P2RX4 signalling enhances acute cigarette smoke-induced lung inflammation and chronic lung emphysema development

Background: COPD is projected to be the third leading cause of death in the world by 2020. Chronic exposure to cigarette smoke is a major cause leading to the development of COPD. Previously we reported that extracellular purines such as ATP or UTP via activation of purinergic receptor subtypes P2Y2R and P2X7R contribute to the CS-induced lung inflammation and lung emphysema. Recent findings indicate that mice exposed to cigarette smoke (CS) exhibit an increased P2rx4 lung expression and elevated ATP levels in the BALF. Thus, we investigated the effect of P2RX4-signalling on COPD pathogenesis. Methods: Male p2rx4-deficient and WT (C57BL/6) animals were exposed to 5 cigarettes CS for 3 consecutive days in comparison, control animals receiving regular room air. 30 min after the last smoke exposure mice were sacrificed and BALF, as well as lung tissue, was collected. In addition, we applied a chronic approach (4m) to assess lung emphysema development. Furthermore, bone marrow (BM) chimeras were generated to compare the effect of p2rx4 deficiency in structural and hematopoietic cells. Results: P2rx4-deficient mice exhibit an alleviated CS-induced airway inflammation compared to wildtype animals, mainly driven by cells of hematopoietic origin as revealed by BM chimera experiments. Particularly, the number of neutrophils, the concentration of inflammatory cytokines and remodelling enzymes in the BALF were diminished. Subsequent chronic experiments with long term smoke exposure revealed protection against emphysema development associated with p2rx4-deficiency. Conclusion: P2X4-signalling contributes to acute CS-induced airway inflammation and chronic lung emphysema development.