Treprostinil reduces endothelial damage in murine sinusoidal obstruction syndrome

Abstract

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, EP2, and EP4 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.

Pulmonary artery targeted therapy in treatment of COVID-19 related ARDS. Literature review

“…So far there are three drugs in this group: treprostinil, iloprost, and selexipag, which have been used in treatment of PAH with similar results as epoprostenol, which was expected, considering that they have the identical mechanism of action, even though they can stimulate adenylyl cyclase and reduce cell cytoplasmic calcium levels through different groups of receptors [65] , [66] , [67] . There is research reporting endothelium protection by Treprostinil, however, there is lack of studies investigating the effectiveness of epoprostenol analogues in treatment of ARDS [68] . Therefore, it is hard to assess the potential of treprostinil, iloprost or selexipag in treatment of COVID-19 associated lung injury but it should be corresponding to that of eporostenol.…”

Hepatic ischemia-reperfusion syndrome and its effect on the cardiovascular system: The role of treprostinil, a synthetic prostacyclin analog

“…Another recent study suggested that the presence of Gs-coupled prostanoid receptors in liver sinusoidal endothelial cells was responsible for the beneficial effect of prostaglandins. In fact, treprostinil binds and activates EP 2 , EP 4 , and IP receptors, resulting in attenuation of ischemia-induced hepatic cell injury[ 101 ].…”