Role of lung endothelial cells during fibrotic lung remodeling.

总结 慢性上皮或血管损伤，随后是失调修复，是触发机制， 间质性肺疾病的发病机制，包括特发性肺纤维化（IPF）。多种细胞类型 与肺纤维化有关，其中成纤维细胞和上皮细胞最受关注。内皮细胞的作用 细胞和微脉管系统仍不清楚。修复失调导致血管重塑，与 血管通透性增加，毛细血管部分损失，病理性血管生成局灶性增加， 内皮功能障碍正常内皮细胞（EC）转录重编程为纤维化- 相关内皮细胞（FEC），支持活化的成纤维细胞并促进肺部炎症。我们长久以来- 长期目标是确定EC到FEC重编程的关键调节因子，并阐明EC到FEC重编程的分子机制。 肺纤维化发生过程中内皮细胞和其他细胞类型之间的相互作用。在我们的初步数据中， 我们使用来自IPF患者肺和小鼠肺纤维化模型的内皮细胞， 肺纤维化过程中EC到FEC重编程的关键转录调节因子。使用转基因小鼠 模型与内皮特异性缺失或过表达的Foxf 1基因，我们建议测试的假设 内皮FOXF 1减少成纤维细胞的活化并防止纤维化中巨噬细胞的积聚， 焦点我们提出了两个具体的目标：（1）确定内皮FOXF 1抑制 肺纤维化，（2）确定恢复FEC中的FOXF 1是否会预防或减少肺纤维化 慢性肺损伤后的重塑。了解EC到TEC重新编程的规则， 肺内皮细胞控制肺纤维化的分子机制，将提供新的 治疗间质性肺病的方法。

Summary Chronic epithelial or vascular injuries followed by dysregulated repair are the trigger mechanisms in pathogenesis of interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF). Multiple cell types are involved in lung fibrogenesis, with fibroblasts and epithelial cells given the most attention. Role of endothelial cells and microvasculature remain unclear. Dysregulated repair causes vascular remodeling, associated with increased vessel permeability, partial loss of capillaries, focal increase in pathological angiogenesis and endothelial dysfunction. Normal endothelial cells (EC) are transcriptionally re-programmed into fibrosis- associated endothelial cells (FEC), that support activated fibroblasts and promote lung inflammation. Our long- term goal is to identify key regulators of EC-to-FEC re-programming and clarify molecular mechanisms of the crosstalk between endothelial cells and other cell types during pulmonary fibrogenesis. In our preliminary data, we used endothelial cells from lungs of patients with IPF and mouse lung fibrosis models to identify FOXF1 as a key transcriptional regulator of EC-to-FEC re-programming during lung fibrogenesis. Using transgenic mouse models with endothelial-specific deletion or over-expression of Foxf1 gene, we propose to test the hypothesis that endothelial FOXF1 decreases activation of fibroblasts and prevents macrophage accumulation in fibrotic foci. We propose two specific aims: (1) identify molecular mechanisms whereby endothelial FOXF1 inhibits lung fibrogenesis, (2) establish whether restoring FOXF1 in FECs will prevent or reduce fibrotic lung remodeling after chronic lung injury. Understanding the regulation of EC-to-TEC re-programming, and the molecular mechanisms utilized by pulmonary endothelial cells to control pulmonary fibrosis, will provide new approaches for treatment of interstitial lung diseases.