Health & Environmental Research Online (HERO)


Print Feedback Export to File
2621423 
Journal Article 
Abstract 
Identification of apolipoprotein E as an endogenous negative regulator of airway hyperreactivity and goblet cell hyperplasia in a house dust mite model of allergic asthma 
Yao, X; Fredriksson, K; Yu, ZX; Xu, X; Raghavachari, N; Munson, PJ; Amar, M; Remaley, AT; Levine, SJ 
2010 
Yes 
American Journal of Respiratory and Critical Care Medicine
ISSN: 1073-449X
EISSN: 1535-4970 
181 
A5583 
English 
WOS:000208771003660 
is part of a larger document 3452678 Proceedings of the American Thoracic Society 2010 International Conference, May 14-19, 2010, New Orleans
Steroid-resistant asthma is associated with dysregulated gene expression. Here, we sought to identify corticosteroid-unresponsive genes that modulate asthma pathogenesis in a house dust mite (HDM)-induced model of allergic asthma. Wild type A/J mice received saline or HDM by nasal administration 5 days per week for a total of 6 weeks. Dexamethasone (1 mg/kg) or saline was administered via an osmotic mini-pump during weeks 4 through 6, after which end-points were analyzed. HDM-induced asthma was associated with airway inflammation, goblet cell hyperplasia, and airway hyperreactivity (AHR). Dexamethasone significantly reduced airway inflammation and goblet cell hyperplasia to baseline levels. Although corticosteroid treatment was associated with a small, but statistically significant decrease in airway hyperreactivity (AHR) in HDM-challenged mice, airway resistance remained significantly elevated as compared to control mice. Therefore, the corticosteroid responsiveness of AHR was dissociated from airway inflammation and goblet cell hyperplasia. Gene expression profiling of the asthmatic lung transcriptome identified apolipoprotein E (apoE) as a corticosteroid-unresponsive gene, which was confirmed by qRT-PCR. Confocal immunofluorescence microscopy demonstrated that apoE is expressed primarily by CD68+ alveolar macrophages in lungs of HDM-challenged mice. We next utilized apoE-/- mice to assess its role in disease pathogenesis. AHR was significantly increased in HDM-challenged apoE-/- mice as compared to HDM-challenged wild-type mice. Furthermore, the basal level of AHR in apoE-/- mice was increased to a level similar to that of HDM-challenged wild-type mice. This demonstrates that apoE functions as an endogenous negative regulator of AHR, both at baseline and in asthma. Goblet cell hyperplasia was also significantly increased, while airway inflammation was not affected in HDM-challenged apoE-/- mice. In conclusion, we utilized a genome-wide screen of lung transcriptome expression in corticosteroid-treated asthmatic mice to identify apolipoprotein E as a novel corticosteroid-unresponsive gene that is primarily expressed by CD68+ alveolar macrophages. Furthermore, we identify a novel role for apolipoprotein E as an endogenous negative regulator of AHR and goblet cell hyperplasia in allergic asthma. 
American Thoracic Society 2010 International Conference 
New Orleans, LA 
May 14-19, 2010