부산대학교 도서관

Summary: RATIONALE: Cigarette smoke is the major cause of chronic obstructive pulmonary disease (COPD), yet pathogenic mechanisms are not fully understood. More than 3 million people died of COPD in 2005; this represented 5% of all deaths worldwide. COPD will become the third-leading cause of death worldwide by 2030. Vascular endothelial growth factor (VEGF) is one of the major regulators of endothelial cell survival and is believed to play a role in the pathogenesis of COPD. Fibroblasts are a significant source of VEGF in the lungs; however the effect of cigarette smoke on VEGF release by fibroblasts is not fully understood. We hypothesized that cigarette smoke-induced disturbance of VEGF release by human lung fibroblasts is a potential pathogenic mechanism that could contribute to COPD. METHODS: Cigarette smoke extract (CSE) was prepared by modification of the methods of Carp and Janoff (Am.Rev.Respir.Dis, 1978). Human fetal lung fibroblasts (HFL-1) were exposed to different concentrations of CSE and for different durations. VEGF release into the media was measured using ELISA. TGF-β1/Smad3 as a potential pathway for the observed effect was also investigated using Smad3 and TGF-β1 receptor (TβR1) siRNA. RESULTS: CSE-induced VEGF release by HFL-1 in concentration and time dependent manner. CSE induced Smad3 phosphorylation and nuclear translocation in HFL-1 cells. Silencing of Smad3 by siRNA not only eliminated the stimulatory effect of CSE on VEGF release but also inhibited baseline VEGF production. Suppression of TβR1 by the pharmacological inhibitor (SB431542) markedly reduced VEGF release by HFL-1 in response to CSE and this effect was confirmed by TβR1 siRNA. In contrast, Nicotine inhibited VEGF release by HFL-1 in a dose and time dependent manner. CONCLUSIONS: Our findings indicate that CSE stimulates VEGF release by lung fibroblasts and Smad3 mediates the stimulation of VEGF release. Nicotine does not account for the CSE stimulation of VEGF production in human lung fibroblasts. The ability of lung fibroblasts to produce VEGF may play a role in pathogenesis of respiratory disease.