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 P2X(7) in the pathogenesis of cigarette smoke (CS)-induced lung inflammation and emphysema in vivo. Expression of the P2X(7) receptor (P2X(7)R) was measured in lung tissue und immune cells of mice with CS-induced lung inflammation. In a series of experiments using P2X(7) antagonists and genetically engineered mice, the functional role of the P2X(7)R in CS-induced lung inflammation was explored. CS-induced inflammation was associated with an up-regulation of the P2X(7)R on blood and airway neutrophils, alveolar macrophages, and in whole lung tissue. Selective intrapulmonary inhibition of the P2X(7)R reduced CS-induced lung inflammation and prevented the development of emphysema. Accordingly, P2X(7)R knockout mice showed a reduced pulmonary inflammation after acute CS exposure. Experiments with P2X(7)R chimera animals revealed that immune cell P2X(7)R 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 P2X(7)R. Inhibition of this receptor may be a new therapeutic target for the treatment of chronic obstructive pulmonary disease.
Department of Pulmonary Medicine, University of Freiburg, Germany. marco.idzko@uniklinik-freiburg.de
Monica
M
Lucattelli
Sanja
S
Cicko
Tobias
T
Müller
Marek
M
Lommatzsch
Giovanna
G
De Cunto
Silvia
S
Cardini
William
W
Sundas
Melanie
M
Grimm
Robert
R
Zeiser
Thorsten
T
Dürk
Gernot
G
Zissel
Stephan
S
Sorichter
Davide
D
Ferrari
Francesco
F
Di Virgilio
J Christian
JC
Virchow
Giuseppe
G
Lungarella
Marco
M
Idzko
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D004195:Disease Models, Animal; D004646:Emphysema / Q000378:metabolism*; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D012906:Smoke; D012907:Smoking / Q000009:adverse effects*
D058486:Receptors, Purinergic P2X7; D012906:Smoke; D000255:Adenosine Triphosphate