title: NTPDase1/CD39 and aberrant purinergic signalling in the pathogenesis of COPD.
abstract: Purinergic receptor activation via extracellular ATP is involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Nucleoside triphosphate diphosphohydrolase-1/CD39 hydrolyses extracellular ATP and modulates P2 receptor signalling.We aimed to investigate the expression and function of CD39 in the pathogenesis of cigarette smoke-induced lung inflammation in patients and preclinical mouse models. CD39 expression and soluble ATPase activity were quantified in sputum and bronchoalveolar lavage fluid (BALF) cells in nonsmokers, smokers and COPD patients or mice with cigarette smoke-induced lung inflammation. In mice, pulmonary ATP and cytokine concentrations, inflammation and emphysema were analysed in the presence or absence of CD39.Following acute cigarette smoke exposure CD39 was upregulated in BALF cells in smokers with further increases in COPD patients. Acute cigarette smoke exposure induced CD39 upregulation in murine lungs and BALF cells, and ATP degradation was accelerated in airway fluids. CD39 inhibition and deficiency led to augmented lung inflammation; treatment with ATPase during cigarette smoke exposure prevented emphysema.Pulmonary CD39 expression and activity are increased in COPD. CD39 deficiency leads to enhanced emphysema in mice, while external administration of a functional CD39 analogue partially rescues the phenotype. The compensatory upregulation of pulmonary CD39 might serve as a protective mechanism in cigarette smoke-induced lung damage.
authors.affiliation: Dept of Pulmonology, University Hospital Freiburg, Freiburg, Germany Dept of Pulmonology, Semmelweis University, Budapest, Hungary These authors contributed equally.
authors.forename: Zsofia
authors.initials: Z
authors.lastname: Lazar
authors.affiliation: Dept of Pulmonology, University Hospital Freiburg, Freiburg, Germany These authors contributed equally.
authors.forename: Nina
authors.initials: N
authors.lastname: Müllner
authors.affiliation: Dept of Life Sciences, University of Siena, Siena, Italy These authors contributed equally.
authors.forename: Monica
authors.initials: M
authors.lastname: Lucattelli
authors.affiliation: Dept of Pulmonology, University Hospital Freiburg, Freiburg, Germany These authors contributed equally.
authors.forename: Cemil Korcan
authors.initials: CK
authors.lastname: Ayata
authors.affiliation: Dept of Pulmonology, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Sanja
authors.initials: S
authors.lastname: Cicko
authors.affiliation: MediCity Research Laboratory, University of Turku, Turku, Finland.
authors.forename: Gennady G
authors.initials: GG
authors.lastname: Yegutkin
authors.affiliation: Dept of Life Sciences, University of Siena, Siena, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: De Cunto
authors.affiliation: Dept of Pulmonology, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Müller
authors.affiliation: Dept of Pulmonology, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Meyer
authors.affiliation: Dept of Pulmonology, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Madelon
authors.initials: M
authors.lastname: Hossfeld
authors.affiliation: Dept of Pulmonology, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Sorichter
authors.affiliation: Dept of Pulmonology, Semmelweis University, Budapest, Hungary.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Horvath
authors.affiliation: Dept of Pulmonology, University Hospital Rostock, Rostock, Germany.
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Virchow
authors.affiliation: Division of Gastroenterology, Dept of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
authors.affiliation: Dept of Life Sciences, University of Siena, Siena, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lungarella
authors.affiliation: Dept of Pulmonology, University Hospital Freiburg, Freiburg, Germany marco.idzko@uniklinik-freiburg.de.
authors.forename: Marco
authors.initials: M
authors.lastname: Idzko
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D001081:Apyrase / Q000235:genetics* / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid; D054426:Chemokine CXCL2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D011014:Pneumonia / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D015398:Signal Transduction; D012906:Smoke; D012907:Smoking / Q000378:metabolism*; D016092:Spumavirus; D014026:Nicotiana; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D054426:Chemokine CXCL2; D016207:Cytokines; D015850:Interleukin-6; D018048:Receptors, Purinergic P2; D012906:Smoke; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; D001081:Apyrase; C067869:CD39 antigen