Purinergic signalling in the lung: involvement in the pathogenesis of asthma and COPD
Final Report Abstract
The chronic obstructive inflammatory lung disease asthma and chronic obstructive pulmonary disease (COPD) are the most common lung disease and are responsible for more than a fourth of death in the developed countries. The exact mediators responsible for the development and chronification of lung inflammation in asthma and COPD are still unknown. Increasing evidenced point out to important role of endogenous released nucleotides (e.g. ATP) and their purinerigic receptors (P2XR and P2YR-family) in inflammatory disorders. Indeed during the Phase I of the Emmy-Noether program we could show that ATP is released into the airways during acute asthma and contributes to the development of allergic airway inflammation. Starting from this observation the aim of the Emmy-Noether Phase II was to 1) further identify the role of the different P2R-subtypes in asthma and 2) to elucidate whether ATP/P2R-pathway is also involved in COPD. 1) By performing complex experiments with specific P2R-subtype antagonist, knockout animals and bone marrow-chimeras we could demonstrate that the P2Y2R and P2X7R on haematopoietic system (HS) and P2Y6R on the non-haematopoietic system (NHS) contributes to acute and chronic allergic airway inflammation. 2) We could demonstrate that endogenous airway ATP levels were increased patients with COPD, correlating with air flow limitation, and in mice with smoke induced lung inflammation and emphysema. These increased ATP-levels are of pathophysiological relevance as functional studies in mice showed that the development of smoke induced lung inflammation and emphysema can be markedly reduced by neutralization of ATP or by blocking of specific purinergic receptors subtypes (e.g. P2Y2R, P2Y6R and P2X7R). In summary our data suggest that targeting of P2Y2, P2Y6 and P2X7R might be a new promising therapeutic option for the treatment of steroid-resistant asthma and COPD.
Publications
- Activation of human alveolar macrophages via P2 receptors: coupling to intracellular Ca2+ increases and cytokine secretion. J Immunol. 2008 Aug1;181(3):2181-8
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
- 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
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
- 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, 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
- Extracellular adenosine triphosphate and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010 May 1;181(9):928-34
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
- Graft-versus-host disease is enhanced by extracellular ATP activating P2X7R. Nat Med. 2010 Dec;16(12):1434-8
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
- Iloprost has potent anti-inflammatory properties on human monocyte-derived dendritic cells. Clin Exp Allergy. 2010 Aug;40(8):1214-21
Müller T, Dürk T, Blumenthal B, Herouy Y, Sorichter S, Grimm M, Panther E,Cicko S, Norgauer J, Idzko M
- Lack of the purinergic receptor P2X(7) results in resistance to contact hypersensitivity. J Exp Med. 2010 Nov 22;207(12):2609-19
Weber FC, Esser PR, Müller T, Ganesan J, Pellegatti P, Simon MM, Zeiser R, Idzko M, Jakob T, Martin SF
- Local administration of uridine suppresses the cardinal features of asthmatic airway inflammation. Clin Exp Allergy. 2010 Oct;40(10):1552-60
Müller T, Grimm M, de Vieira RP, Cicko S, Dürk T, Sorichter S, Zissel 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
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
- The purinergic receptor P2Y2 receptor mediates chemotaxis of dendritic cells and eosinophils in allergic lung inflammation. Allergy. 2010 Dec;65(12):1545-53
Müller T, Robaye B, Vieira RP, Ferrari D, Grimm M, Jakob T, Martin SF, Di Virgilio F, Boeynaems JM, Virchow JC, Idzko M
- P2X7 Receptor Signalling in the Pathogenesis of Smokeinduced Lung Inflammation and Emphysema. Am J Respir Cell Mol Biol. 2011 Mar;44(3):423-9
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
- P2Y6 Receptor Contributes to Airway Inflammation and Remodeling in Experimental Allergic Airway Inflammation. Am J Respir Crit Care Med. 2011 Jul 15;184(2):215-23
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
- AMP affects intracellular Ca2+ signaling, migration, cytokine secretion and T cell priming capacity of dendritic cells. PLoS One. 2012 7(5):e37560
Panther E, Dürk T, Ferrari D, Di Virgilio F, Grimm M, Sorichter S, Cicko S, Herouy Y, Norgauer J, Idzko M, Müller T
(See online at https://doi.org/10.1371/journal.pone.0037560) - Deficiency of CD73/ecto-5'- nucleotidase in mice enhances acute graft-versus-host disease. Blood. 2012 May 10;119(19):4554-64
Tsukamoto H, Chernogorova P, Ayata K, Gerlach UV, Rughani A, Ritchey JW, Ganesan J, Follo M, Zeiser R, Thompson LF, Idzko M
(See online at https://doi.org/10.1182/blood-2011-09-375899) - Purinergic P2Y(2) Receptors Promote Neutrophil Infiltration and Hepatocyte Death in Mice With Acute Liver Injury. Gastroenterology. 2012 Dec;143(6):1620-1629
Ayata CK, Ganal SC, Hockenjos B, Willim K, Vieira RP, Grimm M, Robaye B, Boeynaems JM, Di Virgilio F, Pellegatti P, Diefenbach A, Idzko M, Hasselblatt P
(See online at https://doi.org/10.1053/j.gastro.2012.08.049) - Attenuated allergic airway inflammation in Cd39 null mice. Allergy. 2013;68(4):472-80
Idzko M, K Ayata C, Müller T, Dürk T, Grimm M, Baudiß K, Vieira RP, Cicko S, Boehlke C, Zech A, Sorichter S, Pelletier J, Sévigny J, Robson SC
(See online at https://doi.org/10.1111/all.12119) - Production of serotonin by tryptophan hydroxylase 1 and release via platelets contributes to allergic airwayinflammation Am J Respir Crit Care Med. 2013;187(5):476-85
Dürk T, Duerschmied D, Müller T, Grimm M, Reuter S, Vieira RP, Ayata K, Cicko S, Sorichter S, Walther DJ, Virchow JC, Taube C, Idzko M
(See online at https://doi.org/10.1164/rccm.201208-1440OC) - Purinergic Receptor Y6 Deficiency Limits Vascular Inflammation and Atherosclerosis in Mice. Arterioscler Thromb Vasc Biol. 2014 Aug 7. [Epub ahead of print]
Stachon P, Peikert A, Michel NA, Hergeth S, Marchini T, Wolf D, Dufner B, Hoppe N, Ayata CK, Grimm M, Cicko S, Schulte L, Reinöhl J, von Zur Muhlen C, Bode C, Idzko M, Zirlik A
(See online at https://doi.org/10.1161/ATVBAHA.114.303585)
