential recovery. Results: iNOS knockout in AECII did not reduce elastase-induced functional and structural lung changes such as increased lung compliance, decreased mean linear intercept and increased airspace, decreased right ventricular function, increased right ventricular systolic pressure and increased pulmonary vascular muscularization. In vitro, iNOS inhibition did not reduce apoptosis of AECII following exposure to a noxious stimulus. Conclusion: taken together, our data demonstrate that iNOS deletion in AECII is not sufficient for the regeneration of emphysematous murine lungs, and suggest that iNOS expression in pulmonary vascular or stromal cells might be critically important in this regard. [ABSTRACT FROM AUTHOR]
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- 2023
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21. Role of Reactive Oxygen Species in Acute Pulmonary Oxygen Sensing
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Oleg, Pak, Sommer, Natascha, Ghofrani, Hossein A., Schermuly, Ralph T., Seeger, Werner, Grimminger, Friedrich, and Weissmann, Norbert
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- 2010
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22. 105 Mitochondrial alterations in pulmonary arterial smooth muscle cells in pulmonary arterial hypertension
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Sommer, Natascha, Krug, Philipp, Waisbrod, Sharon, Pak, Oleg, Ghofrani, Hossein A., Seeger, Werner, and Weissmann, Norbert
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- 2010
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23. S12.46 Hypoxic pulmonary vasoconstriction is modulated in ucp2 knock-out mice during acute and sustained hypoxia
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Höres, Timm, Sommer, Natascha, Ghofrani, Hossein A., Schermuly, Ralph T., Seeger, Werner, Grimminger, Fritz, and Weissmann, Norbert
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- 2008
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24. S8.23 Oxygen dependency of mitochondrial respiratory chain function in hypoxic pulmonary vasoconstriction
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Sommer, Natascha, Ghofrani, Hossein A., Schermuly, Ralph T., Seeger, Werner, Grimminger, Fritz, and Weissmann, Norbert
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- 2008
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25. Mitochondrial Cytochrome c Oxidase Subunit 4 Isoform 2 Regulates T-cell activation and inflammation during viral infection.
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Lakshmi, Vidya Srokshna Balasubramanian, Berger, Thilo, Garcia, Claudia, Völkel, Sara, Better, Julian, Estiri, Mohammad, Giordano, Luca, Nardiello, Claudio, Seeger, Werner, Pak, Oleg, Matt, Ulrich, Herold, Susanne, Grossman, Lawrence I., Hüttemann, Maik, Weissmann, Norbert, Skevaki, Chrysanthi, and Sommer, Natascha
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- 2024
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26. Mitochondrial cytochrome c oxidase subunit 4 isoform 2 (Cox4i2) promotes hypoxia-induced reduction of the electron transport system in pulmonary arterial smooth muscle cells.
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Giordano, Luca, Wittig, Ilka, Nolte-Grützner, Anika, Cabrera-Orefice, Alfredo, Jash, Sandipan, Pak, Oleg, Knoepp, Fenja, Ramser, Kerstin, Wahl, Joel, Pecina, Petr, Seeger, Werner, Weissmann, Norbert, Grossman, Lawrence I., Hüttemann, Maik, and Sommer, Natascha
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- 2024
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27. Chronic Lung Allograft Dysfunction Is Associated with Increased Levels of Cell-Free Mitochondrial DNA in Bronchoalveolar Lavage Fluid of Lung Transplant Recipients.
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Schneck, Emmanuel, Askevold, Ingolf, Rath, Ramona, Hecker, Andreas, Reichert, Martin, Guth, Stefan, Koch, Christian, Sander, Michael, Seeger, Werner, Mayer, Konstantin, Padberg, Winfried, Sommer, Natascha, Kuhnert, Stefan, and Hecker, Matthias
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MITOCHONDRIAL DNA , *LUNG transplantation , *BRONCHOALVEOLAR lavage , *HOMOGRAFTS , *LUNGS - Abstract
Chronic Lung Allograft Dysfunction (CLAD) is a life-threatening complication that limits the long-term survival of lung transplantation patients. Early diagnosis remains the basis of efficient management of CLAD, making the need for distinctive biomarkers critical. This explorative study aimed to investigate the predictive power of mitochondrial DNA (mtDNA) derived from bronchoalveolar lavages (BAL) to detect CLAD. The study included 106 lung transplant recipients and analyzed 286 BAL samples for cell count, cell differentiation, and inflammatory and mitochondrial biomarkers, including mtDNA. A receiver operating curve analysis of mtDNA levels was used to assess its ability to detect CLAD. The results revealed a discriminatory pro-inflammatory cytokine profile in the BAL fluid of CLAD patients. The concentration of mtDNA increased in step with each CLAD stage, reaching its highest concentration in stage 4, and correlated significantly with decreasing FEV1. The receiver operating curve analysis of mtDNA in BAL revealed a moderate prediction of CLAD when all stages were grouped together (AUROC 0.75, p-value < 0.0001). This study has found the concentration mtDNA in BAL to be a potential predictor for the early detection of CLAD and the differentiation of different CLAD stages, independent of the underlying pathology. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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28. Association of Clonal Hematopoiesis of Indeterminate Potential with Inflammatory Gene Expression in Patients with COPD.
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Kuhnert, Stefan, Mansouri, Siavash, Rieger, Michael A., Savai, Rajkumar, Avci, Edibe, Díaz-Piña, Gabriela, Padmasekar, Manju, Looso, Mario, Hadzic, Stefan, Acker, Till, Klatt, Stephan, Wilhelm, Jochen, Fleming, Ingrid, Sommer, Natascha, Weissmann, Norbert, Vogelmeier, Claus, Bals, Robert, Zeiher, Andreas, Dimmeler, Stefanie, and Seeger, Werner
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CHOLINE , *HEMATOPOIESIS , *GENE expression , *CHRONIC obstructive pulmonary disease , *PHOSPHOLIPASE D , *IMMUNOSENESCENCE , *SOMATIC mutation - Abstract
Chronic obstructive pulmonary disease (COPD) is a disease with an inflammatory phenotype with increasing prevalence in the elderly. Expanded population of mutant blood cells carrying somatic mutations is termed clonal hematopoiesis of indeterminate potential (CHIP). The association between CHIP and COPD and its relevant effects on DNA methylation in aging are mainly unknown. Analyzing the deep-targeted amplicon sequencing from 125 COPD patients, we found enhanced incidence of CHIP mutations (~20%) with a predominance of DNMT3A CHIP-mediated hypomethylation of Phospholipase D Family Member 5 (PLD5), which in turn is positively correlated with increased levels of glycerol phosphocholine, pro-inflammatory cytokines, and deteriorating lung function. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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29. Gene panel diagnostics reveals new pathogenic variants in pulmonary arterial hypertension.
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Eichstaedt, Christina A., Saßmannshausen, Zoe, Shaukat, Memoona, Cao, Ding, Xanthouli, Panagiota, Gall, Henning, Sommer, Natascha, Ghofrani, Hossein-Ardeschir, Seyfarth, Hans-Jürgen, Lerche, Marianne, Halank, Michael, Kleymann, Janina, Benjamin, Nicola, Harutyunova, Satenik, Egenlauf, Benjamin, Milger, Katrin, Rosenkranz, Stephan, Ewert, Ralf, Klose, Hans, and Hoeper, Marius M.
- Abstract
Background: A genetic predisposition can lead to the rare disease pulmonary arterial hypertension (PAH). Most mutations have been identified in the gene BMPR2 in heritable PAH. However, as of today 15 further PAH genes have been described. The exact prevalence across these genes particularly in other PAH forms remains uncertain. We present the distribution of mutations across PAH genes identified at the largest German referral centre for genetic diagnostics in PAH over a course of > 3 years. Methods: Our PAH-specific gene diagnostics panel was used to sequence 325 consecutive PAH patients from March 2017 to October 2020. For the first year the panel contained thirteen PAH genes: ACVRL1, BMPR1B, BMPR2, CAV1, EIF2AK4, ENG, GDF2, KCNA5, KCNK3, KLF2, SMAD4, SMAD9 and TBX4.These were extended by the three genes ATP13A3, AQP1 and SOX17 from March 2018 onwards following the genes' discovery. Results: A total of 79 mutations were identified in 74 patients (23%). Of the variants 51 (65%) were located in the gene BMPR2 while the other 28 variants were found in ten further PAH genes. We identified disease-causing variants in the genes AQP1, KCNK3 and SOX17 in families with at least two PAH patients. Mutations were not only detected in patients with heritable and idiopathic but also with associated PAH. Conclusions: Genetic defects were identified in 23% of the patients in a total of 11 PAH genes. This illustrates the benefit of the specific gene panel containing all known PAH genes. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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30. Risk assessment in pulmonary hypertension based on routinely measured laboratory parameters.
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Yogeswaran, Athiththan, Tello, Khodr, Lund, Jonas, Klose, Hans, Harbaum, Lars, Sommer, Natascha, Oqueka, Tim, Hennigs, Jan K., Grimminger, Friedrich, Seeger, Werner, Ghofrani, Hossein Ardeschir, Richter, Manuel J., and Gall, Henning
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PULMONARY hypertension , *PULMONARY arterial hypertension , *RISK assessment , *ALANINE aminotransferase , *ASPARTATE aminotransferase - Abstract
γ-glutamyl transferase (GGT), the aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio, and the neutrophil-to-lymphocyte ratio (NLR) are prognostic biomarkers in several cardiovascular diseases, but their relevance in pulmonary hypertension (PH) is not fully understood. We aimed to assess their prognostic value in patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH). We retrospectively analyzed 731 incident patients with idiopathic PAH or CTEPH who entered the Giessen PH registry during 1993–2019. A risk stratification score based on GGT, AST/ALT ratio, and NLR tertiles was compared with a truncated version of the European Society of Cardiology/European Respiratory Society (ESC/ERS) risk stratification scheme. Associations with survival were evaluated using Kaplan-Meier and Cox regression analyses. External validation was performed in 311 patients with various types of PAH or CTEPH from a second German center. GGT levels, AST/ALT, and NLR independently predicted mortality at baseline and during follow-up. The scoring system based on these biomarkers predicted mortality at baseline and during follow-up (both log-rank p < 0.001; hazard ratio [95% confidence interval], high vs low risk: baseline, 7.6 [3.9, 15.0]; follow-up, 13.3 [4.8, 37.1]). Five-year survival of low, intermediate, and high risk groups was 92%, 76%, and 51%, respectively, at baseline and 95%, 78%, and 50%, respectively, during follow-up. Our scoring system showed characteristics comparable to the ESC/ERS scheme, and predicted mortality in the validation cohort. GGT, AST/ALT, and NLR were reliable prognostic biomarkers at baseline and during follow-up, with predictive power comparable to the gold standard for risk stratification. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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31. A Microfluidic System for Simultaneous Raman Spectroscopy, Patch‐Clamp Electrophysiology, and Live‐Cell Imaging to Study Key Cellular Events of Single Living Cells in Response to Acute Hypoxia.
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Knoepp, Fenja, Wahl, Joel, Andersson, Anders, Kraut, Simone, Sommer, Natascha, Weissmann, Norbert, and Ramser, Kerstin
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ELECTROPHYSIOLOGY , *HYPOXEMIA , *DIAGNOSTIC imaging , *SPECIAL events , *MEMBRANE potential - Abstract
The ability to sense changes in oxygen availability is fundamentally important for the survival of all aerobic organisms. However, cellular oxygen sensing mechanisms and pathologies remain incompletely understood and studies of acute oxygen sensing, in particular, have produced inconsistent results. Current methods cannot simultaneously measure the key cellular events in acute hypoxia (i.e., changes in redox state, electrophysiological properties, and mechanical responses) at controlled partial pressures of oxygen (pO2). The lack of such a comprehensive method essentially contributes to the discrepancies in the field. A sealed microfluidic system that combines i) Raman spectroscopy, ii) patch‐clamp electrophysiology, and iii) live‐cell imaging under precisely controlled pO2 have therefore been developed. Merging these modalities allows label‐free and simultaneous observation of oxygen‐dependent alterations in multiple cellular redox couples, membrane potential, and cellular contraction. This technique is adaptable to any cell type and allows in‐depth insight into acute oxygen sensing processes underlying various physiologic and pathologic conditions. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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32. Epigenetic Regulation by in Cardiopulmonary Progenitor Cells Is Required to Prevent Pulmonary Hypertension and Chronic Obstructive Pulmonary Disease.
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Hui Qi, Pullamsetti, Soni Savai, Günther, Stefan, Kuenne, Carsten, Atzberger, Ann, Sommer, Natascha, Hadzic, Stefan, Günther, Andreas, Weissmann, Norbert, Yonggang Zhou, Xuejun Yuan, Braun, Thomas, Qi, Hui, Liu, Hang, Zhou, Yonggang, and Yuan, Xuejun
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OBSTRUCTIVE lung diseases , *PROGENITOR cells , *LUNGS , *HEART cells , *LUNG diseases , *CELL death , *PUPILLARY reflex , *RESEARCH , *PULMONARY hypertension , *ANIMAL experimentation , *RESEARCH methodology , *MEDICAL cooperation , *EVALUATION research , *COMPARATIVE studies , *TRANSFERASES , *STEM cells , *GENES , *MICE - Abstract
Background: The pathogenesis of life-threatening cardiopulmonary diseases such as pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD) originates from a complex interplay of environmental factors and genetic predispositions that is not fully understood. Likewise, little is known about developmental abnormalities or epigenetic dysregulations that might predispose for PH or COPD in adult individuals.Methods: To identify pathology-associated epigenetic alteration in diseased lung tissues, we screened a cohort of human patients with PH and COPD for changes of histone modifications by immunofluorescence staining. To analyze the function of H4K20me2/3 in lung pathogenesis, we developed a series of Suv4-20h1 knockout mouse lines targeting cardiopulmonary progenitor cells and different heart and lung cell types, followed by hemodynamic studies and morphometric assessment of tissue samples. Molecular, cellular, and biochemical techniques were applied to analyze the function of Suv4-20h1-dependent epigenetic processes in cardiopulmonary progenitor cells and their derivatives.Results: We discovered a strong reduction of the histone modifications of H4K20me2/3 in human patients with COPD but not patients with PH that depend on the activity of the H4K20 di-methyltransferase SUV4-20H1. Loss of Suv4-20h1 in cardiopulmonary progenitor cells caused a COPD-like/PH phenotype in mice including the formation of perivascular tertiary lymphoid tissue and goblet cell hyperplasia, hyperproliferation of smooth muscle cells/myofibroblasts, impaired alveolarization and maturation defects of the microvasculature leading to massive right ventricular dilatation and premature death. Mechanistically, SUV4-20H1 binds directly to the 5'-upstream regulatory element of the superoxide dismutase 3 (Sod3) gene to repress its expression. Increased levels of the extracellular SOD3 enzyme in Suv4-20h1 mutants increases hydrogen peroxide concentrations, causing vascular defects and impairing alveolarization.Conclusions: Our findings reveal a pivotal role of the histone modifier SUV4-20H1 in cardiopulmonary codevelopment and uncover the developmental origins of cardiopulmonary diseases. We assume that the study will facilitate the understanding of pathogenic events causing PH and COPD and aid the development of epigenetic drugs for the treatment of cardiopulmonary diseases. [ABSTRACT FROM AUTHOR]- Published
- 2021
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33. The effect of long-term doxycycline treatment in a mouse model of cigarette smoke-induced emphysema and pulmonary hypertension.
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Hadzic, Stefan, Cheng-Yu Wu, Gredic, Marija, Kojonazarov, Baktybek, Pak, Oleg, Kraut, Simone, Sommer, Natascha, Kosanovic, Djuro, Grimminger, Friedrich, Schermuly, Ralph T., Seeger, Werner, Bellusci, Saverio, and Weissmann, Norbert
- Abstract
Chronic obstructive pulmonary disease (COPD) is a major cause of death and a still incurable disease, comprising emphysema and chronic bronchitis. In addition to airflow limitation, patients with COPD can suffer from pulmonary hypertension (PH). Doxycycline, an antibiotic from the tetracycline family, in addition to its pronounced antimicrobial activity, acts as a matrix metalloproteinase (MMP) inhibitor and has anti-inflammatory properties. Furthermore, doxycycline treatment exhibited a beneficial effect in several preclinical cardiovascular disease models. In preclinical research, doxycycline is frequently employed for gene expression modulation in Tet-On/Tet-Off transgenic animal models. Therefore, it is crucial to know whether doxycycline treatment in Tet-On/Tet-Off systems has effects independent of gene expression modulation by such systems. Against this background, we assessed the possible curative effects of long-term doxycycline administration in a mouse model of chronic CS exposure. Animals were exposed to cigarette smoke (CS) for 8 mo and then subsequently treated with doxycycline for additional 3 mo in room air conditions. Doxycycline decreased the expression of MMPs and general pro-inflammatory markers in the lungs from CS-exposed mice. This downregulation was, however, insufficient to ameliorate CS-induced emphysema or PH. Tet-On/Tet-Off induction by doxycycline in such models is a feasible genetic approach to study curative effects at least in established CS-induced emphysema and PH. However, we report several parameters that are influenced by doxycycline and use of a Tet-On/ Tet-Off system when evaluating those parameters should be interpreted with caution. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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34. Amelioration of elastase-induced lung emphysema and reversal of pulmonary hypertension by pharmacological iNOS inhibition in mice.
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Fysikopoulos, Athanasios, Seimetz, Michael, Hadzic, Stefan, Knoepp, Fenja, Wu, Cheng‐Yu, Malkmus, Kathrin, Wilhelm, Jochen, Pichl, Alexandra, Bednorz, Mariola, Tadele Roxlau, Elsa, Ghofrani, Hossein A., Sommer, Natascha, Gierhardt, Mareike, Schermuly, Ralph T., Seeger, Werner, Grimminger, Friedrich, Weissmann, Norbert, Kraut, Simone, and Wu, Cheng-Yu
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ELASTASES , *PULMONARY emphysema , *PULMONARY hypertension , *OBSTRUCTIVE lung diseases , *TOBACCO smoke , *LUNGS , *BIOLOGICAL models , *RESEARCH , *ANIMAL experimentation , *RESEARCH methodology , *SWINE , *PROTEOLYTIC enzymes , *MEDICAL cooperation , *EVALUATION research , *SMOKE , *COMPARATIVE studies , *RESEARCH funding , *MICE - Abstract
Background and Purpose: Chronic obstructive pulmonary disease, encompassing chronic airway obstruction and lung emphysema, is a major worldwide health problem and a severe socio-economic burden. Evidence previously provided by our group has shown that inhibition of inducible NOS (iNOS) prevents development of mild emphysema in a mouse model of chronic tobacco smoke exposure and can even trigger lung regeneration. Moreover, we could demonstrate that pulmonary hypertension is not only abolished in cigarette smoke-exposed iNOS-/- mice but also precedes emphysema development. Possible regenerative effects of pharmacological iNOS inhibition in more severe models of emphysema not dependent on tobacco smoke, however, are hitherto unknown.Experimental Approach: We have established a mouse model using a single dose of porcine pancreatic elastase or saline, intratracheally instilled in C57BL/6J mice. Emphysema, as well as pulmonary hypertension development was determined by both structural and functional measurements.Key Results: Our data revealed that (i) emphysema is fully established after 21 days, with the same degree of emphysema after 21 and 28 days post instillation, (ii) emphysema is stable for at least 12 weeks and (iii) pulmonary hypertension is evident, in contrast to smoke models, only after emphysema development. Oral treatment with the iNOS inhibitor N(6)-(1-iminoethyl)-l-lysine (L-NIL) was started after emphysema establishment and continued for 12 weeks. This resulted in significant lung regeneration, evident in the improvement of emphysema and reversal of pulmonary hypertension.Conclusion and Implications: Our data indicate that iNOS is a potential new therapeutic target to treat severe emphysema and associated pulmonary hypertension.Linked Articles: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc. [ABSTRACT FROM AUTHOR]- Published
- 2021
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35. Risk assessment in severe pulmonary hypertension due to interstitial lung disease.
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Yogeswaran, Athiththan, Tello, Khodr, Faber, Marlene, Sommer, Natascha, Kuhnert, Stefan, Seeger, Werner, Grimminger, Friedrich, Ghofrani, Hossein Ardeschir, Richter, Manuel J., and Gall, Henning
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PULMONARY hypertension , *RISK assessment , *INTERSTITIAL lung diseases , *PULMONARY artery - Abstract
The updated hemodynamic definition of pulmonary hypertension (PH) due to interstitial lung disease (ILD) differentiates severe and non-severe phenotypes, but no further risk stratification strategy has been established or validated for severe PH due to ILD. We aimed to assess the prognostic value of a truncated version of the European Society of Cardiology/European Respiratory Society (ESC/ERS) PH risk stratification scheme in severe PH due to ILD. We retrospectively analyzed 185 patients with severe PH (mean pulmonary artery pressure of ≥35 mm Hg or ≥25 mm Hg with cardiac index <2.0 liter/min/m2) due to ILD who were enrolled in the Giessen PH Registry after being referred for invasive diagnostic work-up of suspected PH during 1995‒2018. A truncated ESC/ERS risk stratification scheme (based on 8 parameters from the full scheme) was applied. Kaplan–Meier and univariate Cox regression analyses were used to evaluate transplant-free survival and hazard ratios, respectively. During follow-up (median [interquartile range]: 19 [7–40] months), 146 events occurred. Using baseline data for risk stratification, 5-year transplant-free survival of low-, intermediate-, and high-risk groups was 43%, 15%, and 4%, respectively (log-rank p = 0.010; hazard ratio of high- vs low-risk group: 3.116 [95% CI: 1.428–6.800]). Using follow-up data (at 11 [6.0–32.5] months) for risk stratification, 5-year survival of low-, intermediate-, and high-risk groups was 22%, 3%, and 0%, respectively (log-rank p = 0.005). The truncated ESC/ERS scheme was clinically useful and demonstrated prognostic relevance in severe PH due to ILD. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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36. Cytochrome P450 epoxygenase‐derived 5,6‐epoxyeicosatrienoic acid relaxes pulmonary arteries in normoxia but promotes sustained pulmonary vasoconstriction in hypoxia.
- Author
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Strielkov, Ievgen, Krause, Nicole C., Knoepp, Fenja, Alebrahimdehkordi, Nasim, Pak, Oleg, Garcia, Claudia, Ghofrani, Hossein A., Schermuly, Ralph T., Seeger, Werner, Grimminger, Friedrich, Sommer, Natascha, and Weissmann, Norbert
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CYTOCHROME P-450 , *PULMONARY artery , *VASOCONSTRICTION , *EPOXIDE hydrolase , *HYPOXEMIA , *OXYGENASES - Abstract
Aims: The aim of the study was to investigate the role of cytochrome P450 (CYP) epoxygenase‐derived epoxyeicosatrienoic acids (EETs) in sustained hypoxic pulmonary vasoconstriction (HPV). Methods: Vasomotor responses of isolated mouse intrapulmonary arteries (IPAs) were assessed using wire myography. Key findings were verified by haemodynamic measurements in isolated perfused and ventilated mouse lungs. Results: Pharmacological inhibition of EET synthesis with MS‐PPOH, application of the EET antagonist 14,15‐EEZE or deficiency of CYP2J isoforms suppressed sustained HPV. In contrast, knockdown of EET‐degrading soluble epoxide hydrolase or its inhibition with TPPU augmented sustained HPV almost twofold. All EET regioisomers elicited relaxation in IPAs pre‐contracted with thromboxane mimetic U46619. However, in the presence of KCl‐induced depolarization, 5,6‐EET caused biphasic contraction in IPAs and elevation of pulmonary vascular tone in isolated lungs, whereas other regioisomers had no effect. In patch‐clamp experiments, hypoxia elicited depolarization in pulmonary artery smooth muscle cells (PASMCs), and 5,6‐EET evoked inward whole cell currents in PASMCs depolarized to the hypoxic level, but not at their resting membrane potential. Conclusions: The EET pathway substantially contributes to sustained HPV in mouse pulmonary arteries. 5,6‐EET specifically appears to be involved in HPV, as it is the only EET regioisomer able to elicit not only relaxation, but also sustained contraction in these vessels. 5,6‐EET‐induced pulmonary vasoconstriction is enabled by PASMC depolarization, which occurs in hypoxia. The discovery of the dual role of 5,6‐EET in the regulation of pulmonary vascular tone may provide a basis for the development of novel therapeutic strategies for treatment of HPV‐related diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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37. Protection against pressure overload-induced right heart failure by uncoupling protein 2 silencing.
- Author
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Esfandiary, Azadeh, Kutsche, Hanna S, Schreckenberg, Rolf, Weber, Martin, Pak, Oleg, Kojonazarov, Baktybek, Sydykov, Akylbek, Hirschhäuser, Christine, Wolf, Annemarie, Haag, Daniela, Hecker, Matthias, Fink, Ludger, Seeger, Werner, Ghofrani, Hossein A, Schermuly, Ralph T, Weißmann, Norbert, Schulz, Rainer, Rohrbach, Susanne, Li, Ling, and Sommer, Natascha
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UNCOUPLING proteins , *HEART failure , *SUPEROXIDES , *MEDICAL sciences , *MITOCHONDRIA formation , *RIGHT ventricular hypertrophy - Published
- 2019
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38. The Giessen Pulmonary Hypertension Registry: Survival in pulmonary hypertension subgroups.
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Gall, Henning, Felix, Janine F., Schneck, Franziska K., Milger, Katrin, Sommer, Natascha, Voswinckel, Robert, Franco, Oscar H., Hofman, Albert, Schermuly, Ralph T., Weissmann, Norbert, Grimminger, Friedrich, Seeger, Werner, and Ghofrani, Hossein A.
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PULMONARY hypertension , *LUNG transplantation , *OBSTRUCTIVE lung diseases , *FOLLOW-up studies (Medicine) , *BIOMARKERS - Abstract
Background Pulmonary hypertension (PH) is a severe, progressive disease. Although 5 PH subgroups are recognized, reports on survival have focused mainly on pulmonary arterial hypertension (PAH). Methods Long-term transplant-free survival and its determinants were investigated in patients with PH (diagnosed by right heart catheterization) within a prospective registry at a single referral center in Giessen, Germany. Results In total, 2,067 patients were enrolled (PAH, 685 patients [33.1%]; pulmonary venous hypertension, 307 patients [14.9%]; PH due to lung diseases (LD-PH), 546 patients [26.4%; mainly interstitial lung disease and chronic obstructive pulmonary disease]; chronic thromboembolic PH, 459 patients [22.2%]; PH owing to miscellaneous/unknown causes, 70 patients [3.4%]). Median follow-up was 37 months. Differences in transplant-free survival between etiologic groups were highly significant ( p < 0.001), with 1-, 3- and 5-year survival rates of 88.2%, 72.2% and 59.4%, respectively, for those with PAH compared with 79.5%, 52.7% and 38.1%, respectively, for patients with LD-PH. Patients’ age, gender and 6-minute walk distance (6MWD), but not New York Heart Association (NYHA) functional class, associated significantly with survival across all PH subtypes in multivariate Cox regression analyses. Conclusions This is the largest single-center PH cohort described so far. Some parameters used in clinical practice do not independently predict survival. Age, gender and 6MWD outperformed NYHA functional class in predicting survival across all etiologic groups. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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39. Mitochondrial oxygen sensing of acute hypoxia in specialized cells - Is there a unifying mechanism?
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Pak, Oleg, Nolte, Anika, Knoepp, Fenja, Giordano, Luca, Pecina, Petr, Hüttemann, Maik, Grossman, Lawrence I., Weissmann, Norbert, and Sommer, Natascha
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VASOCONSTRICTION , *CAROTID body , *REACTIVE oxygen species , *CYTOCHROME oxidase , *MITOCHONDRIA , *HYPOXEMIA , *OXYGEN - Abstract
Acclimation to acute hypoxia through cardiorespiratory responses is mediated by specialized cells in the carotid body and pulmonary vasculature to optimize systemic arterial oxygenation and thus oxygen supply to the tissues. Acute oxygen sensing by these cells triggers hyperventilation and hypoxic pulmonary vasoconstriction which limits pulmonary blood flow through areas of low alveolar oxygen content. Oxygen sensing of acute hypoxia by specialized cells thus is a fundamental pre-requisite for aerobic life and maintains systemic oxygen supply. However, the primary oxygen sensing mechanism and the question of a common mechanism in different specialized oxygen sensing cells remains unresolved. Recent studies unraveled basic oxygen sensing mechanisms involving the mitochondrial cytochrome c oxidase subunit 4 isoform 2 that is essential for the hypoxia-induced release of mitochondrial reactive oxygen species and subsequent acute hypoxic responses in both, the carotid body and pulmonary vasculature. This review compares basic mitochondrial oxygen sensing mechanisms in the pulmonary vasculature and the carotid body. • Acute oxygen sensing shares common mechanisms in different cell types. • Mitochondrial reactive oxygen species (ROS) trigger acute hypoxic responses. • Cytochrome c oxidase subunit 4 isoform 2 is essential for acute oxygen sensing. • ROS may originate from complex I or III depending on the cell type. • Further cell-type specific mediators include cellular redox couples. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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40. The Clinical Significance of HbA1c in Operable Chronic Thromboembolic Pulmonary Hypertension.
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Richter, Manuel Jonas, Milger, Katrin, Haase, Sarah, Sommer, Natascha, Tello, Khodr, Seeger, Werner, Mayer, Eckhard, Wiedenroth, Christoph Benjamin, Grimminger, Friedrich, George, Wolfgang, Ghofrani, Hossein Ardeschir, Guth, Stefan, and Gall, Henning
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PULMONARY hypertension treatment , *THROMBOEMBOLISM , *GLYCOSYLATED hemoglobin , *PULMONARY hypertension , *BIOMARKERS , *PROGNOSIS - Abstract
Background: Glycosylated hemoglobin A1c (HbA1c) has been proposed as an independent predictor of long-term prognosis in pulmonary arterial hypertension. However, the clinical relevance of HbA1c in patients with operable chronic thromboembolic pulmonary hypertension (CTEPH) remains unknown. The aim of the present study was to investigate the clinical significance of HbA1c as a biomarker in CTEPH. Methods: Prospectively, 102 patients underwent pulmonary endarterectomy (PEA) in our national referral center between March 2013 and March 2014, of which after exclusion 45 patients were analyzed. HbA1c- levels, hemodynamic and exercise parameters were analyzed prior and one-year post-PEA. Results: 45 patients (BMI: 27.3 ± 6.0 kg/m2; age: 62.7 ± 12.3 years) with a mean pulmonary arterial pressure (mPAP) of 43.6 ± 9.4 mmHg, a pulmonary vascular resistance (PVR) of 712.1 ± 520.4 dyn*s/cm5, a cardiac index (CI) of 2.4 ± 0.5 l/min/m2 and a mean HbA1c-level of 39.8 ± 5.6 mmol/mol were included. One-year post-PEA pulmonary hemodynamic and functional status significantly improved in our cohort. Baseline HbA1c-levels were significantly associated with CI, right atrial pressure, peak oxygen uptake and the change of 6-minute walking distance using linear regression analysis. However, using logistic regression analysis baseline HbA1c-levels were not significantly associated with residual post-PEA PH. Conclusions: This is the first prospective study to describe an association of HbA1c-levels with pulmonary hemodynamics and exercise capacity in operable CTEPH patients. Our preliminary results indicate that in these patients impaired glucose metabolism as assessed by HbA1c is of clinical significance. However, HbA1c failed as a predictor of the hemodynamic outcome one-year post-PEA. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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41. NADPH oxidases-do they play a role in TRPC regulation under hypoxia?
- Author
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Malczyk, Monika, Veith, Christine, Schermuly, Ralph, Gudermann, Thomas, Dietrich, Alexander, Sommer, Natascha, Weissmann, Norbert, and Pak, Oleg
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NADPH oxidase , *TRP channels , *HYPOXEMIA , *VASOCONSTRICTION , *VENTILATION , *PULMONARY hypertension - Abstract
In the lung, acute alveolar hypoxia causes hypoxic pulmonary vasoconstriction (HPV) to maintain ventilation perfusion matching and thus optimal oxygenation of blood. In contrast, global chronic hypoxia triggers a pathological thickening of pulmonary arterial walls, called pulmonary vascular remodelling, leading to persistence of pulmonary hypertension (PH). Moreover, ischaemia or hypoxia can lead to a damage of pulmonary endothelial cells with subsequent oedema formation. Alterations in reactive oxygen species (ROS) have been suggested as a crucial mediator of such responses. Among the various sources of cellular ROS production, NADPH oxidases (NOXs) have been found to contribute to these physiological and pathophysiological signalling processes. NOXs are the only known examples that generate ROS as the primary function of the enzyme system. However, the downstream targets of NOX-derived ROS signalling in hypoxia are still not known. Canonical transient receptor potential (TRPC) channels recently have been recognised as directly or indirectly ROS-activated channels and have been shown to be essential for hypoxia-dependent vascular regulatory processes in the lung. Against this background, we here summarise the current knowledge on NOX-mediated TRPC channel signalling during hypoxia in the pulmonary circulation. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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42. Essential Role of Mitochondrial Cytochrome c Oxidase Subunit 4 Isoform 2 (Cox4i2) for Acute Pulmonary Oxygen Sensing.
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Giordano, Luca, Nolte, Anika, Wittig, Ilka, Pak, Oleg, Knoepp, Fenja, Ramser, Kerstin, Wahl, Joel, Hϋttemann, Maik, Grossman, Lawrence I., Pecina, Petr, Ghofrani, Hossein A., Seeger, Werner, Weissmann, Norbert, Giehl, Klaudia, and Sommer, Natascha
- Subjects
- *
CYTOCHROME oxidase , *MITOCHONDRIA , *CYTOCHROME c , *OXYGEN - Published
- 2022
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43. PPAR-α activation reduced LPS-induced inflammation in alveolar epithelial cells.
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Hecker, Matthias, Behnk, Aniella, Morty, Rory Edward, Sommer, Natascha, Vadász, István, Herold, Susanne, Seeger, Werner, and Mayer, Konstantin
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EPITHELIAL cells , *LUNG injuries , *FIBRATES , *INFLAMMATION , *PEROXISOME proliferator-activated receptors - Abstract
Purpose of the study: Acute respiratory distress syndrome (ARDS) represents a major cause of mortality in intensive care patients. Activation of peroxisome proliferator-activated receptor-α (PPAR-α) by fibrates, such as WY-14643 (WY), has been described to beneficially influence inflammation and experimental lung injury. The impact of PPAR-α activation on alveolar epithelial cells (AEC) has not been studied yet. Materials and Methods: To investigate the effect of PPAR-α activator WY in wild-type (WT) and in PPAR-α knockout (PPAR-α−/−) animals, mice were treated in different regimes: mice received chow enriched with or without WY for 14 days prior AEC isolation (in-vivo treatment). Furthermore, isolated AEC from both groups were subsequently cultured with or without WY (in-vitro treatment). AEC were stimulated with lipopolysaccharide (LPS). Cell culture supernatant and cell lysate were used for analysis of pro-inflammatory mediators. Results: AEC challenged with LPS showed a significantly increased generation of pro-inflammatory mediators. After in-vivo WY-exposure, AEC displayed significantly reduced concentration of TNF-α, MIP-2, and TxB2 after LPS stimulation. This beneficial effect was abrogated in PPAR-α−/− animals. Interestingly, sole in-vitro application of WY-14643 failed to reduce levels of pro-inflammatory mediators whereas we found an additive effect of a combined in-vivo and in-vitro PPAR-α activation. PGE2 concentration remained high after LPS challenge and was unaffected by WY treatment. Conclusion: PPAR-α activation by in-vivo exposure to fibrates reduced the inflammatory response in isolated AEC. These findings may facilitate further studies investigating the translation of pharmacological PPAR-α activation into clinical therapy of ARDS. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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44. Function of NADPH Oxidase 1 in Pulmonary Arterial Smooth Muscle Cells After Monocrotaline-Induced Pulmonary Vascular Remodeling.
- Author
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Veit, Florian, Pak, Oleg, Egemnazarov, Bakytbek, Roth, Markus, Kosanovic, Djuro, Seimetz, Michael, Sommer, Natascha, Ghofrani, Hossein A., Seeger, Werner, Grimminger, Friedrich, Brandes, Ralf P., Schermuly, Ralph T., and Weissmann, Norbert
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NADPH oxidase regulation , *PULMONARY blood vessels , *REACTIVE oxygen species , *SUPEROXIDE dismutase , *METALLOPROTEINASE regulation , *PHOSPHORYLATION ,SMOOTH muscle inflammation - Abstract
Aims: Chronic hypoxia induces pulmonary hypertension (PH) that is concomitant with pulmonary vascular remodeling. Reactive oxygen species (ROS) are thought to play a major role in this. Recent findings suggest that ROS production by NADPH oxidase 4 (Nox4) is important in this remodeling. We investigated whether ROS production by Nox is also important in an inflammatory model of monocrotaline (MCT)-induced PH. We examined ROS production, their possible sources, and their impact on the function of pulmonary arterial smooth muscle cells (PASMC) isolated from MCT-treated and healthy rats. Results: MCT-PASMC showed increased intracellular superoxide production, migration, and proliferation compared with healthy controls due to increased Nox1 expression. A comparison of PASMC from MCT- and nontreated rats revealed an up-regulation of Sod2, Nrf2, cyclin D1, and matrix metalloproteinase-9 (MMP-9) as well as an increased phosphorylation of cofilin and extracellular signal-regulated kinases (Erk). Expression of Sod2, Nrf2, and cyclin D1 and phosphorylation of cofilin and Erk were Nox1 dependent. Innovation: The role of ROS in PH is not fully understood. Mitochondria and Nox have been suggested as sources of altered ROS generation in PH, yet it remains unclear whether increased or decreased ROS contributes to the development of PH. Our studies provide evidence that for different triggers of PH, different Nox isoforms regulate proliferation and migration of PASMC. Conclusion: In contrast to hypoxia-induced PH, Nox1 but not Nox4 is responsible for pathophysiological proliferation and migration of PASMC in an inflammatory model of MCT-induced PH via increased superoxide production. Thus, different Nox isoforms may be targeted in different forms of PH. Antioxid. Redox Signal. 19, 2213-2231. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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45. Gene regulation of cytochrome c oxidase subunit 4 isoform 2: A tale of three factors
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Aras, Siddhesh, Oleg, Pak, Sommer, Natascha, Hüttemann, Maik, Weissmann, Norbert, and Grossman, Lawrence
- Published
- 2012
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46. Cytochrome c oxidase subunit 4 isoform 2-knockout mice show reduced enzyme activity, airway hyporeactivity, and lung pathology.
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Hüttemann, Maik, Lee, Icksoo, Xiufeng Gao, Pecina, Petr, Pecinova, Alena, Liu, Jenney, Aras, Siddhesh, Sommer, Natascha, Sanderson, Thomas H., Tost, Monica, Neff, Frauke, Aguilar-Pimentel, Juan Antonio, Becker, Lore, Naton, Beatrix, Rathkolb, Birgit, Rozman, Jan, Favor, Jack, Hans, Wolfgang, Prehn, Cornelia, and Puk, Oliver
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CYTOCHROME c , *ELECTRON transport , *LABORATORY mice , *LUNG physiology , *OXIDATIVE stress - Abstract
Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial electron transport chain. The purpose of this study was to analyze the function of lung-specific cytochrome c oxidase subunit 4 isoform 2 (COX4i2) in vitro and in COX4i2-knockout mice in vivo. COX was isolated from cow lung and liver as control and functionally analyzed. COX4i2-knockout mice were generated and the effect of the gene knockout was determined, including COX activity, tissue energy levels, noninvasive and invasive lung function, and lung pathology. These studies were complemented by a comprehensive functional screen performed at the German Mouse Clinic (Neuherberg, Germany). We show that isolated cow lung COX containing COX4i2 is about twice as active (88 and 102% increased activity in the presence of allosteric activator ADP and inhibitor ATP, respectively) as liver COX, which lacks COX4i2. In COX4i2-knockout mice, lung COX activity and cellular ATP levels were significantly reduced (-50 and -29%, respectively). Knockout mice showed decreased airway responsiveness (60% reduced Penh and 58% reduced airway resistance upon challenge with 25 and 100 mg methacholine, respectively), and they developed a lung pathology deteriorating with age that included the appearance of Charcot-Leyden crystals. In addition, there was an interesting sex-specific phenotype, in which the knockout females showed reduced lean mass (-12%), reduced total oxygen consumption rate (-8%), improved glucose tolerance, and reduced grip force (- 14%) compared to wild-type females. Our data suggest that high activity lung COX is a central determinant of airway function and is required for maximal airway responsiveness and healthy lung function. Since airway constriction requires energy, we propose a model in which reduced tissue ATP levels explain protection from airway hyperresponsiveness, i.e., absence of COX4i2 leads to reduced lung COX activity and ATP levels, which results in impaired airway constriction and thus reduced airway responsiveness; long-term lung pathology develops in the knockout mice due to impairment of energy-costly lung maintenance processes; and therefore, we propose mitochondrial oxidative phosphorylation as a novel target for the treatment of respiratory diseases, such as asthma. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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47. Effects of hypercapnia and NO synthase inhibition in sustained hypoxic pulmonary vasoconstriction.
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Ketabchi, Farzaneh, Ghofrani, Hossein A., Schermuly, Ralph T., Seeger, Werner, Grimminger, Friedrich, Egemnazarov, Bakytbek, Shid-Moosavi, S Mostafa, Dehghani, Gholam A., Weissmann, Norbert, and Sommer, Natascha
- Subjects
- *
HYPERCAPNIA , *NITRIC-oxide synthases , *VASOCONSTRICTION , *PULMONARY gas exchange , *HYPOXEMIA , *ACIDOSIS - Abstract
Background: Acute respiratory disorders may lead to sustained alveolar hypoxia with hypercapnia resulting in impaired pulmonary gas exchange. Hypoxic pulmonary vasoconstriction (HPV) optimizes gas exchange during local acute (0-30 min), as well as sustained (> 30 min) hypoxia by matching blood perfusion to alveolar ventilation. Hypercapnia with acidosis improves pulmonary gas exchange in repetitive conditions of acute hypoxia by potentiating HPV and preventing pulmonary endothelial dysfunction. This study investigated, if the beneficial effects of hypercapnia with acidosis are preserved during sustained hypoxia as it occurs, e.g in permissive hypercapnic ventilation in intensive care units. Furthermore, the effects of NO synthase inhibitors under such conditions were examined. Method: We employed isolated perfused and ventilated rabbit lungs to determine the influence of hypercapnia with or without acidosis (pH corrected with sodium bicarbonate), and inhibitors of endothelial as well as inducible NO synthase on acute or sustained HPV (180 min) and endothelial permeability. Results: In hypercapnic acidosis, HPV was intensified in sustained hypoxia, in contrast to hypercapnia without acidosis when HPV was amplified during both phases. L-NG-Nitroarginine (L-NNA), a non-selective NO synthase inhibitor, enhanced acute as well as sustained HPV under all conditions, however, the amplification of sustained HPV induced by hypercapnia with or without acidosis compared to normocapnia disappeared. In contrast 1400 W, a selective inhibitor of inducible NO synthase (iNOS), decreased HPV in normocapnia and hypercapnia without acidosis at late time points of sustained HPV and selectively reversed the amplification of sustained HPV during hypercapnia without acidosis. Hypoxic hypercapnia without acidosis increased capillary filtration coefficient (Kfc). This increase disappeared after administration of 1400 W. Conclusion: Hypercapnia with and without acidosis increased HPV during conditions of sustained hypoxia. The increase of sustained HPV and endothelial permeability in hypoxic hypercapnia without acidosis was iNOS dependent. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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48. Elevated CO2 Levels Cause Mitochondrial Dysfunction and Impair Cell Proliferation.
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Vohwinkel, Christine U., Lecuona, Emilia, Sun, Haying, Sommer, Natascha, Vadász, István, Chandel, Navdeep S., and Sznajder, Jacob I.
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MITOCHONDRIAL DNA , *CELL proliferation , *LUNG diseases , *FIBROBLASTS , *HYPERCAPNIA - Abstract
Elevated CO2 concentrations (hypercapnia) occur in patients with severe lung diseases. Here, we provide evidence that high CO2 levels decrease O2 consumption and ATP production and impair cell proliferation independently of acidosis and hypoxia in fibroblasts (N12) and alveolar epithelial cells (A549). Cells exposed to elevated CO2 died in galactose medium as well as when glucose-6-phosphate isomerase was knocked down, suggesting mitochondrial dysfunction. High CO2 levels led to increased levels of microRNA-183 (miR-183), which in turn decreased expression of IDH2 (isocitrate dehydrogenase 2). The high CO2-induced decrease in cell proliferation was rescued by α-ketoglutarate and overexpression of IDH2, whereas proliferation decreased in normocapnic cells transfected with siRNA for IDH2. Also, overexpression of miR-183 decreased IDH2 (mRNA and protein) as well as cell proliferation under normocapnic conditions, whereas inhibition of miR-183 rescued the normal proliferation phenotype in cells exposed to elevated levels of CO2. Accordingly, we provide evidence that high CO2 induces miR-183, which down-regulates IDH2, thus impairing mitochondrial function and cell proliferation. These results are of relevance to patients with hypercapnia such as those with chronic obstructive pulmonary disease, asthma, cystic fibrosis, bronchopulmonary dysplasia, and muscular dystrophies. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
49. Effects of hypercapnia with and without acidosis on hypoxic pulmonary vasoconstriction.
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Ketabchi, Farzaneh, Egemnazarov, Bakytbek, Schermuly, Ralph T., Ghofrani, Hossein A., Seeger, Werner, Grimminger, Friedrich, Shid-Moosavi, Mostafa, Dehghani, Gholam A., Weissmann, Norbert, and Sommer, Natascha
- Subjects
- *
HYPERCAPNIA , *VASOCONSTRICTION , *RESPIRATORY diseases , *LUNG injuries , *HYPOXEMIA , *ACIDOSIS , *LABORATORY rabbits , *PERMEABILITY - Abstract
Acute respiratory disorders and permissive hypercapnic strategy may lead to alveolar hypoxia and hypercapnic acidosis. However, the effects of hypercapnia with or without acidosis on hypoxic pulmonary vasoconstriction (HPV) and oxygen diffusion capacity of the lung are controversial. We investigated the effects of hypercapnic acidosis and hypercapnia with normal pH (pH corrected with sodium bicarbonate) on HPV, capillary permeability, gas exchange, and ventilation-perfusion matching in the isolated ventilated-perfused rabbit lung. No alteration in vascular tone was noted during normoxic hypercapnia with or without acidosis compared with normoxic normocapnia. Hypercapnia with normal pH resulted in a transient increase in HPV during the course of consecutive ventilation maneuvers, whereas hypercapnic acidosis increased HPV over time. Hypercapnic acidosis decreased exhaled NO during hypoxia more than hypercapnia with normal pH and normocapnia, whereas intravascular NO release was unchanged. However, inhibition of NO synthesis by nitro-L-arginine (L-NNA) resulted in a loss of the increased HPV caused by hypercapnic acidosis but not that caused by hypercapnia with normal pH. Furthermore, capillary permeability increased during hypoxic hypercapnia with normal pH but not hypoxic hypercapnic acidosis. This effect was NO-dependent because it disappeared during L-NNA administration. Ventilation-perfusion matching and arterial Po2 were improved according to the strength of HPV in hypercapnia compared with normocapnia during Tween nebulization-induced lung injury. In conclusion, the increased HPV during hypercapnic acidosis is beneficial to lung gas exchange by improving ventilation-perfusion matching and preserving the capillary barrier function. These effects seem to be linked to NO-mediated pathways. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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- View/download PDF
50. Adenylate Kinase 4—A Key Regulator of Proliferation and Metabolic Shift in Human Pulmonary Arterial Smooth Muscle Cells via Akt and HIF-1α Signaling Pathways.
- Author
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Wujak, Magdalena, Veith, Christine, Wu, Cheng-Yu, Wilke, Tessa, Kanbagli, Zeki Ilker, Novoyatleva, Tatyana, Guenther, Andreas, Seeger, Werner, Grimminger, Friedrich, Sommer, Natascha, Schermuly, Ralph Theo, and Weissmann, Norbert
- Subjects
- *
CELLULAR signal transduction , *VASCULAR remodeling , *PULMONARY arterial hypertension , *SMOOTH muscle , *MUSCLE cells , *GLYCOLYSIS , *HYPOXIA-inducible factor 1 , *PULMONARY circulation - Abstract
Increased proliferation of pulmonary arterial smooth muscle cells (PASMCs) in response to chronic hypoxia contributes to pulmonary vascular remodeling in pulmonary hypertension (PH). PH shares numerous similarities with cancer, including a metabolic shift towards glycolysis. In lung cancer, adenylate kinase 4 (AK4) promotes metabolic reprogramming and metastasis. Against this background, we show that AK4 regulates cell proliferation and energy metabolism of primary human PASMCs. We demonstrate that chronic hypoxia upregulates AK4 in PASMCs in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. RNA interference of AK4 decreases the viability and proliferation of PASMCs under both normoxia and chronic hypoxia. AK4 silencing in PASMCs augments mitochondrial respiration and reduces glycolytic metabolism. The observed effects are associated with reduced levels of phosphorylated protein kinase B (Akt) as well as HIF-1α, indicating the existence of an AK4-HIF-1α feedforward loop in hypoxic PASMCs. Finally, we show that AK4 levels are elevated in pulmonary vessels from patients with idiopathic pulmonary arterial hypertension (IPAH), and AK4 silencing decreases glycolytic metabolism of IPAH-PASMCs. We conclude that AK4 is a new metabolic regulator in PASMCs interacting with HIF-1α and Akt signaling pathways to drive the pro-proliferative and glycolytic phenotype of PH. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
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