PubMed | Pulmonary Critical Care Section
Type: Journal Article | Journal: Journal of molecular medicine (Berlin, Germany) | Year: 2013
Hypoxia-inducible factor (HIF)-1 is a master regulator of inflammatory activities of myeloid cells, including neutrophils and macrophages. These studies examine the role of myeloid cell HIF-1 in regulating asthma induction and pathogenesis, and for the first time, evaluate the roles of HIF-1 and HIF-2 in the chemotactic properties of eosinophils, the myeloid cells most associated with asthma. Wild-type (WT) and myeloid cell-specific HIF-1 knockout (KO) C57BL/6 mice were studied in an ovalbumin (OVA) model of asthma. Administration of the pharmacological HIF-1 antagonist YC-1 was used to corroborate findings from the genetic model. WT, HIF-1, and HIF-2 KO eosinophils underwent in vitro chemotaxis assays. We found that deletion of HIF-1 in myeloid cells and systemic treatment with YC-1 during asthma induction decreased airway hyperresponsiveness (AHR). Deletion of HIF-1 in myeloid cells in OVA-induced asthma also reduced eosinophil infiltration, goblet cell hyperplasia, and levels of cytokines IL-4, IL-5, and IL-13 in the lung. HIF-1 inhibition with YC-1 during asthma induction decreased eosinophilia in bronchoalveolar lavage, lung parenchyma, and blood, as well as decreased total lung inflammation, IL-5, and serum OVA-specific IgE levels. Deletion of HIF-1 in eosinophils decreased their chemotaxis, while deletion of the isoform HIF-2 led to increased chemotaxis. This work demonstrates that HIF-1 in myeloid cells plays a role in asthma pathogenesis, particularly in AHR development. Additionally, treatment with HIF-1 inhibitors during asthma induction decreases AHR and eosinophilia. Finally, we show that HIF-1 and HIF-2 regulate eosinophil migration in opposing ways.