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Sustained Elevated Adenosine Causes Lung Endothelial Apoptosis and Emphysema via Nucleoside Transporter‐ Facilitated Mitochondrial Defects
Author(s) -
Lu Qing,
Newton Julie,
Shamirian Paul,
Hsiao Vivian,
Sakhatskyy Pavlo,
Curren Sean,
Blackburn Michael R.,
Rounds Sharon
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.914.1
Subject(s) - adenosine , apoptosis , adenosine deaminase , oxidative stress , nucleoside , adenosine receptor , lung , pharmacology , mitochondrion , chemistry , endocrinology , medicine , biology , biochemistry , receptor , agonist
Cigarette smoking (CS) and sustained elevated adenosine cause alveolar cell apoptosis and emphysema. Adenosine deaminase (ADA) activity is decreased in the lungs of patients with COPD. However, it is unknown whether CS increases lung adenosine levels and whether increased lung adenosine contributes to CS‐induced endothelial cell (EC) apoptosis and emphysema. In this study, we found that lung tissue adenosine levels were significantly elevated in AKR mice exposed to CS for 3 weeks; an effect associated with increased EC apoptosis and early emphysema. We used our previously established in vitro model of sustained adenosine exposure by incubating lung EC with adenosine and an ADA inhibitor for up to 48 hours. We demonstrated that sustained adenosine exposure caused lung EC apoptosis via nucleoside transporter‐facilitated, not receptor‐mediated, intracellular adenosine uptake and metabolism, subsequent mitochondrial oxidative stress‐mediated activation of p38 and JNK, and ultimately mitochondrial defects and activation of mitochondrial apoptotic pathway. Our results suggest that CS‐induced lung EC apoptosis and emphysema is due to sustained elevated adenosine. Inhibition of adenosine uptake and mitochondria oxidative stress may become new therapeutic targets in treatment of smoke‐induced lung diseases. Funded by HL64936 (Rounds), VA Merit Review (Rounds), ATS/PHA research grant (Lu)