P2X7 receptor signaling in the pathogenesis of smoke-induced lung inflammation and emphysema.

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...