Hypoxia-induced Deoxycytidine Kinase Contributes to Epithelial Proliferation in Pulmonary Fibrosis

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 DCK in experimental pulmonary fibrosis was examined using a DCK inhibitor and alveolar epithelial cell-specific knockout mice. Measurements and Main Results: DCK as 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 la 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 ofepithelial cells and-pulmonary fibrosis was attenuated in mice with conditional deletion of hypo:da-inducible factor la 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.