TGF-β3通过抑制上皮间质转化拮抗放射性肺纤维化

TGF-β3-ameliorated radiation-induced pulmonary fibrosis by inhibiting epithelial-mesenchymal transition

    摘要
  • 摘要:
    目的检测分析放射性肺纤维化过程中上皮间质转化（EMT）情况，探索转化生长因子β3（TGF-β3）是否通过EMT途径抑制放射性肺纤维化的发生。
    方法将180只C57BL/6雌性小鼠按体重完全随机分为对照组、单纯照射组（简称照射组）和照射+TGF-β3组（简称TGF-β3组），照射组和TGF-β3组经20 Gy 60Co γ射线单次胸部照射后，分别腹腔注射0.5 mL 0.9%的生理盐水和TGF-β3（1 μg/kg），每周1次，于照射后1、3和6个月活杀，用苏木素-伊红（HE）染色、Masson三色染色后观察肺组织病理学改变，用免疫组化法检测肺组织EMT相关的上皮标志物紧密连接蛋白（ZO-1）和间质标志物N-钙粘蛋白（N-cadherin）的表达，用Mann-Whitney U秩和检验和Fisher确切概率法对结果进行统计分析。
    结果HE和Masson染色结果显示，照射能够引起小鼠肺泡壁增厚、肺泡间隔明显增宽、肺泡结构严重破坏、胶原纤维大量沉积等典型纤维化病理改变；照射后3和6个月，与照射组比较，TGF-β3组小鼠肺纤维化病变明显减轻，差异有统计学意义（Z=-2.562、-2.807，均P<0.05），胶原沉积显著减少，差异有统计学意义（Z=2.442、2.529，均P<0.05）。免疫组化结果显示，与对照组比较，照射后1、3和6个月，小鼠肺组织ZO-1的表达量明显减少，差异有统计学意义（Z=4.492、5.831、6.064，均P<0.05），N-cadherin的表达量显著增高，差异有统计学意义（Z=-3.269、-5.520、-6.063，均P<0.05）；与照射组比较，TGF-β3组ZO-1表达量显著增高，差异有统计学意义（Z=-2.881、-4.220、-5.695，均P<0.05），而N-cadherin表达量显著减少，差异有统计学意义（Z=4.546、3.560、4.919，均P<0.05）。
    结论TGF-β3可通过抑制EMT拮抗放射性肺纤维化。

     

    Abstract:
    ObjectiveTo detect and analyze the influence of epithelial-mesenchymal transition (EMT) on radiation-induced pulmonary fibrosis and explore whether the anti-fibrosis effect of transforming growth factor-β3 (TGF-β3) is mediated by EMT.
    MethodsC57BL/6 female mice were randomly divided into three groups:control group, irradiation group only (irradiated group), and irradiation and TGF-β3 group (TGF-β3 group). The irradiation group received intraperitoneal injections of 0.5 ml saline, and the TGF-β3 group received intraperitoneal injections of 1 μg/kg human recombinant TGF-β3 every week after single dose of 20 Gy irradiation to their thoraxes. The mice in each group were sacrificed for 1, 3, and 6 months after irradiation. The mouse lung pathological changes were evaluated by hematoxylin-eosin and Masson trichrome. The expression of EMT epithelium-marked protein zonula occludens-1(ZO-1) and interstitial-marked protei N-cadherin were measured by immunohistochemistry. The results were analyzed using Mann-Whitney U test and Fisher's exact probability.
    ResultsAlveolar walls thickened, collagen fibers were deposited, and other typical fibrosis changed after irradiation. Unlike those in the irradiation group, pulmonary fibrosis lesions were significantly reduced (Z=-2.562, -2.807, both P<0.05) and collagen deposition was obviously decreased (Z=2.442, 2.529, both P<0.05) in the TGF-β3 group. The expression of ZO-1 was markedly decreased (Z=4.492, 5.831, 6.064, all P<0.05) and the expression of N-cadherin was significantly increased (Z=-3.269, -5.520, -6.063, all P<0.05) in the lung tissues of mice at 1, 3, and 6 months after irradiation. Unlike the irradiation group, the expression of ZO-1 was increased (Z=-2.881, -4.220, -5.695, all P<0.05) and the expression of N-cadherin was decreased (Z=4.546, 3.560, 4.919, all P<0.05) in the TGF-β3 group. The differences were significant.
    ConclusionTGF-β3 may antagonize radiation-induced pulmonary fibrosis by inhibiting EMT.

     

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