Background
New therapies are necessary to address inadequate asthma control in many patients. This study set out to investigate whether Hypoxia Inducible Factor (HIF) is essential for development of allergic airway inflammation (AAI) and therefore a potential novel target for asthma treatment.
Methods
Mice conditionally knocked out for HIF-1β were examined for their ability to mount an allergic inflammatory response in the lung after intratracheal exposure to ovalbumin. The effects of treating wild-type mice with either ethyl-3,4-dihydroxybenzoate (EDHB) or 2-methoxyestradiol (2ME), which upregulate and downregulate HIF, respectively, were determined. HIF-1α levels were also measured in endobronchial biopsies and bronchial fluid of asthma patients and nasal fluid of rhinitis patients after challenge.
Results
Deletion of HIF-1β resulted in diminished AAI and diminished production of ovalbumin-specific IgE and IgG1. EDHB enhanced the inflammatory response, which was muted upon simultaneous inhibition of Vascular Endothelial Growth Factor (VEGF). EDHB and 2ME antagonized each other with regard to their effects on airway inflammation and mucus production. The levels of HIF-1α and VEGF increased in lung tissue and bronchial fluid of asthma patients and in the nasal fluid of rhinitis patients after challenge.
Conclusions
Our results support the notion that HIF is directly involved in the development of AAI. Most importantly, we demonstrate for the first time that HIF-1α is increased after challenge in asthma and rhinitis patients. Therefore we propose that HIF may be a potential therapeutic target for asthma and possibly for other inflammatory diseases.
We prospectively recorded CSF opening pressure in 242 adults who had a lumbar puncture with concomitant measurement of weight and height. The 95% reference interval for lumbar CSF opening pressure was 10 to 25 cm CSF. Body mass index had a small but clinically insignificant influence on CSF opening pressure.
Quantitative image analysis of high-resolution computed tomography (HRCT) performed at residual volume, before and after methacholine, is a sensitive method of detecting small airways involvement in asthma and response to therapy targeted to the small airways. Since an oral anti-leukotriene reaches the small airways via the circulation, the present authors hypothesised that treatment with montelukast would lead to improved small airway patency.A double-blind crossover study compared the effect of montelukast versus placebo for 4 weeks in 16 mild-to-moderate steroid-naïve asthmatics. Small airways function was evaluated by HRCT at residual volume before and after methacholine to assess regional air-trapping and airways hyperresponsiveness, as well as by physiological studies of small airways.Montelukast treatment resulted in significantly less regional air-trapping on HRCT on the premethacholine images when compared with placebo, as well as improvement in total quality of life scores and symptom sub-scores. However, montelukast treatment had no effect on increases in regional air-trapping on HRCT in response to methacholine. No differences were noted in global measures of small airways physiology between placebo and montelukast.In conclusion, distal airways disease improves in asthmatic subjects treated with montelukast. This improvement can be detected with high-resolution computed tomography, but not with conventional physiological studies.
Many important questions about OVS exist. This American Thoracic Society Research Statement highlights the types of research that leading clinicians and researchers believe will have the greatest impact on better understanding the spectrum of disease, improving diagnosis, and optimizing therapy.
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