Hypoxia response in asthma: differential modulation on inflammation and epithelial injury.
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.
Centre for Excellence in Asthma & Lung disease, CSIR-Institute of Genomics and Integrative Biology, Delhi, India.
Tanveer
T
Ahmad
Manish
M
Kumar
Ulaganathan
U
Mabalirajan
Bijay
B
Pattnaik
Shilpi
S
Aggarwal
Ranjana
R
Singh
Suchita
S
Singh
Mitali
M
Mukerji
Balaram
B
Ghosh
Anurag
A
Agrawal
D056151:Airway Remodeling; D000818:Animals; D017209:Apoptosis; D001249:Asthma / Q000139:chemically induced / Q000276:immunology / Q000473:pathology*; D000073883:CX3C Chemokine Receptor 1; D015687:Cell Hypoxia; D062385:Hydroxybenzoates / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000473:pathology; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D019707:Receptors, Chemokine / Q000096:biosynthesis; D020545:Respiratory Mucosa / Q000276:immunology / Q000473:pathology*; D015398:Signal Transduction
D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D062385:Hydroxybenzoates; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D019707:Receptors, Chemokine; D016210:Methacholine Chloride; C018063:ethyl protocatechuate; D011393:Procollagen-Proline Dioxygenase