CALL Translational Research in Acute Lung Injury and Pulmonary Fibrosis Surfactant dysfunction during overexpression of TGF- (cid:2) 1 precedes profibrotic lung remodeling in vivo
CALL Translational Research in Acute Lung Injury and Pulmonary Fibrosis Surfactant dysfunction during overexpression of TGF- (cid:2) 1 precedes profibrotic lung remodeling in vivo
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发表时间：
2016
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通讯作者：
E. Lopez-Rodriguez;C. Boden;M. Echaide;J. Pérez-Gil;M. Kolb;J. Gauldie;U. Maus;M. Ochs;L. Knudsen
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作者：
E. Lopez-Rodriguez;C. Boden;M. Echaide;J. Pérez-Gil;M. Kolb;J. Gauldie;U. Maus;M. Ochs;L. Knudsen
TGF- (cid:2) 1 过度表达期间的表面活性剂功能障碍先于体内促纤维化肺重塑。 Am J Physiol Lung Cell Mol Physiol 310: L1260–L1271, 2016。转化生长因子- (cid:2) 1 (TGF- (cid:2) 1) 参与细胞增殖、分化和纤维形成的调节，诱导肌成纤维细胞迁移和增加细胞外基质合成。在此，分析了 TGF-(cid:2) 1 对肺结构和功能的影响。在小鼠肺中进行腺病毒介导的 TGF-(cid:2) 1 基因转移，并通过基于设计的体视学、侵入性肺功能测试以及基因转移后 1 周和 2 周表面活性剂系统的详细分析进行评估。 1周后，静态顺应性降低与肺泡急剧收缩相关，但没有形成水肿或间隔壁组织或胶原纤维体积增加。异常高的表面张力与表面活性蛋白 B 和 C 的下调相关。TTF-1 表达降低，并且使用 PLA（邻近配体测定）技术，我们发现 Smad3 和 TTF-1 在体内形成复合物，通常易位到 II 型肺泡上皮细胞 (AE2C) 的细胞核中，但在 TGF-(cid:2) 1 存在的情况下仍保留在细胞质中。 AE2C 显示形态改变，导致每个肺的总顶端表面积和极性损失。 AE2C 的这些变化在基因转移后 2 周进行，并且与肺顺应性相关。尽管静态肺顺应性仍然较低，但基因转移后 2 周，间隔壁组织和胶原纤维的体积有所增加。在该动物模型中，肺中 TGF-(cid:2) 1 信号传导的主要作用是表面活性蛋白的下调、高表面张力、肺泡退缩和机械应力，这些作用先于纤维化组织重塑和 AE2C 极性的逐渐丧失。最初的 TTF-1 功能障碍可能与表面活性剂蛋白的下调有关。
Surfactant dysfunction during overexpression of TGF- (cid:2) 1 precedes profibrotic lung remodeling in vivo. Am J Physiol Lung Cell Mol Physiol 310: L1260–L1271, 2016. Transforming growth factor- (cid:2) 1 (TGF- (cid:2) 1) is involved in regulation of cellular proliferation, differentiation, and fibrogenesis, inducing myofibroblast migration and increasing extracellular matrix synthesis. Here, TGF- (cid:2) 1 effects on pulmonary structure and function were analyzed. Adenovirus-mediated gene transfer of TGF- (cid:2) 1 in mice lungs was performed and evaluated by design-based stereology, invasive pulmonary function testing, and detailed analyses of the surfactant system 1 and 2 wk after gene transfer. After 1 wk decreased static compliance was linked with a dramatic alveolar derecruitment without edema formation or increase in the volume of septal wall tissue or collagen fibrils. Abnormally high surface tension correlated with downregulation of surfactant proteins B and C. TTF-1 expression was reduced, and, using PLA (proximity ligand assay) technology, we found Smad3 and TTF-1 form-ing complexes in vivo, which are normally translocated into the nucleus of the alveolar epithelial type II cells (AE2C) but in the presence of TGF- (cid:2) 1 remain in the cytoplasm. AE2C show altered morphology, resulting in loss of total apical surface area per lung and polarity. These changes of AE2C were progressive 2 wk after gene transfer and correlated with lung compliance. Although static lung compliance remained low, the volume of septal wall tissue and collagen fibrils increased 2 wk after gene transfer. In this animal model, the primary effect of TGF- (cid:2) 1 signaling in the lung is downregulation of surfactant proteins, high surface tension, alveolar derecruitment, and mechanical stress, which precede fibrotic tissue remodeling and progressive loss of AE2C polarity. Initial TTF-1 dysfunction is potentially linked to downregulation of surfactant proteins.