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Hypoxia inducible factor promotes murine allergic airway inflammation and is increased in asthma and rhinitis.

ABSTRACT: New therapies are necessary to address inadequate asthma control in many patients. This study sets out to investigate whether hypoxia-inducible factor (HIF) is essential for development of allergic airway inflammation (AAI) and therefore a potential novel target for asthma treatment.Mice conditionally knocked out for HIF-1? were examined for their ability to mount an allergic inflammatory response in the lung after intratracheal exposure to ovalbumin. The effects of treating wild-type mice with either ethyl-3,4-dihydroxybenzoate (EDHB) or 2-methoxyestradiol (2ME), which upregulate and downregulate HIF, respectively, were determined. HIF-1? levels were also measured in endobronchial biopsies and bronchial fluid of patients with asthma and nasal fluid of patients with rhinitis after challenge.Deletion of HIF-1? resulted in diminished AAI and diminished production of ovalbumin-specific IgE and IgG(1) . EDHB enhanced the inflammatory response, which was muted upon simultaneous inhibition of vascular endothelial growth factor (VEGF). EDHB and 2ME antagonized each other with regard to their effects on airway inflammation and mucus production. The levels of HIF-1? and VEGF increased in lung tissue and bronchial fluid of patients with asthma and in the nasal fluid of patients with rhinitis after challenge.Our results support the notion that HIF is directly involved in the development of AAI. Most importantly, we demonstrate for the first time that HIF-1? is increased after challenge in patients with asthma and rhinitis. Therefore, we propose that HIF may be a potential therapeutic target for asthma and possibly for other inflammatory diseases.

SUBMITTER: Huerta-Yepez S

PROVIDER: S-EPMC3107385 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Hypoxia inducible factor promotes murine allergic airway inflammation and is increased in asthma and rhinitis.

Huerta-Yepez S S Baay-Guzman G J GJ Bebenek I G IG Hernandez-Pando R R Vega M I MI Chi L L Riedl M M Diaz-Sanchez D D Kleerup E E Tashkin D P DP Gonzalez F J FJ Bonavida B B Zeidler M M Hankinson Oliver O

Allergy 20110426 7

<h4>Background</h4>New therapies are necessary to address inadequate asthma control in many patients. This study sets out to investigate whether hypoxia-inducible factor (HIF) is essential for development of allergic airway inflammation (AAI) and therefore a potential novel target for asthma treatment.<h4>Methods</h4>Mice conditionally knocked out for HIF-1β were examined for their ability to mount an allergic inflammatory response in the lung after intratracheal exposure to ovalbumin. The effec ...[more]

PMID: 21517900

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Project description:Allergic asthma is characterized by airway eosinophilia, increased mucin production and allergen-specific IgE. Fc gamma receptor IIb (FcgammaRIIb), an inhibitory IgG receptor, has recently emerged as a negative regulator of allergic diseases like anaphylaxis and allergic rhinitis. However, no studies to date have evaluated its role in allergic asthma. Our main objective was to study the role of FcgammaRIIb in allergic lung inflammation. We used a murine model of allergic airway inflammation. Inflammation was quantified by BAL inflammatory cells and airway mucin production. FcgammaRIIb expression was measured by qPCR and flow cytometry and the cytokines were quantified by ELISA. Compared to wild type animals, FcgammaRIIb deficient mice mount a vigorous allergic lung inflammation characterized by increased bronchoalveolar lavage fluid cellularity, eosinophilia and mucin content upon ragweed extract (RWE) challenge. RWE challenge in sensitized mice upregulated FcgammaRIIb in the lungs. Disruption of IFN-gamma gene abrogated this upregulation. Treatment of naïve mice with the Th1-inducing agent CpG DNA increased FcgammaRIIb expression in the lungs. Furthermore, treatment of sensitized mice with CpG DNA prior to RWE challenge induced greater upregulation of FcgammaRIIb than RWE challenge alone. These observations indicated that RWE challenge upregulated FcgammaRIIb in the lungs by IFN-gamma- and Th1-dependent mechanisms. RWE challenge upregulated FcgammaRIIb on pulmonary CD14+/MHC II+ mononuclear cells and CD11c+ cells. FcgammaRIIb deficient mice also exhibited an exaggerated RWE-specific IgE response upon sensitization when compared to wild type mice. We propose that FcgammaRIIb physiologically regulates allergic airway inflammation by two mechanisms: 1) allergen challenge mediates upregulation of FcgammaRIIb on pulmonary CD14+/MHC II+ mononuclear cells and CD11c+ cells by an IFN-gamma dependent mechanism; and 2) by attenuating the allergen specific IgE response during sensitization. Thus, stimulating FcgammaRIIb may be a therapeutic strategy in allergic airway disorders.

Dataset Information

Hypoxia inducible factor promotes murine allergic airway inflammation and is increased in asthma and rhinitis.

Publications

Hypoxia inducible factor promotes murine allergic airway inflammation and is increased in asthma and rhinitis.

Similar Datasets

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