Hypoxia Response in Asthma

Abstract

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.

Peri-adolescent asthma symptoms cause adult anxiety-related behavior and neurobiological processes in mice

“…In addition, although methacholine (MCH) is often used to verify airway hyperresponsiveness [50,74,90], here, we showed that weekly peri-adolescent MCH treatments effectively induced labored breathing bouts at multiple ages throughout mouse peri-adolescence. Previous studies have demonstrated that late adolescent/early-adult respiratory allergies and inflammation lead to increased anxiety [91].…”

“…Second, asthma involves unpredictable respiratory distress with heavily labored breathing. This hypoxic state can lead to limited airflow, increased airway muscle activity, risk for respiratory failure, and airway remodeling [49,50]. Given these two distinct symptoms of asthma – lung inflammation and labored breathing – we independently manipulated these two features in a mouse model.…”

Asthma Metabolomics and the Potential for Integrative Omics in Research and the Clinic

“…Increased hypoxic responses by the inflamed airway have been observed in asthma and were reported to lead to exacerbations in acute and chronic experimental allergic models of asthma, but not in healthy, noninflamed lung tissue. 29 The increase in oxidative and hypoxic stress responses in asthma coincides with considerable alterations in cellular energy metabolism. Levels of metabolites participating in the tricarboxylic acid cycle were altered in asthma, and fluctuations of metabolites in pathways involved in cellular energy metabolism in the lungs have been observed in mouse models of experimental asthma.…”

PHD2: from hypoxia regulation to disease progression

“…Using a nonspecific HIF1 inhibitor, Huerta-Yepez et al130 have reported that the inhibition of this pathway reduced the allergic inflammation and lung remodeling in an ovalbumin-triggered mouse model. Furthermore, inhibition of PHD2 by ethyl 3,4-dihydroxybenzoic acid, an oxoglutarate analog, has been shown to lead to a dose-dependent increase of airway hyperresponsiveness in a mouse model of asthma, associated with an increased cell infiltration, mucus production, and collagen deposition in the basal membrane of the epithelium 129. Although this data points to a possible protective role of PHD2 in the development of asthma, not much is known regarding the mechanism through which PHD2 seems to mediate these effects.…”