title: Sustained adenosine exposure causes lung endothelial apoptosis: a possible contributor to cigarette smoke-induced endothelial apoptosis and lung injury.
abstract: Pulmonary endothelial cell (EC) apoptosis has been implicated in the pathogenesis of emphysema. Cigarette smoke (CS) causes lung EC apoptosis and emphysema. In this study, we show that CS exposure increased lung tissue adenosine levels in mice, an effect associated with increased lung EC apoptosis and the development of emphysema. Adenosine has a protective effect against apoptosis via adenosine receptor-mediated signaling. However, sustained elevated adenosine increases alveolar cell apoptosis in adenosine deaminase-deficient mice. We established an in vitro model of sustained adenosine exposure by incubating lung EC with adenosine in the presence of an adenosine deaminase inhibitor, deoxycoformicin. We demonstrated that sustained adenosine exposure caused lung EC apoptosis via nucleoside transporter-facilitated intracellular adenosine uptake, subsequent activation of p38 and JNK in mitochondria, and ultimately mitochondrial defects and activation of the mitochondria-mediated intrinsic pathway of apoptosis. Our results suggest that sustained elevated adenosine may contribute to CS-induced lung EC apoptosis and emphysema. Our data also reconcile the paradoxical effects of adenosine on apoptosis, demonstrating that prolonged exposure causes apoptosis via nucleoside transporter-mediated intracellular adenosine signaling, whereas acute exposure protects against apoptosis via activation of adenosine receptors. Inhibition of adenosine uptake may become a new therapeutic target in treatment of CS-induced lung diseases.
authors: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Department of Medicine, Alpert Medical School of Brown University, Providence, RI 02908, USA. Qing_Lu@brown.edu
authors: Qing
authors: Q
authors: Lu
authors: Pavlo
authors: P
authors: Sakhatskyy
authors: Julie
authors: J
authors: Newton
authors: Paul
authors: P
authors: Shamirian
authors: Vivian
authors: V
authors: Hsiao
authors: Sean
authors: S
authors: Curren
authors: Gustavo Andres
authors: GA
authors: Gabino Miranda
authors: Mesias
authors: M
authors: Pedroza
authors: Michael R
authors: MR
authors: Blackburn
authors: Sharon
authors: S
authors: Rounds
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000243:Adenosine Deaminase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D058892:Adenosine Deaminase Inhibitors / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002417:Cattle; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D004727:Endothelium / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D055370:Lung Injury; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D033703:Nucleoside Transport Proteins / Q000378:metabolism; D015649:Pentostatin / Q000494:pharmacology; D012906:Smoke / Q000009:adverse effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D058892:Adenosine Deaminase Inhibitors; D033703:Nucleoside Transport Proteins; D012906:Smoke; D015649:Pentostatin; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000243:Adenosine Deaminase; D000241:Adenosine