Hypoxia response in asthma: differential modulation on inflammation and epithelial injury

Ahmad, Tanveer ; Kumar, Manish ; Mabalirajan, Ulaganathan ; Pattnaik, Bijay ; Aggarwal, Shilpi ; Singh, Ranjana ; Singh, Suchita ; Mukerji, Mitali ; Ghosh, Balaram ; Agrawal, Anurag (2012) Hypoxia response in asthma: differential modulation on inflammation and epithelial injury American Journal of Respiratory Cell and Molecular Biology, 47 (1). pp. 1-10. ISSN 1044-1549

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Official URL: http://ajrcmb.atsjournals.org/content/47/1/1

Related URL: http://dx.doi.org/10.1165/rcmb.2011-0203OC


Oxygen-sensing prolyl-hydroxylase (PHD)-2 negatively regulates hypoxia-inducible factor (HIF)1-α and suppresses the hypoxic response. Hypoxia signaling is thought to be proinflammatory but also attenuates cellular injury and apoptosis. Although increased hypoxic response has been noted in asthma, its functional relevance is unknown. The objectives of this study were to dissect the mechanisms and role of the hypoxic response in asthma pathophysiology. 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 pharmacologic PHD inhibitors (ethyl-3–4-dihydroxybenzoic acid [DHB], 1–10 mg/kg) or siRNA-mediated genetic knockdowns. Increased hypoxia response led to exacerbation of the asthma phenotype, with HIF-1α knockdown being beneficial. Chronically inflamed lungs from mice treated with 10 mg/kg DHB showed diffuse up-regulation of the hypoxia response, severe airway remodeling, and inflammation. Fatal asphyxiation during methacholine challenge was noted. However, bronchial epithelium restricted up-regulation of the hypoxia response seen with low-dose DHB (1 mg/kg) reduced epithelial injury and attenuated the asthmatic phenotype. Up-regulation of the hypoxia response was associated with increased expression of CX3CR1, a lymphocyte survival factor, and increased inflammatory cell infiltrate. This study shows that an exaggerated hypoxia response may contribute to airway inflammation, remodeling, and the 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.

Item Type:Article
Source:Copyright of this article belongs to American Thoracic Society.
Keywords:Hypoxia; HIF-1α; PHD2; Apoptosis
ID Code:96397
Deposited On:18 Dec 2012 06:49
Last Modified:18 Dec 2012 06:49

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