| The inhibitory effects of Epidermal growth factor receptor inhibitor (erlotinib) in a mouse model of smoking |
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Sung Yong Lee |
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순천향대학교 의과대학 내분비대사내과 |
| 청람연구비 결과보고 : 담배 흡연에 의한 기관지내 점액 생성 모델에서 상피세포 성장인자 수용체 억제제의 기도 염증 억제효과에 대한 연구 |
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이승룡 |
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Department of Endocrinology and Metabolism, Soonchunhyang University Medical College, Seoul, Korea |
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| Abstract |
Background/Aims
Cigarette smoke may be the main cause of chronic bronchitis. Exposure to cigarette smoke has been reported to induce goblet cell hyperplasia and mucus production. Cigarette smoke also recruits inflammatory cells, including neutrophils, in airway epithelium and release tumor necrosis factor α (TNFα). It has been reported that TNFα induces goblet cell hyperplasia by activating an epidermal growth factor receptor (EGFR) cascade, resulting in mucin production. We evaluated the effects of an EGFR tyrosine kinase inhibitor, erlotinib, on mouse model of smoking. Methods: In vitro studies, cigarette smoke solution was treated in NCI-H292 cells and then checked the TNF-α and the MUC5AC production. And we checked the pEGFR, pAtk and MAPK expression by western blotting. In vivo studies, a total of 50 mice (male Balb/C mice) were randomized into a normal control, a high (5 mg/kg) dose erlotinib treated mice, a smoking control, and a low (1 mg/kg) and a high dose erlotinib treated smoking mice. Mice in the smoking groups were exposed to five cigarettes a day for 28 days. Mice were euthanized one day after the last exposure of cigarette smoke for bronchoalveolar lavage (BAL) and lung extraction. Results: In vitro studies, cigarette smoke solution was found to increase the phosphorylation of EGFR-specific tyrosine, Akt and MAPK, and to elevate MUC5AC production. These effects were inhibited dose-dependently by pretreatment with EGFR inhibitors (AG1478 and erlotinib, p<0.05). In vivo studies, cigarette smoke was found to cause inflammatory cell recruitment and to increase the secretion of TNFα in BAL fluids (p<0.05). However, erlotinib treatment did not effect on inflammatory cell recruitment and the production of TNFα in BAL fluids. In the goblet cell hyperplasia, the pretreatment of mice with erlotinib inhibited goblet cell hyperplasia, dose-dependently (p<0.05). Conclusion: The exposure of airway epithelium to cigarette smoke increase MUC5AC mucin synthesis through the neutrophil recruitment and upregulated EGFR expression. Erlotinib treatment decreases the MUC5AC mucin synthesis and goblet cell hyperplasia through the inhibition of EGFR signal pathway. |
| Key Words:
smoking, mucin, EGFR, erlotinib |
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