title: Hypoxia-induced deoxycytidine kinase contributes to epithelial proliferation in pulmonary fibrosis.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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 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.
  
  
  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.
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, The University of Texas-Houston Medical School, Houston, Texas.
authors.forename: Tingting
authors.initials: T
authors.lastname: Weng
authors.forename: Jens M
authors.initials: JM
authors.lastname: Poth
authors.forename: Harry
authors.initials: H
authors.lastname: Karmouty-Quintana
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Garcia-Morales
authors.forename: Ernestina
authors.initials: E
authors.lastname: Melicoff
authors.forename: Fayong
authors.initials: F
authors.lastname: Luo
authors.forename: Ning-yuan
authors.initials: NY
authors.lastname: Chen
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Evans
authors.forename: Raquel R
authors.initials: RR
authors.lastname: Bunge
authors.forename: Brian A
authors.initials: BA
authors.lastname: Bruckner
authors.forename: Matthias
authors.initials: M
authors.lastname: Loebe
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Volcik
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
authors.forename: Michael R
authors.initials: MR
authors.lastname: Blackburn
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000502:physiology; D003842:Deoxycytidine Kinase / Q000502:physiology*; D006801:Humans; D000860:Hypoxia / Q000150:complications* / Q000201:enzymology / Q000503:physiopathology; D054990:Idiopathic Pulmonary Fibrosis / Q000201:enzymology / Q000209:etiology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000503:physiopathology; D060888:Real-Time Polymerase Chain Reaction; D020545:Respiratory Mucosa / Q000201:enzymology
chemical_list: D003842:Deoxycytidine Kinase
keywords: airway remodeling; hyperplastic epithelial cells; hypoxia-inducible factor 1α