Hypoxia-inducible factor-1α inhibition modulates airway hyperresponsiveness and nitric oxide levels in a BALB/c mouse model of asthma

Hypoxia-inducible factor (HIF)-1 alpha is a master regulator of inflammation and is upregulated in alveolar macrophages and lung parenchyma in asthma. HIF-l alpha regulates select pathways in allergic inflammation, and thus may drive particular asthma phenotypes. This work examines the role of pharmacologic HIF-l alpha inhibition in allergic inflammatory airway disease (AIAD) pathogenesis in BALB/c mice, which develop an airway hyperresponsiveness (AHR) asthma phenotype. Systemic treatment with HIF-la antagonist YC-1 suppressed the increase in HIF-l alpha expression seen in control AIAD mice. Treatment with YC-1 also decreased AHR, blood eosinophilia, and allergic inflammatory gene expression: IL-5, IL-13, myeloperoxidase and iNOS. AIAD mice had elevated BAL levels of NO, and treatment with YC-1 eliminated this response. However, YC-1 did not decrease BAL, lung or bone marrow eosinophilia. We conclude that HIF-l alpha inhibition in different genetic backgrounds, and thus different AIAD phenotypes, decreases airway resistance and markers of inflammation in a background specific manner. Capsule summary: Asthma is a common disease that can be difficult to control with current therapeutics. We describe how pharmacologic targeting of a specific transcription factor, HIF-l alpha, suppresses asthmatic airway reactivity and inflammation. Published by Elsevier Inc.