Treprostinil reduces endothelial damage in murine sinusoidal obstruction syndrome

• Published in: Journal of molecular medicine (Berlin, Germany) Vol. 97; no. 2; pp. 201 - 213
• Main Authors: Themanns, Madeleine, Koban, Florian, Bergmayr, Christian, Chrzan, Alicja, Strohmaier, Wolfgang, Haybaeck, Johannes, Freissmuth, Michael, Zebedin-Brandl, Eva
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-02-2019; Springer Nature B.V
• Subjects: Animals; Apoptosis; Biomedical and Life Sciences; Biomedicine; Body weight; Busulfan; Cell death; Cell Death - drug effects; Cell injury; Cytoprotection - drug effects; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - pathology; Epoprostenol - analogs & derivatives; Epoprostenol - therapeutic use; Fibrosis; Gangrene; Hematopoietic Stem Cell Transplantation - adverse effects; Hematopoietic stem cells; Hepatic Veno-Occlusive Disease - drug therapy; Hepatic Veno-Occlusive Disease - etiology; Hepatic Veno-Occlusive Disease - pathology; Hepatocytes; Human Genetics; Internal Medicine; Liver; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Molecular Medicine; Necrosis; Original; Original Article; Prostacyclin; Prostaglandin receptors; Prostaglandins; Protective Agents - therapeutic use; Stem cell transplantation; Transplantation; Transplants & implants; Transplant-related toxicity; Prostacyclin; VOD; HSCT; SOS; Defibrotide
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-018-1726-6

Sinusoidal obstruction syndrome (SOS) is a major complication after hematopoietic stem cell transplantation and belongs to a group of diseases increasingly identified as transplant-related systemic endothelial disease. Administration of defibrotide affords some protection against SOS, but the effect is modest. Hence, there is unmet medical need justifying the preclinical search for alternative approaches. Prostaglandins exert protective actions on endothelial cells of various vascular beds. Here, we explored the therapeutic potential of the prostacyclin analog treprostinil to prevent SOS. Treprostinil acts via stimulation of IP, EP
2
, and EP
4
receptors, which we detected in murine liver sinusoidal endothelial cells (LSECs). Busulfan-induced cell death was reduced when pretreated with treprostinil in vitro. In a murine in vivo model of SOS, concomitantly administered treprostinil caused lower liver weight-to-body weight ratios indicating liver protection. Histopathological changes were scored to assess damage to liver sinusoidal endothelial cells, to hepatocytes, and to the incipient fibrotic reaction. Treprostinil indeed reduced sinusoidal endothelial cell injury, but this did not translate into reduced liver cell necrosis or fibrosis. In summary, our observations provide evidence for a beneficial effect of treprostinil on damage to LSECs but unexpectedly treprostinil was revealed as a double-edged sword in SOS.
Key messages
Murine liver sinusoidal endothelial cells (LSECs) express prostanoid receptors.
Treprostinil reduces busulfan-induced cell death in vitro.
Treprostinil lowers liver weight-to-body weight ratios in mice.
Treprostinil positively affects LSECs in mice but not hepatic necrosis/fibrosis.