Abstract
Background: Cigarette smoke (CS) is the major risk factor for the development of COPD. Beside symptoms control, the current therapeutic options focusing on the reduction of acute exacerbations of COPD (AECOPD), as AE are associated with high morbidity and aggravated health status. Previously, we reported that CS induces endogenous ATP release, which via activation of P2-receptors contributes to the pathogenesis of CS-induced lung inflammation and emphysema. However, the role of P2R-signalling in the bacterial-induced acute exacerbations of CS-induced lung inflammation is unknown.
Methods: Wildtype (C56BL/6N), p2rx4- and p2rx7-deficient mice were exposed to CS for either four consecutive days or four months to induce CS-lung inflammation and emphysema, respectively. To exacerbate CS-induced airway inflammation animals received a single intratracheal dose of NTHI 3 hours after CS-exposure. 24hrs NTHI-administration BALF and lung tissues were collected. Furthermore, bone marrow-derived macrophages (BMMC) were stimulated with CS-extract +/- LPS and inflammatory cytokines in the supernatant were measured.
Results: BMMC from P2rx4- and P2rx7-deficient mice revealed an attenuated inflammatory cytokine production compared to wildtype animals. In vivo P2rx4- and P2rx7-deficiency protects from airway neutrophilia, decreases BALF-concentrations of cytokines (Il-1ß, TNFa) as well as tissue remodelling enzymes (MMP-9, NE) and dampens emphysema development in the chronic approach.
Conclusion: In summary, we demonstrate that P2X4/P2X7 are also involved in the pathogenesis of NTHI-induced AE of CS-induced lung inflammation. Thus, targeting P2X4R and P2X7R might be a new strategy to reduce bacterial driven AECOPD in patients.
Footnotes
Cite this article as: European Respiratory Journal 2019; 54: Suppl. 63, PA5445.
This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).
- Copyright ©the authors 2019