Late Breaking Abstract - Role of HIF2a oxygen sensing pathway in bronchial epithelium biology

Introduction: Pulmonary epithelium is the first contact line with oxygen but the role of hypoxia-inducible factors (HIFs) in the airway’s primary response to oxygen fluctuations as well as cigarette smoke remains largely unknown. The lung exhibits the highest levels of HIF2α, which is the main regulator of renal erythropoietin (Epo) in response to hypoxia. Objectives: Here, we first explored whether HIF2a isoform could also induce Epo in the lung as a compensatory response to hypoxia and second, whether the HIF-dependent program could also be induced in other scenarios different from hypoxia such as cigarrete smoke exposure. Methods: We used mouse models of loss and gain of function of HIF2a pathway as well as mice exposure to atmospheric hypoxia and cigarette smoke. Lung tissues from these mice were subjected to protein and RNA analysis as well as immunohistochemistry analysis. Results: Our novel data shows that lung induces Epo expression in response to hypoxia as well as upon constitutive activation of the HIF pathway. Importantly, this extra-renal source of erythropoietin (Epo) is completely dependent on the HIF2a isoform and mainly confined in the bronchial epithelium. Regarding the relevance of HIF2a in bronchial epithelium, we previously showed that HIF2a-dependent genes such as Resistin-like molecular-alpha (RELM-a) are induced in Club cells in response to hypoxia. Significantly our latest data also shows that RELM-a and other HIF-dependent genes are also remarkably induced in cigarette smoke-exposed mice. Conclusions: Our findings have unveiled that bronchial epithelium acts as an extra-renal source of Epo and suggests the role of airway HIF expression in response to cigarette smoke exposure.