Endothelial Cells Recruit Macrophages and Contribute to a Fibrotic Milieu in Bleomycin Lung Injury
Endothelial Cells Recruit Macrophages and Contribute to a Fibrotic Milieu in Bleomycin Lung Injury
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DOI：
10.1165/rcmb.2013-0152oc
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发表时间：
2013-12-01
影响因子：
6.4
通讯作者：
Trojanowska, Maria
中科院分区：
文献类型：
--
作者：
Leach, Heather G.;Chrobak, Izabela;Trojanowska, Maria
系统性硬化症 (SSc) 是一种系统性自身免疫性疾病，会导致皮肤和内脏器官炎症、血管病变以及纤维化。 SSc 最严重的并发症之一是肺纤维化的发生。内皮细胞损伤先于纤维化的发展，并且被认为是一个起始事件。因此，我们的目的是使用完善的博来霉素（BLM）肺纤维化模型来表征内皮细胞在肺纤维化进展中的作用。通过细胞分选分离内皮细胞，并通过定量RT-PCR进行基因表达分析。血管损伤标志物基质金属肽酶 12 和冯维勒布兰德因子的表达升高表明，第一周和第二周之间诱导了内皮损伤。损伤后，选择素、CCL 趋化因子和炎症介质（包括补体过敏毒素受体（C3aR 和 C5aR）、制瘤素 M 和白血病抑制因子）的上调表明内皮激活。在第二周和第四周观察到内皮细胞过度表达纤维化介质，包括结缔组织生长因子、纤溶酶原激活剂抑制剂-1、骨桥蛋白、纤连蛋白和成纤维细胞特异性蛋白-1。这项研究表明，内皮细胞通过多种机制积极促进疾病进程，包括在 BLM 诱导的肺纤维化发展过程中招募炎症细胞和建立促纤维化环境。
Systemic sclerosis (SSc) is a systemic autoimmune disease that causes inflammation, vasculopathy, and fibrosis of the skin and internal organs. One of the most severe complications of SSc involves the development of pulmonary fibrosis. Endothelial cell injury precedes the development of fibrosis, and is believed to be an initiating event. Therefore, we aimed to characterize the role of endothelial cells in the progression of pulmonary fibrosis, using a well-established bleomycin(BLM) model of pulmonary fibrosis. Endothelial cells were isolated by cell sorting, and the analysis of gene expression was performed with quantitative RT-PCR. Endothelial injury was induced between the first and second week, as shown by the elevated expression of the vascular injury markers matrix metallopeptidase-12 and von Willebrand factor. After injury, endothelial activation was indicated by the up-regulation of selectins, CCL chemokines, and inflammatory mediators, including complement anaphylatoxin receptors (C3aR and C5aR), oncostatin M, and leukemia inhibitory factor. The endothelial cell overexpression of fibrotic mediators, including connective tissue growth factor, plasminogen activator inhibitor-1, osteopontin, fibronectin, and fibroblast specific protein-1, was observed in the second and fourth weeks. This study suggests that endothelial cells actively contribute to the disease process via multiple mechanisms, including the recruitment of inflammatory cells and the establishment of a profibrotic environment during the development of BLM-induced pulmonary fibrosis.