Herbsttagung Programm & Abstracts - Deutsche Gesellschaft für ...

P2Y6 receptor signalling in COPD patients and cigarette smoke-exposed mice
C. Korcan Ayata* 1 , Ken R. Bracke* 2 , Sanja Cicko 1 , Monica Lucattelli 3 , Davide Ferrari 4 , J. Christian
Virchow 5 , Giuseppe Lungarella 3 , Rembert Koczulla 6 , Guy G. Brusselle 2 and Marco Idzko 1 .
1 Department of Pneumology, University Medical Center, Freiburg, Germany.
2 Department of
Respiratory Medicine, Ghent University, Ghent, Belgium. 3 Department of Physiopathology and
Experimental Medicine, University of Siena, Italy. 4 Department of Experimental and Diagnostic
Medicine, Center for the Study of Inflammation, University of Ferrara, Italy. 5 Department of
Pneumology, University Hospital, Rostock, Germany. 6 Department of Pneumology, University
Hospital, Marburg, Germany.
Rationale: Extracellular ATP, via activation of the purinergic receptor subtypes P2Y2 and P2X7, has
been identified as a new player in the pathogenesis of chronic obstructive pulmonary disease (COPD)
and cigarette smoke (CS)-induced lung inflammation. Recent evidence suggests a role of the
UDP/P2Y6R axis in inflammatory lung diseases; however its denotation in COPD needs to be
elucidated.
Objectives: To explore the relevance of P2Y6R signalling in the pathogenesis of COPD.
Methods: Expression of the P2Y6R was assessed on lung tissue from never smokers, smokers
without airflow obstruction and patients with COPD, as well as in mice with CS-induced lung
inflammation. Additionally, pulmonary UDP/UTP levels were quantified in bronchoalveolar lavage fluid
(BALF) of CS-exposed mice. Next, in a series of in vivo experiments using P2Y6R
agonists/antagonists and genetically engineered mice, the functional relevance of P2Y6R in CSinduced
lung inflammation was explored. Finally, the release and expression of inflammatory
mediators upon UDP stimulation was assessed in vitro in primary human airway epithelial cells (AEC).
Measurements and Main Results: P2Y6R expression was strongly increased in airway epithelium of
patients with COPD and correlated significantly with disease severity. Accordingly, P2Y6R expression
was also upregulated in airway epithelium of mice with CS-induced lung inflammation, and was
accompanied by increased levels of UTP/UDP in the BALF. Interestingly, selective inhibition or
deficiency of P2Y6R both resulted in attenuated lung inflammation and protection against the
development of emphysema upon CS-exposure. Mechanistically, UDP stimulation of the P2Y6R
resulted in increased expression and release of various chemokines/cytokines, either in vivo in CSexposed
mice, or in vitro in human primary AEC, thereby favouring the recruitment of blood
neutrophils to the lung.
Conclusion: As the UDP/P2Y6R axis is involved in the pathogenesis of COPD, selective P2Y6R
antagonists might be a new therapeutic option for this devastating disease.
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