TY - JOUR
T1 - Hypoxia-induced deoxycytidine kinase contributes to epithelial proliferation in pulmonary fibrosis
AU - Weng, Tingting
AU - Poth, Jens M.
AU - Karmouty-Quintana, Harry
AU - Garcia-Morales, Luis J.
AU - Melicoff, Ernestina
AU - Luo, Fayong
AU - Chen, Ning Yuan
AU - Evans, Christopher M.
AU - Bunge, Raquel R.
AU - Bruckner, Brian A.
AU - Loebe, Matthias
AU - Volcik, Kelly A.
AU - Eltzschig, Holger K.
AU - Blackburn, Michael R.
N1 - Publisher Copyright:
Copyright © 2014 by the American Thoracic Society.
PY - 2014/12/15
Y1 - 2014/12/15
N2 - 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.
AB - 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.
KW - Airway remodeling
KW - Hyperplastic epithelial cells
KW - Hypoxia-inducible factor 1α
UR - http://www.scopus.com/inward/record.url?scp=84919341532&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84919341532&partnerID=8YFLogxK
U2 - 10.1164/rccm.201404-0744OC
DO - 10.1164/rccm.201404-0744OC
M3 - Article
C2 - 25358054
AN - SCOPUS:84919341532
VL - 190
SP - 1402
EP - 1412
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
SN - 1073-449X
IS - 12
ER -