Abstract
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.
Highlights
Defibrotide (DFB) is an antithrombotic profibrinolytic drug characterized by anticoagulant activity and low hemorrhage risk [1]
We carried out a preliminary exploratory heatmap analysis to evaluate gene expression profile clustering in different experimental conditions (Figure 1)
Two principal branches were identified, with the left branch including control cultures and endothelial cells exposed to DFB and the right one cells exposed to LPS, to LPS and DFB together, or pre-exposed to DFB and to LPS and DFB
Summary
Defibrotide (DFB) is an antithrombotic profibrinolytic drug characterized by anticoagulant activity and low hemorrhage risk [1]. It consists of a polydisperse mixture of predominantly single-stranded polydeoxyribonucleotide sodium salts [2]. Since the first report of its clinical utilization in bone marrow transplant-associated veno-occlusive disease (VOD), DFB has come on the stage for its efficacy in such life-threatening condition [3, 4]. Hepatic VOD, currently termed sinusoidal obstruction syndrome (SOS), is a potentially fatal complication occurring in hematological patients receiving conditioning regimens for hematopoietic stem cell transplantation (HSCT) or chemotherapy [4]. The exact mechanism by which DFB exerts its beneficial activity in this condition has been only partly deciphered, and probably it affects multiple endothelial pathways
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