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Endotoxin-Induced Endothelial Fibrosis Is Dependent on Expression of Transforming Growth Factors β1 and β2

机译：内毒素诱导的内皮纤维化取决于转化生长因子β1和β2的表达

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During endotoxemia-induced inflammatory disease, bacterial endotoxins circulate in the bloodstream and interact with endothelial cells (ECs), inducing dysfunction of the ECs. We previously reported that endotoxins induce the conversion of ECs into activated fibroblasts. Through endotoxin-induced endothelial fibrosis, ECs change their morphology and their protein expression pattern, thereby suppressing endothelial markers and upregulating fibrotic proteins. The most commonly used fibrotic inducers are transforming growth factor β1 (TGF-β1) and TGF-β2. However, whether TGF-β1 and TGF-β2 participate in endotoxin-induced endothelial fibrosis remains unknown. We have shown that the endotoxin-induced endothelial fibrosis process is dependent on the TGF-β receptor, ALK5, and the activation of Smad3, a protein that is activated by ALK5 activation, thus suggesting that endotoxin elicits TGF-β production to mediate endotoxin-induced endothelial fibrosis. Therefore, we investigated the dependence of endotoxin-induced endothelial fibrosis on the expression of TGF-β1 and TGF-β2. Endotoxin-treated ECs induced the expression and secretion of TGF-β1 and TGF-β2. TGF-β1 and TGF-β2 downregulation inhibited the endotoxin-induced changes in the endothelial marker VE-cadherin and in the fibrotic proteins α-SMA and fibronectin. Thus, endotoxin induces the production of TGF-β1 and TGF-β2 as a mechanism to promote endotoxin-induced endothelial fibrosis. To the best of our knowledge, this is the first report showing that endotoxin induces endothelial fibrosis via TGF-β secretion, which represents an emerging source of vascular dysfunction. These findings contribute to understanding the molecular mechanism of endotoxin-induced endothelial fibrosis, which could be useful in the treatment of inflammatory diseases.
机译：在内毒素血症引起的炎症性疾病期间，细菌内毒素在血液中循环并与内皮细胞（EC）相互作用，从而诱发EC的功能障碍。我们以前曾报道过内毒素诱导EC转化为活化的成纤维细胞。通过内毒素诱导的内皮纤维化，EC改变了它们的形态和蛋白质表达模式，从而抑制了内皮标记并上调了纤维化蛋白。最常用的纤维化诱导剂是转化生长因子β1（TGF-β1）和TGF-β2。但是，尚不清楚TGF-β1和TGF-β2是否参与内毒素诱导的内皮纤维化。我们已经证明内毒素诱导的内皮纤维化过程取决于TGF-β受体ALK5和Smad3的激活，Smad3是一种由ALK5激活的蛋白，因此表明内毒素引起TGF-β的产生以介导内毒素-诱导内皮纤维化。因此，我们研究了内毒素诱导的内皮纤维化对TGF-β1和TGF-β2表达的依赖性。内毒素处理的内皮细胞诱导TGF-β1和TGF-β2的表达和分泌。 TGF-β1和TGF-β2下调抑制了内毒素诱导的内皮标志物VE-钙黏着蛋白以及纤维化蛋白α-SMA和纤连蛋白的变化。因此，内毒素诱导TGF-β1和TGF-β2的产生，作为促进内毒素诱导的内皮纤维化的机制。据我们所知，这是第一个报告，表明内毒素通过TGF-β分泌诱导了内皮纤维化，这是血管功能障碍的一个新兴来源。这些发现有助于理解内毒素诱导的内皮纤维化的分子机制，这可用于治疗炎性疾病。

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