| Hypoxia Response in Asthma: Differential Modulation on Inflammation and Epithelial Injury. | |
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MedLine Citation:
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PMID: 22312019 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Rationale: Oxygen sensing prolyl-hydroxylase-2 (PHD-2) negatively regulates hypoxia-inducible-factor 1-alpha (HIF-1α) and suppresses the hypoxic response. Hypoxia-signaling is thought to be pro-inflammatory, but also attenuates cellular injury and apoptosis. While increased hypoxic-response has been noted in asthma, its functional relevance is unknown.Objectives: To dissect the mechanisms and role of hypoxic-response in asthma pathophysiology. Methods: Experimental studies were conducted in mice, using acute and chronic allergic models of asthma. The hypoxic-response in allergically inflamed lungs was modulated by using either pharmacologic PHD inhibitors (ethyl-3-4-dihydroxybenzoic acid, DHB, 1-10mg/kg) or siRNA mediated genetic knockdowns. Results: Increased hypoxia-response led to exacerbation of the asthma phenotype, with HIF-1α knockdown being beneficial. Chronically inflamed lungs from mice treated with 10mg/kg DHB showed diffuse upregulation of the hypoxia-response, severe airway remodeling and inflammation. Fatal asphyxiation during methacholine challenge was noted. However, bronchial epithelium restricted upregulation of hypoxia-response seen with low dose DHB (1mg/kg) reduced epithelial injury and attenuated the asthmatic phenotype. Upregulation of hypoxia-response was associated with increased expression of CX3CR1, a lymphocyte survival factor, and increased inflammatory cell infiltrate. Conclusion: Exaggerated hypoxia-response may contribute to airway inflammation, remodeling, and development of asthma. However, the hypoxia-response may also be protective of epithelial apoptosis at lower levels, and the net effects of modulating the hypoxia-response may vary based on the context.Key words: Hypoxia, HIF-1α, PHD2, apoptosis. |
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Authors:
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Tanveer Ahmad; Manish Kumar; Ulaganathan Mabalirajan; Bijay Pattnaik; Shilpi Aggarwal; Ranjana Singh; Suchita Singh; Mitali Mukerji; Balaram Ghosh; Anurag Agrawal |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-2-3 |
Journal Detail:
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Title: American journal of respiratory cell and molecular biology Volume: - ISSN: 1535-4989 ISO Abbreviation: - Publication Date: 2012 Feb |
Date Detail:
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Created Date: 2012-2-8 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8917225 Medline TA: Am J Respir Cell Mol Biol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Centre of Excellence for Translational Research in Asthma and Lung Disease, CSIR-Institute of Genomics and Integrative Biology, Delhi, India. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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