L1CAM诱导肺泡上皮细胞EMT参与IPF发病机制的研究

Idiopathic pulmonary ?brosis (IPF) is de?ned as a of chronic, progressive ?brotic interstitial pneumonia with unknown mechanism, occurring primarily in older adults, and limited to the lungs. It is characterized by progressive worsening of dyspnea and lung function and is associated with a poor prognosis.Up to date,there is no potent medicine for IPF. Recent studies have shown that epithelial to mesenchymal transition(EMT) takes an important role in IPF as well as in tumor metastasis. Besides, L1 cell adhesion molecular (L1CAM) has been linked to EMT during tumor metastasis.In addition, anti-L1CAM monoclonal antibody can inhibit tumor growth and dissemination efficiently.In our previous experiments,it showed that the serum concentration of soluble L1CAM in IPF patients was significantly higher than that of control. Based on literatures and our result, we suppose that L1CAM might be involved in EMT for the pathogenesis of IPF, and blockage of L1CAM could interfere in EMT and thus contribute to improve the outcome of IPF. To prove this hypothesis, L1CAM knockout(L1 y/-)mice,alveolar epithelial cells from fetal rats, blood or BALF from IPF patients will be investigated in this study.This study will uncover the uderlying mechanism of L1CAM-induced EMT during IPF. If our grant would be supported, it will shed the light on the novel targeting therapy for IPF in future.

IPF是一种慢性纤维化性间质性肺疾病，发病率、死亡率均高，预后凶险。至今发病机制不清、无有效药物治疗。现有的研究表明，EMT在IPF发生、发展中起到了关键作用，同时，EMT也是肿瘤侵袭和转移的重要过程；近期肿瘤学领域发现L1CAM参与并调节EMT，抗L1CAM单抗能有效遏制肿瘤的增殖、转移。我们前期研究发现，与正常人相比IPF患者血清中可溶性L1CAM浓度显著升高，因此推测，在IPF中也有L1CAM参与，阻断L1CAM可以干扰EMT而最终影响IPF的发生。本课题拟在前期研究的基础上，通过体内、外实验，结合人体标本（IPF患者血液、体液及组织学标本等）深入探讨L1CAM参与或调节EMT在IPF发生机制中的作用，为寻找IPF新的治疗靶点提供依据。

特发性肺纤维化( Idiopathic pulmonary fibrosis, IPF)是一种慢性纤维化性间质性肺疾病，发病率、死亡率均高，预后凶险。现有的研究显示上皮细胞向间质细胞转化(epithelial to mesenchymal transition，EMT) 与肺纤维化的发生密切相关；同时，EMT也是肿瘤侵袭和转移的重要过程。近期肿瘤学领域发现细胞粘附分子L1（L1 cell adhesion molecular， L1CAM）参与并调节EMT，抗L1CAM单抗能有效遏制肿瘤的增殖、转移。但L1CAM是否参与IPF中的EMT，进而影响IPF的发生发展有待研究。本课题收集了IPF病人的血清和支气管肺泡灌洗液标本，并以博莱霉素灌注气管建造了小鼠肺纤维化模型，培养了肺泡上皮细胞系（RLE-6TN）。为研究L1CAM是否参与IPF发生提供了重要的实验室证据。