Hypoxia-induced deoxycytidine kinase contributes to epithelial proliferation in pulmonary fibrosis

Tingting Weng, Jens M. Poth, Harry Karmouty-Quintana, Luis J. Garcia-Morales, Ernestina Melicoff, Fayong Luo, Ning Yuan Chen, Christopher M. Evans, Raquel R. Bunge, Brian A. Bruckner, Matthias Loebe, Kelly A. Volcik, Holger K. Eltzschig, Michael R. Blackburn

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Rationale: Idiopathic pulmonary fibrosis (IPF) is a deadly lung disease with few therapeutic options. Apoptosis of alveolar epithelial cells, followed by abnormal tissue repair characterized by hyperplastic epithelial cell formation, is a pathogenic process that contributes to the progression of pulmonary fibrosis. However, the signaling pathways responsible for increased proliferation of epithelial cells remain poorly understood.

Objectives: To investigate the role of deoxycytidine kinase (DCK), an important enzyme for the salvage of deoxynucleotides, in the progression of pulmonary fibrosis.

Methods: DCK expression was examined in the lungs of patients with IPF and mice exposed to bleomycin. The regulation of DCK expression by hypoxia was studied in vitro and the importance of DCKin experimental pulmonary fibrosis was examined using aDCK inhibitor and alveolar epithelial cell-specific knockout mice. Measurements and Main Results: DCK was elevated in hyperplastic alveolar epithelial cells of patients with IPF and in mice exposed to bleomycin. Increased DCK was localized to cells associated with hypoxia, and hypoxia directly induced DCK in alveolar epithelial cells in vitro. Hypoxia-induced DCK expression was abolished by silencing hypoxia-inducible factor 1a and treatment of bleomycin-exposed mice with a DCK inhibitor attenuated pulmonary fibrosis in association with decreased epithelial cell proliferation. Furthermore, DCK expression, and proliferation of epithelial cells and pulmonary fibrosis was attenuated in mice with conditional deletion of hypoxia-inducible factor 1a in the alveolar epithelium.

Conclusions: Our findings suggest that the induction of DCK after hypoxia plays a role in the progression of pulmonary fibrosis by contributing to alveolar epithelial cell proliferation.

Original languageEnglish (US)
Pages (from-to)1402-1412
Number of pages11
JournalAmerican journal of respiratory and critical care medicine
Volume190
Issue number12
DOIs
StatePublished - Dec 15 2014

Keywords

  • Airway remodeling
  • Hyperplastic epithelial cells
  • Hypoxia-inducible factor 1α

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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