In vivo disruption of TGF-beta signaling by Smad7 in airway epithelium alleviates allergic asthma but aggravates lung carcinogenesis in mouse.
In vivo disruption of TGF-beta signaling by Smad7 in airway epithelium alleviates allergic asthma but aggravates lung carcinogenesis in mouse.
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DOI：
10.1371/journal.pone.0010149
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发表时间：
2010-04-13
期刊：
影响因子：
3.7
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Luo X;Ding Q;Wang M;Li Z;Mao K;Sun B;Pan Y;Wang Z;Zang YQ;Chen Y
TGF-β一直被认为在维持上皮稳态和上皮源性癌症的发生中发挥重要作用。然而，以往的研究大多集中在免疫细胞中TGF-β在过敏性哮喘发生中的作用，以及气道上皮本身TGF-β信号在过敏性炎症中的作用机制尚不清楚。此外，体内TGF-β在肺癌发展过程中在气道上皮中的特异性功能在很大程度上是难以捉摸的。为了评估肺上皮中TGF-β信号在变应性疾病和肺癌发展中的作用，我们建立了一个转基因小鼠模型，Smad7是TGF-β信号的细胞内抑制剂，使用小鼠CC10启动子在小鼠气道Clara细胞中组成性表达。小鼠遭受ova诱导的过敏性哮喘和聚氨酯诱导的肺癌的发展。Smad7转基因动物显著保护免受ova诱导的哮喘，减少气道炎症、气道粘液产生、细胞外基质沉积和ova特异性IgE的产生。进一步分析肺均质液细胞因子谱发现，经卵细胞诱导后，转基因小鼠的Th2细胞因子IL-4、IL-5和IL-13以及其他细胞因子IL-17、IL-1、IL-6、IP10、G-CSF和GM-CSF均显著降低。相比之下，Smad7转基因动物在接受氨基甲酸酯处理时，肺癌发病率增加。因此，这些研究首次证明了TGF-β信号在变应性哮喘和肺癌发生过程中特异性在气道上皮中的体内功能。
TGF-β has been postulated to play an important role in the maintenance of epithelial homeostasis and the development of epithelium-derived cancers. However, most of previous studies are mainly focused on the function of TGF-β in immune cells to the development of allergic asthma and how TGF-β signaling in airway epithelium itself in allergic inflammation is largely unknown. Furthermore, the in vivo TGF-β function specifically in the airway epithelium during lung cancer development has been largely elusive. To evaluate the in vivo contribution of TGF-β signaling in lung epithelium to the development of allergic disease and lung cancer, we generated a transgenic mouse model with Smad7, an intracellular inhibitor of TGF-β signaling, constitutively expressed in mouse airway Clara cells using a mouse CC10 promoter. The mice were subjected to the development of OVA-induced allergic asthma and urethane-induced lung cancer. The Smad7 transgenic animals significantly protected from OVA-induced asthma, with reduced airway inflammation, airway mucus production, extracellular matrix deposition, and production of OVA-specific IgE. Further analysis of cytokine profiles in lung homogenates revealed that the Th2 cytokines including IL-4, IL-5 and IL-13, as well as other cytokines including IL-17, IL-1, IL-6, IP10, G-CSF, and GM-CSF were significantly reduced in the transgenic mice upon OVA induction. In contrast, the Smad7 transgenic animals had an increased incidence of lung carcinogenesis when subjected to urethane treatment. These studies, therefore, demonstrate for the first time the in vivo function of TGF-β signaling specifically in airway epithelium during the development of allergic asthma and lung cancer.
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影响因子：
1.4
作者：
Lai, Shu-Tse;Hung, Chih-Hsing;Suen, Jau-Ling
通讯作者：
Suen, Jau-Ling
影响因子：
4.3
作者：
Barczyk, A;Pierzchala, W;Sozañska, E
通讯作者：
Sozañska, E
DOI：
10.1111/j.1365-2222.2004.01895.x
发表时间：
2004-03
期刊：
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology
影响因子：
--
作者：
McMillan SJ;Lloyd CM
通讯作者：
Lloyd CM
影响因子：
4.4
作者：
McMillan, SJ;Xanthou, G;Lloyd, CM
通讯作者：
Lloyd, CM
影响因子：
64.5
作者：
Kuilman, Thomas;Michaloglou, Chrysiis;Peeper, Daniel S.
通讯作者：
Peeper, Daniel S.