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TIMP-1 Nucleates a Critical Bronchial Epithelial Response Network to Tobacco Smoke in Asthma

¹ Division of Emergency Medicine, and ² Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC; ³ School of Medicine and Health Sciences, and ⁵ Institute of Biomedical Sciences, The George Washington University, Washington, DC; and ⁴ The Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Arlington, Virginia

Correspondence and requests for reprints should be addressed to Robert J. Freishtat, M.D., M.P.H., Assistant Professor of Pediatrics, Emergency Medicine, and Integrative Systems Biology, Research Center for Genetic Medicine and Division of Emergency Medicine, Children's National Medical Center, 111 Michigan Avenue, NW, Washington, DC 20010. E-mail: rfreishtat{at}cnmcresearch.org

Tobacco smoke exposure induces a respiratory epithelial response that is mediated in part by reactive oxygen species. Using data from publicly available microarrays, we analyzed four projects (n = 124 arrays) with adequate signal/noise levels using a two-way clustering approach. Thirty transcripts coordinately regulated both in asthma models and tobacco-exposed human bronchial epithelium were identified and showed similar expression changes in a direct respiratory epithelium oxidative stress model (n = 104 arrays). This 30-transcript network was centered on tissue inhibitor of metalloproteinase (TIMP)-1, which specifically inactivates matrix metalloproteinase (MMP)-9 in lungs. In vitro analysis validated that TIMP-1 increased after oxidative stress (P = 0.017). However, the basally secreted MMP-9:TIMP-1 ratio was 7-fold lower in cigarette smoke condensate–exposed than vehicle-exposed asthmatic respiratory epithelium (0.003 ± 0.002 versus 0.014 ± 0.004; P = 0.035), a milieu known to favor subepithelial airway remodeling in chronic asthma. We propose that the canonical TIMP-1 network is an oxidative stress pathway critical for the respiratory epithelium response to tobacco smoke in asthma. Our model suggests that tobacco smoke–exposed children with asthma are more susceptible to metalloproteinase-mediated airway remodeling due to a blunted TIMP-1 response.

FOOTNOTES

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form November 26, 2008; accepted in final form December 3, 2008)

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