11 results on '"Anouk Oldenburger"'
Search Results
2. Modulation of vascular contraction via soluble guanylate cyclase signaling in a novel ex vivo method using rat precision‐cut liver slices
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Andre Broermann, Birgit Stierstorfer, Steven S. Pullen, Marco Schlepütz, Gerald Birk, Anouk Oldenburger, and Jörg F. Rippmann
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Liver Cirrhosis ,Male ,Ketanserin ,Contraction (grammar) ,translation ,Pharmacology ,030226 pharmacology & pharmacy ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Adenosine Triphosphate ,Soluble Guanylyl Cyclase ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,General Pharmacology, Toxicology and Pharmaceutics ,Carbon Tetrachloride ,Endothelin-1 ,Chemistry ,NASH ,portal hypertension ,Vasodilation ,medicine.anatomical_structure ,Liver ,Neurology ,030220 oncology & carcinogenesis ,cardiovascular system ,Original Article ,ex vivo model ,Signal Transduction ,medicine.drug ,Blood vessel ,Serotonin ,RM1-950 ,Riociguat ,Nitric oxide ,03 medical and health sciences ,medicine ,Animals ,blood vessel contraction ,Rats, Wistar ,Activator (genetics) ,Original Articles ,medicine.disease ,cGMP ,Oxidative Stress ,Pyrimidines ,Vasoconstriction ,Blood Vessels ,Pyrazoles ,Therapeutics. Pharmacology ,Steatohepatitis ,Ex vivo - Abstract
Fibrotic processes in the liver of non‐alcoholic steatohepatitis (NASH) patients cause microcirculatory dysfunction in the organ which increases blood vessel resistance and causes portal hypertension. Assessing blood vessel function in the liver is challenging, necessitating the development of novel methods in normal and fibrotic tissue that allow for drug screening and translation toward pre‐clinical settings. Cultures of precision cut liver slices (PCLS) from normal and fibrotic rat livers were used for blood vessel function analysis. Live recording of vessel diameter was used to assess the response to endothelin‐1, serotonin and soluble guanylate cyclase (sGC) activation. A cascade of contraction and relaxation events in response to serotonin, endothelin‐1, Ketanserin and sGC activity could be established using vessel diameter analysis of rat PCLS. Both the sGC activator BI 703704 and the sGC stimulator Riociguat prevented serotonin‐induced contraction in PCLS from naive rats. By contrast, PCLS cultures from the rat CCl4 NASH model were only responsive to the sGC activator, thus establishing that the sGC enzyme is rendered non‐responsive to nitric oxide under oxidative stress found in fibrotic livers. The role of the sGC pathway for vessel relaxation of fibrotic liver tissue was identified in our model. The obtained data shows that the inhibitory capacities on vessel contraction of sGC compounds can be translated to published preclinical data. Altogether, this novel ex vivo PCLS method allows for the differentiation of drug candidates and the translation of therapeutic approaches towards the clinical use., Cultures of rat precision cut liver slices (PCLS) were used for ex vivo blood vessel function analysis via live recording. The sGC activator BI703704 differentiates from the sGC stimulator Riociguat in the prevention of serotonin induced blood vessel contraction of normal and fibrotic rat liver slices.
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- 2021
3. Effects of (a Combination of) the Beta
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Harm, Maarsingh, Anouk, Oldenburger, Bing, Han, Annet B, Zuidhof, Carolina R S, Elzinga, Wim, Timens, Herman, Meurs, Ramadan B, Sopi, and Martina, Schmidt
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Male ,β2-agonist ,glycopyrrolate ,Bronchoconstriction ,Guinea Pigs ,Muscarinic Antagonists ,Quinolones ,Article ,chronic obstructive pulmonary disease ,glycopyrronium ,Pulmonary Disease, Chronic Obstructive ,airway responsiveness ,anticholinergic ,indacaterol ,Animals ,Humans ,human ,Adrenergic beta-2 Receptor Agonists ,Lung ,Receptor, Muscarinic M3 ,small airways ,Dose-Response Relationship, Drug ,large airways ,Drug Synergism ,respiratory system ,respiratory tract diseases ,Bronchodilator Agents ,Case-Control Studies ,Indans ,Drug Therapy, Combination ,Female ,Receptors, Adrenergic, beta-2 ,guinea pig - Abstract
Expression of bronchodilatory β2-adrenoceptors and bronchoconstrictive muscarinic M3-receptors alter with airway size. In COPD, (a combination of) β2-agonists and muscarinic M3-antagonists (anticholinergics) are used as bronchodilators. We studied whether differential receptor expression in large and small airways affects the response to β2-agonists and anticholinergics in COPD. Bronchoprotection by indacaterol (β2-agonist) and glycopyrrolate (anticholinergic) against methacholine- and EFS-induced constrictions of large and small airways was measured in guinea pig and human lung slices using video-assisted microscopy. In guinea pig lung slices, glycopyrrolate (1, 3 and 10 nM) concentration-dependently protected against methacholine- and EFS-induced constrictions, with no differences between large and small intrapulmonary airways. Indacaterol (0.01, 0.1, 1 and 10 μM) also provided concentration-dependent protection, which was greater in large airways against methacholine and in small airways against EFS. Indacaterol (10 μM) and glycopyrrolate (10 nM) normalized small airway hyperresponsiveness in COPD lung slices. Synergy of low indacaterol (10 nM) and glycopyrrolate (1 nM) concentrations was greater in LPS-challenged guinea pigs (COPD model) compared to saline-challenged controls. In conclusion, glycopyrrolate similarly protects large and small airways, whereas the protective effect of indacaterol in the small, but not the large, airways depends on the contractile stimulus used. Moreover, findings in a guinea pig model indicate that the synergistic bronchoprotective effect of indacaterol and glycopyrrolate is enhanced in COPD.
- Published
- 2021
4. Investigating fibrosis and inflammation in an ex vivo NASH murine model
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Emilia Gore, Anouk Oldenburger, Joerg F. Rippmann, Detlef Schuppan, Miriam Boersema, Peter Olinga, Emilia Bigaeva, Andre Broermann, Yvette J. M. Jansen, Pharmaceutical Technology and Biopharmacy, Biopharmaceuticals, Discovery, Design and Delivery (BDDD), and Groningen Institute for Organ Transplantation (GIOT)
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0301 basic medicine ,Lipopolysaccharides ,Liver Cirrhosis ,Male ,Physiology ,HEPATOCYTES ,Liver disease ,Mice ,0302 clinical medicine ,Chalcones ,Fibrosis ,Non-alcoholic Fatty Liver Disease ,Nonalcoholic fatty liver disease ,Cells, Cultured ,INSULIN-RESISTANCE ,Gastroenterology ,Elafibranor ,TGF-BETA ,Liver ,030211 gastroenterology & hepatology ,CHOLINE-DEFICIENT DIET ,EXPRESSION ,medicine.medical_specialty ,EARLY-ONSET ,In Vitro Techniques ,Collagen Type I ,Proinflammatory cytokine ,Transforming Growth Factor beta1 ,03 medical and health sciences ,In vivo ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,HEPATIC STEATOSIS ,FATTY LIVER-DISEASE ,Inflammation ,PRECISION-CUT LIVER ,Hepatology ,business.industry ,medicine.disease ,Lipid Metabolism ,Diet ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,PROLIFERATOR-ACTIVATED RECEPTORS ,Steatosis ,Propionates ,business ,Transcriptome ,Ex vivo - Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease, characterized by excess fat accumulation (steatosis). Nonalcoholic steatohepatitis (NASH) develops in 15–20% of NAFLD patients and frequently progresses to liver fibrosis and cirrhosis. We aimed to develop an ex vivo model of inflammation and fibrosis in steatotic murine precision-cut liver slices (PCLS). NASH was induced in C57Bl/6 mice on an amylin and choline-deficient l-amino acid-defined (CDAA) diet. PCLS were prepared from steatohepatitic (sPCLS) and control (cPCLS) livers and cultured for 48 h with LPS, TGFβ1, or elafibranor. Additionally, C57Bl/6 mice were placed on CDAA diet for 12 wk to receive elafibranor or vehicle from weeks 7 to 12. Effects were assessed by transcriptome analysis and procollagen Iα1 protein production. The diets induced features of human NASH. Upon culture, all PCLS showed an increased gene expression of fibrosis- and inflammation-related markers but decreased lipid metabolism markers. LPS and TGFβ1 affected sPCLS more pronouncedly than cPCLS. TGFβ1 increased procollagen Iα1 solely in cPCLS. Elafibranor ameliorated fibrosis and inflammation in vivo but not ex vivo, where it only increased the expression of genes modulated by PPARα. sPCLS culture induced inflammation-, fibrosis-, and lipid metabolism-related transcripts, explained by spontaneous activation. sPCLS remained responsive to proinflammatory and profibrotic stimuli on gene expression. We consider that PCLS represent a useful tool to reproducibly study NASH progression. sPCLS can be used to evaluate potential treatments for NASH, as demonstrated in our elafibranor study, and serves as a model to bridge results from rodent studies to the human system. NEW & NOTEWORTHY This study showed that nonalcoholic steatohepatitis can be studied ex vivo in precision-cut liver slices obtained from murine diet-induced fatty livers. Liver slices develop a spontaneous inflammatory and fibrogenic response during culture that can be augmented with specific modulators. Additionally, the model can be used to test the efficacy of pharmaceutical compounds (as shown in this investigation with elafibranor) and could be a tool for preclinical assessment of potential therapies.
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- 2020
5. Small airway hyperresponsiveness in COPD: relationship between structure and function in lung slices
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Harm, Maarsingh, Cécile M, Bidan, Bindi S, Brook, Annet B, Zuidhof, Carolina R S, Elzinga, Marieke, Smit, Anouk, Oldenburger, Reinoud, Gosens, Wim, Timens, and Herman, Meurs
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Adult ,Lipopolysaccharides ,Male ,human lung ,biomechanical modeling ,Guinea Pigs ,Muscle, Smooth ,respiratory system ,Middle Aged ,Asthma ,respiratory tract diseases ,Disease Models, Animal ,Pulmonary Disease, Chronic Obstructive ,airway remodeling ,airway constriction ,emphysema ,Respiratory Hypersensitivity ,Animals ,Humans ,Female ,Lung ,Aged ,Research Article - Abstract
The direct relationship between pulmonary structural changes and airway hyperresponsiveness (AHR) in chronic obstructive pulmonary disease (COPD) is unclear. We investigated AHR in relation to airway and parenchymal structural changes in a guinea pig model of COPD and in COPD patients. Precision-cut lung slices (PCLS) were prepared from guinea pigs challenged with lipopolysaccharide or saline two times weekly for 12 wk. Peripheral PCLS were obtained from patients with mild to moderate COPD and non-COPD controls. AHR to methacholine was measured in large and small airways using video-assisted microscopy. Airway smooth muscle mass and alveolar airspace size were determined in the same slices. A mathematical model was used to identify potential changes in biomechanical properties underlying AHR. In guinea pigs, lipopolysaccharide increased the sensitivity of large (>150 μm) airways toward methacholine by 4.4-fold and the maximal constriction of small airways (
- Published
- 2019
6. A-kinase anchoring proteins contribute to loss of E-cadherin and bronchial epithelial barrier by cigarette smoke
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Herman Meurs, Martina Schmidt, Harold G. de Bruin, Anouk Oldenburger, Irene H. Heijink, Fleur Kos, Wim Timens, Wolter Rijks, Wilfred J. Poppinga, H. Maarsingh, Molecular Pharmacology, Groningen Research Institute for Asthma and COPD (GRIAC), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
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Adult ,Male ,Chronic Obstructive ,Physiology ,A Kinase Anchor Proteins ,Bronchi ,Cell Cycle Proteins ,Respiratory Mucosa ,Biology ,Small Interfering ,Cell Line ,Minor Histocompatibility Antigens ,Pulmonary Disease ,Cell membrane ,Pulmonary Disease, Chronic Obstructive ,Proto-Oncogene Proteins ,Smoke ,Tobacco ,80 and over ,medicine ,Humans ,Gene silencing ,RNA, Small Interfering ,Protein kinase A ,Barrier function ,Aged ,Aged, 80 and over ,Cadherin ,Cell Membrane ,Smoking ,Cell Biology ,Middle Aged ,AKAP12 ,Cadherins ,Cell biology ,Cytoskeletal Proteins ,medicine.anatomical_structure ,RNA ,Respiratory epithelium ,Female ,RNA Interference - Abstract
Airway epithelium, which forms the first barrier towards environmental insults, is disturbed by cigarette smoking, a major risk factor for developing chronic obstructive pulmonary disease (COPD). A-kinase anchoring proteins (AKAP) maintain endothelial barrier function and coordinate subcellular localization of protein kinase A (PKA). However, the role of AKAPs in epithelial barrier function is unknown. We studied the role of AKAPs in regulating human bronchial epithelial (Hogg JC, Timens W. Annu Rev Pathol 4: 435–459, 2009; HBE) barrier. Cigarette smoke extract (CSE) reduced barrier function in 16HBE cells and the expression of the adhesion molecule E-cadherin specifically at the cell membrane. In addition, CSE reduced the protein expression of the AKAP family member AKAP9 at the cell membrane. The expression of AKAP5 and AKAP12 was unaffected by CSE. AKAP9 interacted and colocalized with E-cadherin at the cell membrane, suggesting that the reduction of both proteins may be related. Interestingly, disruption of AKAP-PKA interactions by st-Ht31 prevented the CSE-induced reduction of E-cadherin and AKAP9 protein expression and subsequent loss of barrier function. Silencing of AKAP9 reduced the functional epithelial barrier and prevented the ability of st-Ht31 to restore membrane localization of E-cadherin. Our data suggest the possibility of a specific role for AKAP9 in the maintenance of the epithelial barrier. E-cadherin, but not AKAP9, protein expression was reduced in lung tissue from COPD patients compared with controls. However, AKAP9 mRNA expression was decreased in primary bronchial epithelial cells from current smokers compared with non/ex-smokers. In conclusion, our results indicate that AKAP proteins, most likely AKAP9, maintain the bronchial epithelial barrier by regulating the E-cadherin expression at the cell membrane.
- Published
- 2014
7. Epac1 and Epac2 regulate airway smooth muscle tone in mice
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Martina Schmidt, Anouk Oldenburger, and Harm Maarsingh
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medicine.medical_specialty ,Adrenergic receptor ,business.industry ,Airway smooth muscle ,respiratory system ,Endocrinology ,Mechanism of action ,In vivo ,Isoprenaline ,Internal medicine ,medicine ,Deficient mouse ,Bronchial constriction ,medicine.symptom ,business ,Protein kinase A ,medicine.drug - Abstract
Dysfunctional regulation of airway smooth muscle (ASM) tone is a feature of obstructive airway diseases. cAMP-elevating agents, such as β 2 -adrenoceptor agonists, are potent inhibitors of bronchial constriction. Although used clinically for many years, their precise mechanism of action is still under debate. Activation of protein kinase A (PKA) by β 2 -agonists induces ASM relaxation. Next to PKA, activation of the exchange protein directly activated by cAMP (Epac) induces ASM relaxation. We have recently shown that Epac1 and Epac2 are differentially involved in inflammatory and remodeling processes in vivo. Here, we studied the roles of Epac1 and Epac2 in regulating ASM tone. In precontracted rings, isoprenaline dose-dependently reduced methacholine-induced ASM tone by approximately 80 % (pD2-value 7.58±0.22), both effects were reduced but not diminished by the PKA inhibitor Rp, pointing to PKA-independent mechanisms (Emax 63.4±3.5; pD2-value 7.34±0.13). Epac activators dose-dependently reduced methacholine-induced ASM tone (pEC50=4.22±0.12 and 4.30±0.10, respectively). The reduction was 25.2±3.0% and 46.0±1.8% for the highest dose used (300 μM). The effects of the Epac activator9s were unaffected by Rp. Isoprenaline-induced relaxation was not altered in Epac1-/- or Epac2-/- mice. The effects of 8-pCPT were reduced in Epac deficient mice, although to a smaller extent in Epac1-/-. Pharmacological inhibition of Epac1 - to a lesser extent of Epac2 – dose-dependently increased isoprenaline-induced relaxation, effects blunted in Epac deficient mice, confirming the specificity of the Epac inhibitors. Collectively, these data show that Epac1 and Epac2 regulate airway smooth muscle tone in mice by currently unknown mechanisms.
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- 2016
8. A‐kinase anchoring proteins (AKAPs) regulate airway smooth muscle secretory function
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Laura J. Holtzer, Harm Maarsingh, Saskia Driessen, Anouk Oldenburger, Martina Schmidt, Wilfred J. Poppinga, and Irene H. Heijink
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Chemistry ,Genetics ,Anchoring ,A kinase ,Airway smooth muscle ,Molecular Biology ,Biochemistry ,Function (biology) ,Biotechnology ,Cell biology - Published
- 2013
9. Epac2 and PLC ε contribute to the inflammatory response to cigarette smoke in vivo
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Sophie Bos, Alan V. Smrcka, Anouk Oldenburger, Harm Maarsingh, Herman Meurs, and Martina Schmidt
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In vivo ,business.industry ,Inflammatory response ,Immunology ,Genetics ,Cigarette smoke ,Medicine ,business ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2013
10. Role for A‐kinase anchoring proteins in cigarette smoke‐induced barrier dysfunction
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Wolter Rijks, Anouk Oldenburger, Wim Timens, Herman Meurs, Wilfred J. Poppinga, Fleur Kos, Harm Maarsingh, Martina Schmidt, and Irene H. Heijink
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Chemistry ,Genetics ,Cigarette smoke ,Anchoring ,A kinase ,Molecular Biology ,Biochemistry ,Biotechnology ,Cell biology - Published
- 2013
11. Cigarette smoke and A‐kinase anchoring proteins (AKAPs) in human airway smooth muscle function
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Wim Timens, Harm Maarsingh, Sara S. Roscioni, Enno Klussmann, Wilfred J. Poppinga, Martina Schmidt, Irene H. Heijink, Philip Skroblin, and Anouk Oldenburger
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Smooth muscle ,Chemistry ,Genetics ,Anchoring ,Cigarette smoke ,Human airway ,A kinase ,Molecular Biology ,Biochemistry ,Function (biology) ,Biotechnology ,Cell biology - Published
- 2011
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