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COPD and Asthma Research Group (CARG)

Emmy-Noether-Group

 Members

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 Research Topics

Die Rolle von Serotonin und seinen Rezeptoren in der Pathogenese von allergischem Asthma bronchiale

Schon seit längerem ist bekannt, dass der Botenstoff 5-Hydroxytryptamin (Serotonin) nicht nur ein wichtiger Neurotransmitter ist, sondern auch eine Rolle im Immunsystem spielt. Verschiedene klinische Studien weisen zwar auf einen Zusammenhang zwischen dem allergischen Asthma bronchiale und Serotonin hin, allerdings ist bisher unbekannt wie und über welche 5-HT-Rezeptoren Serotonin an der Pathogenese des allergischen Asthma bronchiale beteiligt ist.
Ziel unseres Forschungsprojektes ist es daher die Beteiligung von Serotonin und seinen verschieden 5-HTR an der asthmatischen Entzündungsreaktion am Menschen sowie am experimentellem Asthmamausmodell zu identifizieren. Mit Hilfe der segmentalen Allergenprovokation beim Menschen können wir die Serotonin-Freisetzung und Wirkung, aber auch Serotonin-Rezeptor-Expression und -Regulation bei der allergen-induzierten asthmatischen Entzündung im Menschen in vivo untersuchen. Mit Hilfe des Asthmamausmodell soll dann geklärt, ob endogen freigesetztes Serotonin essentiell für die Entstehung der asthmatischen Entzündungsreaktion ist, und es sollen diese 5-HTR-Subtypen identifiziert werden die an der Pathogenese der asthmatischen Entzündungsreaktion in vivo involviert sind. Schließlich soll anhand von humane dendritschen Zellen und dem DC-vermittelten Asthma-Mausmodells analysiert werden ob Serotonin seine pro-asthmatische Effekte primär über myeloide DC vermittelt. Die Ergebnisse dieses Forschungsprojekts werden neue Erkenntnisse über die Rolle von Serotonin und seinen Rezeptoren in der Pathogenese des Asthmas bronchiale liefern und könnten neue Therapieoption für das v.a. schwere therapierefraktäre Asthma bronchiale aufzeigen.

Contact person: Dr. Tobias Müller tobias.mueller@uniklinik-freiburg.de and Melanie Grimm melanie.grimm@uniklinik-freiburg.de

Funded by Landesstiftung Baden-Württenberg

Effect of aerobic exercise on dendritic cell function in allergic airway inflammation

Aerobic exercise (AE) is an essential part of a rehabilitation program for asthmatic patients, improving health related quality of life by decreasing asthmatic-symptoms and corticosteroids consumption, suggests an anti-inflammatory effect of AE on allergic airway inflammation (AAI). Animal studies have revealed that AE reduces all cardinal features of allergic airway inflammation. Recently, it has been postulated that AE might influence the function of myeloid rat dendritic cells, which play an essential role in the pathogenesis of asthma. In the present study we want to investigate whether: 1) AE can influence the number and maturation of blood-, lung-, and lymph node DC in naïve and animals with AAI. 2) Does AE affect the function and Th2- cell priming capacity of bone-marrow derived DC in vitro and in vivo? 3) Does AE modulate the migration and T-cell priming capacity of endogenous mDC in vivo. 4) Finally, is AE able to alter the number and function of blood and BALF-DC in patients with allergic asthma? This project will elucidate whether the protective affect of AE on allergic airway inflammation is linked to disturbed DC function.

Contact person: Dr. rer. nat. Rodolfo Paula de Vieira rodolfo.de.paula.vieira@uniklinik-freiburg.de

Funded by the DFG

Targeting DC a new therapeutic option for the treatment of allergic airway inflammation

Allergic asthma is one of the most common chronic diseases in western society. Dendritic cells are crucial for the induction and maintenance of allergic airway inflammation. The aim of our group is to study the influence of different mediators on dendritic cell function. Thereby, our focus is on developing new therapeutic approaches for severe steroid-resistant asthma.

Contact person: Melanie Grimm melanie.grimm@uniklinik-freiburg.de and PD Dr Marco Idzko marco.idzko@uniklinik-freiburg.de

P2R signalling in acute and chronic inflammatory airway disease

a) Purinergic receptors in the pathogenesis of asthma

Allergic asthma is one of the most common chronic diseases in western society. Over the last years others and we demonstrated that extracellular nucleotides such as ATP can modulates the recruitment and/or function of various cell types such as mast cells, eosinophils, neutrophils, CD4+ T-cells, blood-/alveolar-marcophages and dendritic cells, which play an important role in the induction and/or maintance of allergic airway inflammation. In addition we could recently show that extracellular ATP released into the airway of asthmatic patients and mice with experimental asthma indeed plays a crucial role in the induction and maintenance of allergic inflammation in asthma in vivo. Starting from these observations the aim of the project is to identify the precise P2R-subtypes involved and to elucidate whether targeting P2R might be a new therapeutic option for the treatment of asthma.

b) Purinergic receptors in the pathogenesis of COPD

Chronic obstructive pulmonary disease (COPD) is a major global health problem that has a large impact on quality of life for patients and their families. The major inflammatory cell types participating in COPD are neutrophils, macrophages and CD8+ T-lymphocytes. The aim of our group is to determine the involvement of purinergic receptors in the pathogenesis of COPD by using in vivo mouse model for cigarettes smoke induced lung inflammation and lung emphysema as well as material from COPD patients.

Funded by the Emmy-Noether Program of the DFG

Contact person: Melanie Grimm melanie.grimm@uniklinik-freiburg.de and PD Dr Marco Idzko marco.idzko@uniklinik-freiburg.de

Purinergic receptors in the pathogenesis lung fibrosis

Idiopathic pulmonary fibrosis (IPF) is a disease with poor prognosis and no effective therapy currently available. The pathogenesis of this devastating disease is not fully understood. In the past, extracellular nucleotides, e.g. adenosine-5’-triphosphate (ATP) have gained attention as mediators of inflammation and immuno-regulation via purinergic receptor (P2R) signalling. Preliminary results showed that extracellular ATP levels are elevated in patients suffering from IPF or in mice with experimental lung fibrosis Thus aim of our group is to determine the involvement of purinergic receptors in the pathogenesis of IPF by using the BLM-induced lung fibrosis mouse model and BALF-cells and lung tissue from lung fibrosis patients.

Contact person: Melanie Grimm melanie.grimm@uniklinik-freiburg.de, Dr. Tobias Müller tobias.mueller@uniklinik-freiburg.de and PD Dr Marco Idzko marco.idzko@uniklinik-freiburg.de

Freiburger-network on “P2R-signalling in health and disease”

1. Purinergic receptors in GvHD
Cooperation with AG Zeiser

Related Publications: Wilhelm K, Ganesan J, Müller T, Dürr C, Grimm M, Beilhack A, Krempl CD, Sorichter S, Gerlach UV, Jüttner E, Zerweck A, Gärtner F, Pellegatti P, Di Virgilio F, Ferrari D, Kambham N, Fisch P, Finke J, Idzko M*, Zeiser R*. Graft-versus-host disease is enhanced by extracellular ATP activating P2X7R. Nat Med. 2010 Dec;16(12):1434-8.

Contact person: PD Dr. med. Robert Zeiser robert.zeiser@unklinik-freiburg.de

Funded by Wilhelm Sanders Foundation

2. Purinergic receptors in atopic contact dermatitis
Cooperation with AG Jakob/Martin

Related Publication: Weber FC, Esser PR, Müller T, Ganesan J, Pellegatti P, Simon MM, Zeiser R, Idzko M*, Jakob T, Martin SF*. Lack of the purinergic receptor P2X(7) results in resistance to contact hypersensitivity. J Exp Med. 2010 Nov 22;207(12):2609-19.

Contact person: Prof Dr. rer. nat. Stefan Martin stefan.martin@uniklinik-freiburg.de

3. Purinergic receptors in hepatitis and hepatocellulary carcinoma
Cooperation with AG Hasselblatt

Contact person: Dr. Peter Hasselblatt peter.hasselblatt@uniklinik-freiburg.de

Funded by Forschungskommission of the University Freiburg and a Seeding Grant of “Deutsche Krebshilfe”

4. Purinergic receptors in kidney diseases
Cooperation with AG Huber

Contact person: Prof. Dr. Tobias Huber tobias.huber@uniklinik-freiburg.de

 Dissertationen und Diplomarbeiten

2010: Nathalie Deer, Nadine Mark, Caroline Fischer, Eva Brencicova (summa cum laude)

2009: Dipl. rer nat. Volker von Grenler

2008: Susanne Eggerking, Verena Geyer (summa cum laude)

2007: Anja Dembinski, Jana Hintz

2006: Cornelia Egger

2005: Kathie Eberhardt, Tobias Müller (summa cum laude), Wolfgang Rüscher, Domagoj Damjanovic, Andreas Fluck

2004: Thorsten Dürk (summa cum laude), Johannes Bayer (summa cum laude)

2003: Martin Laut (summa cum laude)

 Our projects are funded by

• DFG
• Forschungskommission der University Freiburg
• Deutsche Krebshilfe
• Wilhelm Sander Stiftung
• Landesstiftung Baden-Württemberg
• Emmy Noether Programme of the German Research Foundation DFG

 Selected Publications

Paula Vieira R, Müller T, Grimm M, von Gernler V, Vetter B, Dürk T, Cicko S, Ayata CK, Sorichter S, Robaye B, Zeiser R, Ferrari D, Kirschbaum A, Zissel G, Virchow JC, Boeynaems JM, Idzko M. P2Y6 Receptor Contributes to Airway Inflammation and Remodeling in Experimental Allergic Airway Inflammation. Am J Respir Crit Care Med. 2011 Apr 21. [Epub ahead of print]

Riegel AK, Faigle M, Zug S, Rosenberger P, Robaye B, Boeynaems JM, Idzko M, Eltzschig HK. Selective induction of endothelial P2Y6 nucleotide receptor promotes vascular inflammation. Blood. 2011 Feb 24;117(8):2548-55

Ferrari D, Gulinelli S, Salvestrini V, Lucchetti G, Zini R, Manfredini R, Caione L, Piacibello W, Ciciarello M, Rossi L, Idzko M, Ferrari S, Di Virgilio F, Lemoli RM. Purinergic stimulation of human mesenchymal stem cells potentiates their chemotactic response to CXCL12 and increases the homing capacity and production of proinflammatory cytokines. Exp Hematol. 2011 Mar;39(3):360-74, 374.e1-5.

Wilhelm K, Ganesan J, Müller T, Dürr C, Grimm M, Beilhack A, Krempl CD, Sorichter S, Gerlach UV, Jüttner E, Zerweck A, Gärtner F, Pellegatti P, Di Virgilio F, Ferrari D, Kambham N, Fisch P, Finke J, Idzko M*, Zeiser R*. Graft-versus-host disease is enhanced by extracellular ATP activating P2X7R. Nat Med. 2010 Dec;16(12):1434-8. * These authors contributed equally to the work

Müller T, Robaye B, Vieira RP, Ferrari D, Grimm M, Jakob T, Martin SF, Di Virgilio F, Boeynaems JM, Virchow JC, Idzko M. The purinergic receptor P2Y2 receptor mediates chemotaxis of dendritic cells and eosinophils in allergic lung inflammation. Allergy. 2010 Dec;65(12):1545-53.

Weber FC, Esser PR, Müller T, Ganesan J, Pellegatti P, Simon MM, Zeiser R, Idzko M*, Jakob T, Martin SF*. Lack of the purinergic receptor P2X(7) results in resistance to contact hypersensitivity. J Exp Med. 2010 Nov 22;207(12):2609-19. *These authors contributed equally to the work

Müller T, Dürk T, Blumenthal B, Herouy Y, Sorichter S, Grimm M, Panther E,Cicko S, Norgauer J, Idzko M. Iloprost has potent anti-inflammatory properties on human monocyte-derived dendritic cells. Clin Exp Allergy. 2010 Aug;40(8):1214-21.

Cicko S, Lucattelli M, Müller T, Lommatzsch M, De Cunto G, Cardini S, Sundas W, Grimm M, Zeiser R, Dürk T, Zissel G, Boeynaems JM, Sorichter S, Ferrari D, Di Virgilio F, Virchow JC, Lungarella G, Idzko M. Purinergic Receptor Inhibition Prevents the Development of Smoke-Induced Lung Injury and Emphysema. J Immunol. 2010 Jul 1;185(1):688-97.

Lucattelli M, Cicko S, Müller T, Lommatzsch M, de Cunto G, Cardini S, Sundas W, Grimm M, Zeiser R, Dürk T, Zissel G, Sorichter S, Ferrari D, di Virgilio F, Virchow JC, Lungarella G, Idzko M. P2X7 Receptor Signalling in the Pathogenesis of Smoke-induced Lung Inflammation and Emphysema. Am J Respir Cell Mol Biol. 2011 Mar;44(3):423-9.

Müller T, Paula Vieira R, Grimm M, Dürk T, Cicko S, Zeiser R, Jakob T, Martin SF, Blumenthal B, Sorichter S, Ferrari D, di Virgilio F, Idzko M. A Potential Role for P2X7R in Allergic Airway Inflammation in Mice and Humans. Am J Respir Cell Mol Biol. 2010 May 27. Epub ahead of print]

Müller T, Grimm M, de Vieira RP, Cicko S, Dürk T, Sorichter S, Zissel G, Idzko M. Local administration of uridine suppresses the cardinal features of asthmatic airway inflammation. Clin Exp Allergy. 2010 Oct;40(10):1552-60.

Lommatzsch M, Cicko S, Müller T, Lucattelli M, Bratke K, Stoll P, Grimm M, Dürk T, Zissel G, Ferrari D, Di Virgilio F, Sorichter S, Lungarella G, Virchow JC, Idzko M. Extracellular adenosine triphosphate and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010 May 1;181(9):928-34.

Müller T, Dürk T, Blumenthal B, Grimm M, Cicko S, Panther E, Sorichter S, Herouy Y, Di Virgilio F, Ferrari D, Norgauer J, Idzko M. 5-hydroxytryptamine modulates migration, cytokine and chemokine release and T-cell priming capacity of dendritic cells in vitro and in vivo. PLoS One. 2009 Jul 31;4(7):e6453. PMID: 19649285.

Sanz JM, Chiozzi P, Ferrari D, Colaianna M, Idzko M, Falzoni S, Fellin R, Trabace L, Di Virgilio F. Activation of microglia by amyloid requires P2X7 receptor expression. J Immunol. 2009 Apr 1;182(7):4378-85.

Myrtek D, Müller T, Geyer V, Derr N, Ferrari D, Zissel G, Dürk T, Sorichter S, Luttmann W, Kuepper M, Norgauer J, Di Virgilio F, Virchow JC Jr, Idzko M. Activation of human alveolar macrophages via P2 receptors: coupling to intracellular Ca2+ increases and cytokine secretion. J Immunol. 2008 Aug1;181(3):2181-8..

Idzko M, Hammad H, van Nimwegen M, Kool M, Willart MA, Muskens F, Hoogsteden HC, Luttmann W, Ferrari D, Di Virgilio F, Virchow JC Jr, Lambrecht BN. Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells. Nat Med. 2007 Aug;13(8):913-9.

Idzko M, Hammad H, van Nimwegen M, Kool M, Vos N, Hoogsteden HC, Lambrecht BN. Inhaled iloprost suppresses the cardinal features of asthma via inhibition of airway dendritic cell function. J Clin Invest. 2007 Feb;117(2):464-72.

Idzko M, Hammad H, van Nimwegen M, Kool M, Muller T, Soullie T, Willart MA, Hijdra D, Hoogsteden HC, Lambrecht BN. Local application of FTY720 to the lung abrogates experimental asthma by altering dendritic cell function. J Clin Invest. 2006 Nov;116(11):2935-44.

Bayer H, Muller T, Myrtek D, Sorichter S, Ziegenhagen M, Norgauer J, Zissel G, Idzko M. Serotoninergic receptors on human airway epithelial cells. Am J Respir Cell Mol Biol. 2007 Jan;36(1):85-93.

Muller T, Bayer H, Myrtek D, Ferrari D, Sorichter S, Ziegenhagen MW, Zissel G, Virchow JC Jr, Luttmann W, Norgauer J, Di Virgilio F, Idzko M. The P2Y14 receptor of airway epithelial cells: coupling to intracellular Ca2+ and IL-8 secretion. Am J Respir Cell Mol Biol. 2005 Dec;33(6):601-9.

Durk T, Panther E, Muller T, Sorichter S, Ferrari D, Pizzirani C, Di Virgilio F, Myrtek D, Norgauer J, Idzko M. 5-Hydroxytryptamine modulates cytokine and chemokine production in LPS-primed human monocytes via stimulation of different 5-HTR subtypes. Int Immunol. 2005 May;17(5):599-606.

Idzko M, Panther E, Sorichter S, Herouy Y, Berod L, Geissler M, Mockenhaupt M, Elsner P, Girolomoni G, Norgauer J. Characterization of the biological activities of uridine diphosphate in human dendritic cells: Influence on chemotaxis and CXCL8 release. J Cell Physiol. 2004 Nov;201(2):286-93.

Idzko M, Panther E, Stratz C, Muller T, Bayer H, Zissel G, Durk T, Sorichter S, Di Virgilio F, Geissler M, Fiebich B, Herouy Y, Elsner P, Norgauer J, Ferrari D. The serotoninergic receptors of human dendritic cells: identification and coupling to cytokine release. J Immunol. 2004 May 15;172(10):6011-9.

Idzko M, Laut M, Panther E, Sorichter S, Durk T, Fluhr JW, Herouy Y, Mockenhaupt M, Myrtek D, Elsner P, Norgauer J. Lysophosphatidic acid induces chemotaxis, oxygen radical production, CD11b up-regulation, Ca2+ mobilization, and actin reorganization in human eosinophils via pertussis toxin-sensitive G proteins.J Immunol. 2004 Apr 1;172(7):4480-5.

Idzko M, Panther E, Bremer HC, Sorichter S, Luttmann W, Virchow CJ Jr, Di Virgilio F, Herouy Y, Norgauer J, Ferrari D. Stimulation of P2 purinergic receptors induces the release of eosinophil cationic protein and interleukin-8 from human eosinophils. Br J Pharmacol. 2003 Apr;138(7):1244-50.

Idzko M, Dichmann S, Ferrari D, Di Virgilio F, la Sala A, Girolomoni G, Panther E, Norgauer J. Nucleotides induce chemotaxis and actin polymerization in immature but not mature human dendritic cells via activation of pertussis toxin-sensitive P2y receptors. Blood 2002 Aug 1;100(3):925-32.

Idzko M, la Sala A, Ferrari D, Panther E, Herouy Y, Dichmann S, Mockenhaupt M, Di Virgilio F, Girolomoni G, Norgauer J. Expression and function of histamine receptors in human monocyte-derived dendritic cells. J Allergy Clin Immunol. 2002 May;109(5):839-46.

Idzko M, Panther E, Corinti S, Morelli A, Ferrari D, Herouy Y, Dichmann S, Mockenhaupt M, Gebicke-Haerter P, Di Virgilio F, Girolomoni G, Norgauer J. Sphingosine 1-phosphate induces chemotaxis of immature and modulates cytokine-release in mature human dendritic cells for emergence of Th2 immune responses. FASEB J. 2002 Apr;16(6):625-7.

Idzko M, Dichmann S, Panther E, Ferrari D, Herouy Y, Virchow C Jr, Luttmann W, Di Virgilio F, Norgauer J. Functional characterization of P2Y and P2X receptors in human eosinophils. J Cell Physiol. 2001 Sep;188(3):329-36.

Dichmann S, Idzko M, Zimpfer U, Hofmann C, Ferrari D, Luttmann W, Virchow C Jr, Di Virgilio F, Norgauer J. Adenosine triphosphate-induced oxygen radical production and CD11b up-regulation: Ca(++) mobilization and actin reorganization in human eosinophils. Blood. 2000 Feb 1;95(3):973-8.

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