The purinergic receptor subtype P2Y2 mediates chemotaxis of neutrophils and fibroblasts in fibrotic lung disease
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Tobias Müller1,2,*, Susanne Fay1,*, Rodolfo Paula Vieira1,*, Harry Karmouty-Quintana3, Sanja Cicko1, Korcan Ayata1, Gernot Zissel1, Torsten Goldmann4, Giuseppe Lungarella5, Davide Ferrari6, Francesco Di Virgilio6, Bernard Robaye7, Jean-Marie Boeynaems7, Michael R. Blackburn3, Marco Idzko1
1University Hospital Freiburg, Department of Pneumology, Freiburg, Germany
2University Hospital RWTH Aachen, Division of Pneumology, Aachen, Germany
3Department of Biochemistry and Molecular Biology, Houston Medical School, University of Texas, Houston, USA
4Research Center Borstel, Clinical and Experimental Pathology, Borstel, Germany
5Department of Physiopathology and Experimental Medicine, University of Siena, Siena, Italy
6Department of Experimental and Diagnostic Medicine, Section of General Pathology and Interdisciplinary Center for the Study of Inflammation (ICSI), University of Ferrara, Ferrara, Italy
7IRIBHM and Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
*These authors contributed equally to this work
Tobias Müller, email: [email protected]
Keywords: ATP, chemotaxis, neutrophils, nucleotides, pulmonary fibrosis
Received: November 16, 2016 Accepted: March 10, 2017 Published: March 21, 2017
Idiopathic pulmonary fibrosis (IPF) is a devastating disease with few available treatment options. Recently, the involvement of purinergic receptor subtypes in the pathogenesis of different lung diseases has been demonstrated. Here we investigated the role of the purinergic receptor subtype P2Y2 in the context of fibrotic lung diseases.
The concentration of different nucleotides was measured in the broncho-alveolar lavage (BAL) fluid derived from IPF patients and animals with bleomycin-induced pulmonary fibrosis. In addition expression of P2Y2 receptors by different cell types was determined. To investigate the functional relevance of P2Y2 receptors for the pathogenesis of the disease the bleomycin model of pulmonary fibrosis was used. Finally, experiments were performed in pursuit of the involved mechanisms.
Compared to healthy individuals or vehicle treated animals, extracellular nucleotide levels in the BAL fluid were increased in patients with IPF and in mice after bleomycin administration, paralleled by a functional up-regulation of P2Y2R expression. Both bleomycin-induced inflammation and fibrosis were reduced in P2Y2R-deficient compared to wild type animals. Mechanistic studies demonstrated that recruitment of neutrophils into the lungs, proliferation and migration of lung fibroblasts as well as IL6 production are key P2Y2R mediated processes.
Our results clearly demonstrate the involvement of P2Y2R subtypes in the pathogenesis of fibrotic lung diseases in humans and mice and hence support the development of selective P2Y2R antagonists for the treatment of IPF.
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