Role of intermittent hypoxia in the treatment of bronchial asthma and chronic obstructive pulmonary disease

Vogtel, Myriam; Michels, Alexandra

doi:10.1097/aci.0b013e32833903a6

Cited by 22 publications

(14 citation statements)

References 49 publications

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“…This was seen in acute and chronic models of asthma but was not seen in normal uninflamed lungs. We speculate that induction of the hypoxia response in the bronchial epithelium, as seen in control mice with a mild asthma phenotype, is a protective mechanism to attenuate cell injury and apoptosis (3,25,26). This best explains the observed protective effect of low-dose DHB inhibition in the chronic model and is consistent with other reports where accentuation of the hypoxic response or loss of prolyl hydroxylases leads to increased cell survival (25).…”

Section: Discussionsupporting

confidence: 90%

Hypoxia Response in Asthma

Ahmad

Kumar²,

Mabalirajan³

et al. 2012

Am J Respir Cell Mol Biol

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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.

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Section: Discussionsupporting

confidence: 90%

Hypoxia Response in Asthma

Ahmad

Kumar²,

Mabalirajan³

et al. 2012

Am J Respir Cell Mol Biol

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“…zebrafish) [48] based on different exposure times and hypoxia levels in order to make it possible the transfer of results to humans. These findings could be of particular interest for the selection of specific molecular targets for prognosis or for pharmacological interventions in diseases like COPD in which muscle adaptation to hypoxia can facilitate a positive outcome [49]. The described results underline the potential of differential proteomics in providing new insight into the mechanisms of adaptation to reduced O 2 pressure in conditions in which hypoxia is not the consequence of a disease.…”

Section: Subacute Hypoxiamentioning

confidence: 64%

Diversity of human skeletal muscle in health and disease: Contribution of proteomics

Gelfi

Vasso

Cerretelli

2011

Journal of Proteomics

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“…Hence the study of MRPL4, BCAP other molecules involved in the HIF-1α and PI3K/Akt signaling pathways might help understand the pathophysiology of allergic rhinitis and other atopic phenotypes. Recent research has also shown promise of therapeutic intervention of the HIF-1α as well PI3K/Akt signaling pathways for treatment of asthma and other related allergic conditions [57], [58], [59].…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association Study for Atopy and Allergic Rhinitis in a Singapore Chinese Population

et al. 2011

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Allergic rhinitis (AR) is an atopic disease which affects about 600 million people worldwide and results from a complex interplay between genetic and environmental factors. However genetic association studies on known candidate genes yielded variable results. The aim of this study is to identify the genetic variants that influence predisposition towards allergic rhinitis in an ethnic Chinese population in Singapore using a genome-wide association study (GWAS) approach. A total of 4461 ethnic Chinese volunteers were recruited in Singapore and classified according to their allergic disease status. The GWAS included a discovery stage comparing 515 atopic cases (including 456 AR cases) and 486 non-allergic non-rhinitis (NANR) controls. The top SNPs were then validated in a replication cohort consisting of a separate 2323 atopic cases (including 676 AR cases) and 511 NANR controls. Two SNPs showed consistent association in both discovery and replication phases; MRPL4 SNP rs8111930 on 19q13.2 (OR = 0.69, Pcombined = 4.46×10−05) and BCAP SNP rs505010 on chromosome 10q24.1 (OR = 0.64, Pcombined = 1.10×10−04). In addition, we also replicated multiple associations within known candidates regions such as HLA-DQ and NPSR1 locus in the discovery phase. Our study suggests that MRPL4 and BCAP, key components of the HIF-1α and PI3K/Akt signaling pathways respectively, are two novel candidate genes for atopy and allergic rhinitis. Further study on these molecules and their signaling pathways would help in understanding of the pathogenesis of allergic rhinitis and identification of targets for new therapeutic intervention.

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Role of intermittent hypoxia in the treatment of bronchial asthma and chronic obstructive pulmonary disease

Cited by 22 publications

References 49 publications

Hypoxia Response in Asthma

Hypoxia Response in Asthma

Diversity of human skeletal muscle in health and disease: Contribution of proteomics

Genome-Wide Association Study for Atopy and Allergic Rhinitis in a Singapore Chinese Population

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