title: Hypoxia-inducible factor-1α inhibition modulates airway hyperresponsiveness and nitric oxide levels in a BALB/c mouse model of asthma.
abstract: 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.
  
  
  
  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-1α, suppresses asthmatic airway reactivity and inflammation.
authors.affiliation: Pulmonary & Critical Care Section, Department of Veterans Affairs San Diego Healthcare System (VASDHS), La Jolla, CA, United States; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
authors.forename: Carola
authors.initials: C
authors.lastname: Dewitz
authors.affiliation: Pulmonary & Critical Care Section, Department of Veterans Affairs San Diego Healthcare System (VASDHS), La Jolla, CA, United States; Weill Cornell Medical College, New York, NY, United States.
authors.forename: Elisa
authors.initials: E
authors.lastname: McEachern
authors.affiliation: Pulmonary & Critical Care Section, Department of Veterans Affairs San Diego Healthcare System (VASDHS), La Jolla, CA, United States; Division of Pulmonary & Critical Care Medicine, University of California at San Diego, La Jolla, CA, United States.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Shin
authors.affiliation: Division of Pulmonary & Critical Care Medicine, University of California at San Diego, La Jolla, CA, United States.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Akong
authors.affiliation: Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, MS, United States.
authors.forename: Dale G
authors.initials: DG
authors.lastname: Nagle
authors.affiliation: Division of Allergy and Immunology, University of California at San Diego, CA, United States.
authors.forename: David H
authors.initials: DH
authors.lastname: Broide
authors.affiliation: Division of Pulmonary & Critical Care Medicine, University of California at San Diego, La Jolla, CA, United States.
authors.forename: Praveen
authors.initials: P
authors.lastname: Akuthota
authors.affiliation: Pulmonary & Critical Care Section, Department of Veterans Affairs San Diego Healthcare System (VASDHS), La Jolla, CA, United States; Division of Pulmonary & Critical Care Medicine, University of California at San Diego, La Jolla, CA, United States. Electronic address: lcrotty@ucsd.edu.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Crotty Alexander
mesh_terms: D000818:Animals; D001249:Asthma / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004195:Disease Models, Animal; D004804:Eosinophils / Q000378:metabolism; D006967:Hypersensitivity / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018793:Interleukin-13; D015848:Interleukin-5; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II
keywords: Allergic inflammation; Asthma; Eosinophils; Hypoxia inducible factor (HIF)-1α; Nitric oxide; YC-1