Hypoxia-induced deoxycytidine kinase expression contributes to apoptosis in chronic lung disease

Tingting Weng, Harry Karmouty-Quintana, Luis J. Garcia-Morales, Jose G. Molina, Mesias Pedroza, Raquel R. Bunge, Brian A. Bruckner, Matthias Loebe, Harish Seethamraju, Michael R. Blackburn

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by persistent inflammation and tissue remodeling and is a leading cause of death in the United States. Increased apoptosis of pulmonary epithelial cells is thought to play a role in COPD development and progression. Identification of signaling pathways resulting in increased apoptosis in COPD can be used in the development of novel therapeutic interventions. Deoxyadenosine (dAdo) is a DNA breakdown product that amplifies lymphocyte apoptosis by being phosphorylated to deoxyadenosine triphosphate (dATP). dAdo is maintained at low levels by adenosine deaminase (ADA). This study demonstrated that mice lacking ADA developed COPD manifestations in association with elevated dAdo and dATP levels and increased apoptosis in the lung. Deoxycitidine kinase (DCK), a major enzyme for dAdo phosphorylation, was up-regulated in mouse and human airway epithelial cells in association with air-space enlargement. Hypoxia was identified as a novel regulator of DCK, and inhibition of DCK resulted in diminished dAdo-mediated apoptosis in the lungs. Our results suggest that activating the dAdo-DCK-dATP pathway directly results in increased apoptosis in the lungs of mice with air-space enlargement and suggests a novel therapeutic target for the treatment of COPD.

Original languageEnglish (US)
Pages (from-to)2013-2026
Number of pages14
JournalFASEB Journal
Volume27
Issue number5
DOIs
StatePublished - May 2013

Keywords

  • Adenosine deaminase
  • COPD
  • Deoxyadenosine
  • Emphysema

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Weng, T., Karmouty-Quintana, H., Garcia-Morales, L. J., Molina, J. G., Pedroza, M., Bunge, R. R., Bruckner, B. A., Loebe, M., Seethamraju, H., & Blackburn, M. R. (2013). Hypoxia-induced deoxycytidine kinase expression contributes to apoptosis in chronic lung disease. FASEB Journal, 27(5), 2013-2026. https://doi.org/10.1096/fj.12-222067