Journal Article

P2X7 Receptor Signaling in the Pathogenesis of Smoke-Induced Lung Inflammation and Emphysema

Idzko, Marco, Lungarella, Giuseppe, Müller, Tobias, Zissel, Gernot, Sundas, William, Ferrari, Davide, Lommatzsch, Marek, Lucattelli, Monica, Zeiser, Robert, Dürk, Thorsten, Cunto, Giovanna De, Virchow, J. Christian, Grimm, Melanie, Sorichter, Stephan, Virgilio, Francesco Di, Cicko, Sanja, Cardini, Silvia

2011

Overview

Extracellular ATP is up-regulated in the airways of patients with chronic obstructive pulmonary disease, and may contribute to the pathogenesis of the disease. However, the precise mechanisms are poorly understood. Our objective was to investigate the functional role of the ATP receptor P2X7 in the pathogenesis of cigarette smoke (CS)–induced lung inflammation and emphysema in vivo. Expression of the P2X7 receptor (P2X7R) was measured in lung tissue und immune cells of mice with CS-induced lung inflammation. In a series of experiments using P2X7 antagonists and genetically engineered mice, the functional role of the P2X7R in CS-induced lung inflammation was explored. CS-induced inflammation was associated with an up-regulation of the P2X7R on blood and airway neutrophils, alveolar macrophages, and in whole lung tissue. Selective intrapulmonary inhibition of the P2X7R reduced CS-induced lung inflammation and prevented the development of emphysema. Accordingly, P2X7R knockout mice showed a reduced pulmonary inflammation after acute CS exposure. Experiments with P2X7R chimera animals revealed that immune cell P2X7R expression plays an important role in CS-induced lung inflammation and emphysema. Extracellular ATP contributes to the development of CS-induced lung inflammation and emphysema via activation of the P2X7R. Inhibition of this receptor may be a new therapeutic target for the treatment of chronic obstructive pulmonary disease.

• Publisher: Oxford University Press
• Subject: Adenosine Triphosphate - metabolism / Alveoli / Animals / Bronchoalveolar Lavage Fluid / Chimeras / Chronic obstructive pulmonary disease / Cigarette smoke / Disease Models, Animal / Emphysema / Emphysema - metabolism / Flow Cytometry - methods / Genetic engineering / Humans / Inflammation / Inflammation - metabolism / Leukocytes (neutrophilic) / Lung diseases / Macrophages / Mice / Mice, Inbred C57BL / Mice, Knockout / Pathogenesis / Receptors, Purinergic P2X7 - metabolism / Reverse Transcriptase Polymerase Chain Reaction / Signal Transduction / Smoke / Smoking - adverse effects / Therapeutic targets