title: Role Of Hif2α Oxygen Sensing Pathway In Bronchial Epithelial Club Cell Proliferation.
abstract: Oxygen-sensing pathways executed by the hypoxia-inducible factors (HIFs) induce a cellular adaptive program when oxygen supply becomes limited. However, the role of the HIF oxygen-sensing pathway in the airway response to hypoxic stress in adulthood remains poorly understood. Here we found that in vivo exposure to hypoxia led to a profound increase in bronchial epithelial cell proliferation mainly confined to Club (Clara) cells. Interestingly, this response was executed by hypoxia-inducible factor 2α (HIF2α), which controls the expression of FoxM1, a recognized proliferative factor of Club cells. Furthermore, HIF2α induced the expression of the resistin-like molecules α and β (RELMα and β), previously considered bronchial epithelial growth factors. Importantly, despite the central role of HIF2α, this proliferative response was not initiated by in vivo Vhl gene inactivation or pharmacological inhibition of prolyl hydroxylase oxygen sensors, indicating the molecular complexity of this response and the possible participation of other oxygen-sensing pathways. Club cells are principally involved in protection and maintenance of bronchial epithelium. Thus, our findings identify a novel molecular link between HIF2α and Club cell biology that can be regarded as a new HIF2α-dependent mechanism involved in bronchial epithelium adaptation to oxygen fluctuations.
authors.affiliation: Research Unit, Santa Cristina Hospital, Research Institute Princesa (IP), Autonomous University of Madrid, Madrid 28009, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Torres-Capelli
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Marsboom
authors.affiliation: Research Unit, Santa Cristina Hospital, Research Institute Princesa (IP), Autonomous University of Madrid, Madrid 28009, Spain.
authors.forename: Qilong Oscar Yang
authors.initials: QO
authors.lastname: Li
authors.affiliation: Research Unit, Santa Cristina Hospital, Research Institute Princesa (IP), Autonomous University of Madrid, Madrid 28009, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Tello
authors.affiliation: Research Unit, Santa Cristina Hospital, Research Institute Princesa (IP), Autonomous University of Madrid, Madrid 28009, Spain.
authors.forename: Florinda Melendez
authors.initials: FM
authors.lastname: Rodriguez
authors.affiliation: Pulmonology Department, La Princesa Hospital, Research Institute Princesa (IP) Madrid, Spain.
authors.forename: Tamara
authors.initials: T
authors.lastname: Alonso
authors.affiliation: Research Unit, Santa Cristina Hospital, Research Institute Princesa (IP), Autonomous University of Madrid, Madrid 28009, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Sanchez-Madrid
authors.affiliation: Pulmonology Department, La Paz Hospital, IdiPAZ, Madrid, Spain; Autonomous University of Madrid, Madrid, Spain CIBER -CIBERES, Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: García-Rio
authors.affiliation: Pulmonology Department, La Princesa Hospital, Research Institute Princesa (IP) Madrid, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Ancochea
authors.affiliation: Research Unit, Santa Cristina Hospital, Research Institute Princesa (IP), Autonomous University of Madrid, Madrid 28009, Spain.
authors.forename: Julián
authors.initials: J
authors.lastname: Aragonés
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001980:Bronchi / Q000166:cytology* / Q000378:metabolism; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D000072278:Forkhead Box Protein M1 / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D010100:Oxygen / Q000378:metabolism*; D015398:Signal Transduction; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000072278:Forkhead Box Protein M1; D036341:Intercellular Signaling Peptides and Proteins; D010100:Oxygen; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C107585:FOXM1 protein, human; C486574:RETNLB protein, human; C497446:VHL protein, human