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

摘要

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 signaloise levels using a two-way clustering approach. Thirty transcripts co-ordinately 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)-l, 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 epithe- lium 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.