Purinergic receptor inhibition prevents the development of smoke-induced lung injury and emphysema.
Extracellular ATP acts as a "danger signal" and can induce inflammation by binding to purinergic receptors. Chronic obstructive pulmonary disease is one of the most common inflammatory diseases associated with cigarette smoke inhalation, but the underlying mechanisms are incompletely understood. In this study, we show that endogenous pulmonary ATP levels are increased in a mouse model of smoke-induced acute lung inflammation and emphysema. ATP neutralization or nonspecific P2R-blockade markedly reduced smoke-induced lung inflammation and emphysema. We detected an upregulation the purinergic receptors subtypes on neutrophils (e.g., P2Y2R), macrophages, and lung tissue from animals with smoke-induced lung inflammation. By using P2Y(2)R deficient ((-/-)) animals, we show that ATP induces the recruitment of blood neutrophils to the lungs via P2Y(2)R. Moreover, P2Y(2)R deficient animals had a reduced pulmonary inflammation following acute smoke-exposure. A series of experiments with P2Y(2)R(-/-) and wild type chimera animals revealed that P2Y(2)R expression on hematopoietic cell plays the pivotal role in the observed effect. We demonstrate, for the first time, that endogenous ATP contributes to smoke-induced lung inflammation and then development of emphysema via activation of the purinergic receptor subtypes, such as P2Y(2)R.
Department of Pulmonary Medicine, University Hospital, Freiburg, Germany.
Sanja
S
Cicko
Monica
M
Lucattelli
Tobias
T
Müller
Marek
M
Lommatzsch
Giovanna
G
De Cunto
Silvia
S
Cardini
William
W
Sundas
Melanine
M
Grimm
Robert
R
Zeiser
Thorsten
T
Dürk
Gernot
G
Zissel
Jean-Marie
JM
Boeynaems
Stephan
S
Sorichter
Davide
D
Ferrari
Francesco
F
Di Virgilio
J Christian
JC
Virchow
Giuseppe
G
Lungarella
Marco
M
Idzko
D000208:Acute Disease; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000502:physiology; D000818:Animals; D002465:Cell Movement / Q000276:immunology; D002908:Chronic Disease; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D011656:Pulmonary Emphysema / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000172:deficiency / Q000502:physiology*; D058473:Receptors, Purinergic P2Y2; D015208:Smoke Inhalation Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
C546386:P2ry2 protein, mouse; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; D000255:Adenosine Triphosphate