P2Y6 receptor signalling in COPD patients and cigarette smoke-exposed mice

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 involvement of the UDP/P2Y6R axis in inflammatory lung diseases; however its role 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 CS-induced 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 CS-exposed 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.