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| Status |
Public on Jun 22, 2009 |
| Title |
Corticosteroid Resistant Asthma Is Associated with Classical Activation Of Airway Macrophages and Exposure To LPS |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Background: A subset of asthmatics does not respond to steroid therapy and therefore is at risk for escalation of disease severity. The cause of corticosteroid resistant (CR) asthma is unknown. Gene microarray technologies have the potential to substantiate new hypotheses regarding the etiology of corticosteroid resistance.
Methods: Gene microarray analysis was performed with bronchoalveolar lavage (BAL) cells of CR and corticosteroid sensitive (CS) asthmatics. Increased gene expression was verified with real time PCR and at the protein level by ELISA.
Findings: Microarray analyses demonstrated significantly higher levels (over two-fold increase, p<0.05) of TNF-alpha, IL-1alpha, IL-1beta, IL-6, CXCL1, CXCL2, CXCL3, CXCL8 (IL-8), CCL3, CCL4, CCL20 gene expression in BAL cells of CR than CS asthmatics. These findings, confirmed by RT-PCR in additional BAL samples, were consistent with classical macrophage activation by bacterial products. In contrast, markers of alternatively-activated macrophages, Arginase I and CCL24, were decreased in CR asthmatics. Genes associated with activation of the LPS signaling pathway (EGR1, DUSP2, MAIL, TNFAIP3) were significantly elevated in CR BAL samples (p<0.05). CR asthmatics had significantly higher amounts (1444.0±457.3 pg per mg of total protein) of LPS in BAL fluid than CS asthmatics (270.5±216.0 pg; p<0.05). Prolonged exposure to LPS induced functional steroid resistance to dexamethasone (DEX) in normal monocytes, demonstrated by persistently elevated IL-6 levels in the presence of DEX. Interpretation: Classical macrophage activation and induction of LPS signaling pathways along with high endotoxin levels detected in BAL fluid from CR asthmatics suggest that LPS exposure may contribute to CR asthma.
Keywords: Disease state analysis
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| Overall design |
Patients with a diagnosis of asthma according to American Thoracic Society criteria were selected for evaluation. Asthmatics had a baseline FEV1% predicted of 55% to 85% of predicted, a beta2-adrenergic response of ≥12% of baseline FEV1% predicted and/or a methacholine PC20 value of ≤8 mg/ml. Asthma patients were further subdivided in CR and CS groups, based on their response to steroids. The definition was based on change in FEV1 % predicted over a one-week course of 40 mg/day of oral prednisone. Asthmatic patients were defined as CS if they had an increase in FEV1% predicted of greater than 15% after a one-week course of prednisone, and as CR if less than 12% change in FEV1% predicted was observed. None of the asthmatic subjects recruited for this study had evidence for other types of lung diseases. None of the subjects had received systemic corticosteroid therapy for at least one month prior to bronchoscopy. All subjects provided written informed consent to participate in the study. The study was approved by the Institutional Review Board at National Jewish Medical and Research Center, Denver, CO. Gene array studies of BAL macrophages were performed in 3 CR and 3 CS asthmatics.
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| Contributor(s) |
Goleva E, Hauk PJ, Hall CF, Liu AH, Martin RJ, Leung DY |
| Citation(s) |
18774390 |
| Submission date |
Mar 26, 2007 |
| Last update date |
Feb 03, 2020 |
| Contact name |
Clifton Hall |
| E-mail(s) |
hallc@njc.org
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| Fax |
303.398.1225
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| Organization name |
National Jewish
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| Street address |
1400 Jackson Street
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| City |
Denver |
| State/province |
CO |
| ZIP/Postal code |
80206 |
| Country |
USA |
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| Platforms (1) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA100393 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE7368_RAW.tar |
124.1 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| Processed data provided as supplementary file |
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