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 messagesMurine 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.
Highlights
Sinusoidal obstruction syndrome (SOS), previously referred to as veno-occlusive disease (VOD), is a severe hepatic complication that occurs after hematopoietic stem cell transplantation (HSCT)
Target receptors of treprostinil are expressed by murine liver sinusoidal endothelial cells (LSECs)
The expression of treprostinil-target receptors Ep2, Ep4, and Ip was robust in LSECs with exceeding expression levels of the Ep4 receptor
Summary
Sinusoidal obstruction syndrome (SOS), previously referred to as veno-occlusive disease (VOD), is a severe hepatic complication that occurs after hematopoietic stem cell transplantation (HSCT). The murine model of SOS described by Zeng et al [27, 28] is based on an allogeneic hematopoietic stem cell transplantation (allo-HSCT), where preconditioning is achieved by whole body irradiation. The primary outcome parameter was hepatomegaly, and the number of animals was based on the following assumptions: the liver-to-body weight ratio (liver weight as % of body weight) was to increase from a mean of 5.5% with a standard deviation of 0.5% to 7.5 ± 0.7% on day 15 [27]. This increase was to be halved by treprostinil. We included one and two additional mice in the treprostinil-treated and in the control recipient group, respectively, to account for possible dropouts due to bone marrow transplant failure; treprostinil enhances bone marrow
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