Department of Image, Radiation therapy, Oncology and Hematology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
Front Immunol. 2020 Dec 3;11:585519. doi: 10.3389/fimmu.2020.585519. eCollection 2020.
Defibrotide (DFB) effects on different endothelial cell pathways have been investigated focusing on a limited number of genes or molecules. This study explored the modulation of the gene expression profile of steady-state or lipopolysaccharide (LPS)-activated endothelial cells, following the DFB exposure. Starting from differentially regulated gene expression datasets, we utilized the Ingenuity Pathway Analysis (IPA) to infer novel information about the activity of this drug. We found that effects elicited by LPS deeply differ depending on cells were exposed to DFB and LPS at the same time, or if the DFB priming occurs before the LPS exposure. Only in the second case, we observed a significant down-regulation of various pathways activated by LPS. In IPA, the pathways most affected by DFB were leukocyte migration and activation, vasculogenesis, and inflammatory response. Furthermore, the activity of DFB seemed to be associated with the modulation of six key genes, including matrix-metalloproteinases 2 and 9, thrombin receptor, sphingosine-kinase1, alpha subunit of collagen XVIII, and endothelial-protein C receptor. Overall, our findings support a role for DFB in a wide range of diseases associated with an exaggerated inflammatory response of endothelial cells.
已针对专注于少数基因或分子的不同内皮细胞途径研究了去纤维蛋白（DFB）的作用。本研究在 DFB 暴露后，探究了对稳定状态或脂多糖（LPS）激活的内皮细胞的基因表达谱的调节。从差异调节基因表达数据集出发，我们利用 IPA 推断出有关该药物活性的新信息。我们发现，LPS 引起的作用在很大程度上取决于 DFB 和 LPS 是否同时作用于细胞，或者 DFB 是否在 LPS 暴露之前进行预刺激。仅在后一种情况下，我们观察到 LPS 激活的各种途径显著下调。在 IPA 中，受 DFB 影响最大的途径是白细胞迁移和激活、血管发生和炎症反应。此外，DFB 的活性似乎与对六个关键基因的调节有关，包括基质金属蛋白酶 2 和 9、凝血酶受体、鞘氨醇激酶 1、胶原 XVIII 的α亚基和内皮蛋白 C 受体。总的来说，我们的研究结果支持 DFB 在与内皮细胞过度炎症反应相关的广泛疾病中的作用。
