• 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, and Michael R Blackburn.
• 1 Department of Biochemistry and Molecular Biology, The University of Texas-Houston Medical School, Houston, Texas.
• Am. J. Respir. Crit. Care Med. 2014 Dec 15; 190 (12): 1402-12.

RationaleIdiopathic 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.ObjectivesTo investigate the role of deoxycytidine kinase (DCK), an important enzyme for the salvage of deoxynucleotides, in the progression of pulmonary fibrosis.MethodsDCK 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 DCK in experimental pulmonary fibrosis was examined using a DCK inhibitor and alveolar epithelial cell-specific knockout mice.Measurements And Main ResultsDCK 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 1α 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 1α in the alveolar epithelium.ConclusionsOur 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.

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