Rationale: Extracellular adenosine triphosphate (ATP) is upregulated in the airways of patients with chronic obstructive pulmonary disease (COPD) and may contribute to the pathogenesis of the disease. However, the precise mechanisms are poorly understood. Objectives: To investigate the functional role of the ATP receptor P2X7 in the pathogenesis of cigarette smoke (CS)-induced lung inflammation and emphysema in vivo. Methods: Expression of the P2X7 receptor 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 P2X7 receptor in CS-induced lung inflammation was explored. Measurements and Main Results: CS-induced inflammation was associated with an upregulation of the P2X7 receptor on blood and airway neutrophils, alveolar macrophages and in whole lung tissue. Selective intrapulmonary inhibition of the P2X7 receptor reduced CS-induced lung inflammation and prevented the development of emphysema. Accordingly, P2X7 receptor knockout mice showed a reduced pulmonary inflammation following acute CS exposure. Experiments with P2X7 receptor chimera animals revealed that immune cell P2X7 receptor expression plays an important role in CS-induced lung inflammation and emphysema. Conclusions: Extracellular ATP contributes to the development of CS-induced lung inflammation and emphysema via activation of the P2X7 receptor. Inhibition of this receptor may be a new therapeutic target for the treatment of COPD.
P2X7 receptor signalling in the pathogenesis of smoke-induced lung inflammation
FERRARI, Davide;DI VIRGILIO, Francesco;
2011
Abstract
Rationale: Extracellular adenosine triphosphate (ATP) is upregulated in the airways of patients with chronic obstructive pulmonary disease (COPD) and may contribute to the pathogenesis of the disease. However, the precise mechanisms are poorly understood. Objectives: To investigate the functional role of the ATP receptor P2X7 in the pathogenesis of cigarette smoke (CS)-induced lung inflammation and emphysema in vivo. Methods: Expression of the P2X7 receptor 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 P2X7 receptor in CS-induced lung inflammation was explored. Measurements and Main Results: CS-induced inflammation was associated with an upregulation of the P2X7 receptor on blood and airway neutrophils, alveolar macrophages and in whole lung tissue. Selective intrapulmonary inhibition of the P2X7 receptor reduced CS-induced lung inflammation and prevented the development of emphysema. Accordingly, P2X7 receptor knockout mice showed a reduced pulmonary inflammation following acute CS exposure. Experiments with P2X7 receptor chimera animals revealed that immune cell P2X7 receptor expression plays an important role in CS-induced lung inflammation and emphysema. Conclusions: Extracellular ATP contributes to the development of CS-induced lung inflammation and emphysema via activation of the P2X7 receptor. Inhibition of this receptor may be a new therapeutic target for the treatment of COPD.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
