近日，PLoS ONE发表了中国科学院上海生命科学研究院营养科学研究所陈雁和秦莹课题组合作研究的最新成果，揭示了在肺上皮细胞中TGF-b信号通路在对于过敏性哮喘和肺癌两种常见肺部疾病中的作用。
TGF-b信号通路是细胞中关键的信号通路之一，影响了细胞的各种生命活动，包括细胞增殖、分化、凋亡等。以前的研究发现，在肺部炎症反应发生过程中，TGF-b信通路通过调控免疫细胞的功能对疾病的发生发展行使了很大的作用。但TGF-b信号通路在呼吸道上皮细胞中的功能目前所知甚少。
陈雁组博士生罗小琳和丁秋蓉成功构建了特异性在肺上皮细胞Clara细胞中表达Smad7的转基因小鼠模型，Smad7的过表达特异性抑制了Clara细胞中的TGF-b信号通路。通过与营养所秦莹课题组和巴斯德所孙兵课题组的合作研究，他们发现在卵白蛋白（OVA)诱导的急性哮喘模型中该转基因小鼠显示明显的哮喘缓解的表型，主要表现为呼吸道炎症减轻、粘液产生和胞质外基质沉积减少、以及OVA特异性免疫球蛋白减少。进一步在肺组织匀浆检测多种细胞因子的表达发现多种细胞因子，包括白介素4（IL-4），白介素5（IL-5），白介素13（IL-13），白介素17（IL-17），白介素1（IL-1），白介素6（IL-6），粒细胞集落刺激因子（G-CSF），和巨噬细胞集落刺激因子（GM-CSF）在转基因小鼠中均有明显的下降，提示呼吸道上皮细胞中TGF-b信号通路的阻断可能抑制了免疫反应中上皮细胞和免疫细胞之间的通讯（crosstalk），继而导致炎症反应的降低。同时，在Smad7转基因小鼠模型中，乌拉坦（urethane）诱导的肺癌发生率明显高于对照组，提示在呼吸道上皮细胞中阻断TGF-b信号通路能够促进肺癌的发生发展。
这项研究第一次运用体内模型阐释了在急性哮喘和肺癌这两种常见的肺部病变中TGF-b信号通路在上皮细胞中所起的作用，进一步揭示了呼吸道上皮细胞中的TGF-b号通路不仅对于肺部炎症疾病的发生发展过程，而且对肺部癌变的过程都发挥了关键的作用。
推荐原文出处：
PLoS ONE 5(4): e10149. doi:10.1371/journal.pone.0010149
In Vivo Disruption of TGF-β Signaling by Smad7 in Airway Epithelium Alleviates Allergic Asthma but Aggravates Lung Carcinogenesis in Mouse
Xiaolin Luo1#, Qiurong Ding1#, Min Wang1#, Zhigang Li1, Kairui Mao2, Bing Sun2, Yi Pan1, Zhenzhen Wang1, Ying Qin Zang1*, Yan Chen1*
1 Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Chinese Academy of Sciences, Shanghai, China, 2 Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
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.
