Role Of Hif2? 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 2? (HIF2?), which controls the expression of FoxM1, a recognized proliferative factor of Club cells. Furthermore, HIF2? induced the expression of the resistin-like molecules ? and ? (RELM? and ?), previously considered bronchial epithelial growth factors. Importantly, despite the central role of HIF2?, 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 HIF2? and Club cell biology that can be regarded as a new HIF2?-dependent mechanism involved in bronchial epithelium adaptation to oxygen fluctuations.

SUBMITTER: Torres-Capelli M 

PROVIDER: S-EPMC4858655 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature