Hypoxia Inducible Factor-1α Inhibition Modulates Airway Hyperresponsiveness and Nitric Oxide Levels in a BALB/c Mouse Model of Asthma

Publication date: Available online 14 January 2017
Source:Clinical Immunology
Author(s): Carola Dewitz, Elisa McEachern, Stephanie Shin, Kathryn Akong, Dale G. Nagle, David H. Broide, Praveen Akuthota, Laura E. Crotty Alexander
Hypoxia inducible factor (HIF)-1α is a master regulator of inflammation and is upregulated in alveolar macrophages and lung parenchyma in asthma. HIF-1α regulates select pathways in allergic inflammation, and thus may drive particular asthma phenotypes. This work examines the role of pharmacologic HIF-1α inhibition in allergic inflammatory airway disease (AIAD) pathogenesis in BALB/c mice, which develop an airway hyperresponsiveness (AHR) asthma phenotype. Systemic treatment with HIF-1α antagonist YC-1 suppressed the increase in HIF-1α 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-1α inhibition in different genetic backgrounds, and thus different AIAD phenotypes, decreases airway resistance and markers of inflammation in a background specific manner.Capsule SummaryAsthma is a common disease that can be difficult to control with current therapeutics. We describe how pharmacologic targeting of a specific transcription factor, HIF-1α, suppresses asthmatic airway reactivity and inflammation.

Graphical abstract

http://ift.tt/2jjVVbg