Extracellular nucleotides contribute to the pathogenesis of viral-induced exacerbations in COPD via P2X4/P2X7-receptor activation

Abstract

Background: Chronic cigarette smoke (CS) exposure remains the major burden contributing to the development of COPD. COPD is characterized by progressive airflow obstruction, chronic lung inflammation and the occurrence of acute exacerbations (AECOPD). AECOPD is a major predictor for morbidity, mortality and mainly induced by respiratory viral infections. Previous findings revealed elevated extracellular ATP levels in the BALF of mice after CS and poly(I:C) stimulation. Whereas the exact mechanism, by which P2R-signalling contributes to viral-induced AE of CS triggered lung inflammation needs to be further identified. Methods: WT (C56BL/6N), p2rx4- and p2rx7-deficient mice were exposed to CS for four consecutive days and received a single intratracheal application of poly(I:C) on day 2 prior to CS exposure to trigger AE. At day 4 mice were sacrificed and BALF and lung tissue were collected. Human monocytic (THP-1) and epithelial (NCI H292) cell lines were stimulated with CS extract and poly(I:C) following P2X4/P2X7 antagonist application in vitro. Results: P2rx4- and P2rx7-deficient mice exhibit an alleviated poly(I:C) exacerbated CS-induced airway inflammation by means of diminished airway neutrophilia and proinflammatory/tissue remodelling proteins in the BALF in comparison to WT animals. Treating NCI and THP-1 cells produce less inflammatory cytokines in response to antagonist treatment. Conclusion: P2X4 and P2X7-signalling contribute to viral exacerbation of CS-induced acute airway inflammation by inducing secretion of inflammatory cytokines and tissue remodelling enzymes. Thus, targeting P2X4R/P2X7R displays a promising approach to antagonize AECOPD.