Eastern Regional Meeting - 2008 Program & Abstracts
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A TIMP-1-NUCLEATED NETWORK IS CRITICAL FOR THE BRONCHIAL EPITHELIAL RESPONSE TO TOBACCO SMOKE IN ASTHMA
R. J. Freishtat 1, 2, 3, A. S. Benton 2, Z. Wang 2, 4, E. P. Hoffman 2, 3; 1. Division of Emergency Medicine, Children's National Medical Center, Washington, DC, MD, USA. 2. Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA. 3. School of Medicine and Health Sciences, The George Washington University, Washington,DC, USA. 4. The Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic University, Arlington, VA, USA.
Purpose of Study: Environmental tobacco smoke (ETS) exposure is associated with asthma morbidity, yet the molecular and cellular basis of this association is poorly understood. We used a novel data integration approach to test our hypothesis that ETS exposure in asthmatic bronchial epithelium initiates molecular networks associated with an oxidative stress response.
Methods Used: We studied 14 human and murine bronchial epithelial mRNA expression profile datasets relevant to asthma or tobacco. We identified four high-quality experiments (n=136 microarrays) via analysis of signal-to-noise ratios and normalized them with dChip mismatch model algorithms. Using a novel bi-clustering approach in the 2 asthma and 2 tobacco smoke datasets, we identified 60 probe sets coordinately-regulated in asthma and tobacco-exposed bronchial epithelium. This gene cluster was then overlaid on a phosgene model of direct bronchial epithelial oxidative stress (murine; 9 time points; n=104 microarrays).
Summary of Results: In the phosgene bronchial epithelium time-series, 39 out of 60 probe sets showed significant (p=0.01) expression patterns, representing a core set of bronchial epithelial genes involved in the response to asthma, ETS, and oxidative stress. This gene group was imported into Ingenuity Pathways Analysis software to explore the molecular networks prominently represented. These data corresponded highly to a gene/protein network centered on tissue inhibitor of metalloproteinase (TIMP)-1. Study of this TIMP-1 network in additional datasets of methylprednisilone-treated tissues (rat; 9 time points) showed key members, including TIMP-1, are up-regulated by corticosteroids.
Conclusions: We argue that this TIMP-1 network is an oxidative stress pathway critical for the bronchial epithelial response to ETS in asthma. Similar to steroid-resistant asthma, where children show a blunted TIMP-1 response, certain ETS-exposed children with asthma could be more susceptible to metalloproteinase-mediated airway remodeling.
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