Thromboxane A receptor signaling in endothelial cells attenuates monocrotaline-induced liver injury.

Toxicol Appl Pharmacol

Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa 252-0374, Japan; Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan. Electronic address:

Published: October 2019

AI Article Synopsis

  • - Sinusoidal obstruction syndrome (SOS) is a serious complication related to chemotherapy and stem cell transplants, mainly affecting liver cells and leading to platelet aggregation and injury.
  • - In a study using a mouse model, TP-deficient mice showed more severe liver damage from monocrotaline (MCT) treatment compared to normal mice, indicated by higher biomarkers and liver necrosis.
  • - Although platelet buildup occurred in both groups, the research found that TP signaling protects liver sinusoidal endothelial cells (LSECs) from damage rather than affecting platelet accumulation during liver injury.

Article Abstract

Sinusoidal obstruction syndrome (SOS) is a major complication of chemotherapy and hematopoietic stem cell transplantation. The early stage of SOS is characterized by liver sinusoidal endothelial cell (LSEC) injury accompanied by platelet aggregation. Thromboxane A (TxA) induces platelet aggregation through the thromboxane prostanoid (TP) receptor. In this study, we explored the role of TP signaling in a monocrotaline (MCT)-induced mouse model of SOS. Relative to wild-type (WT) mice, TP-deficient (TP) mice exhibited more severe MCT-liver injury, as indicated by elevated levels of alanine aminotransferase (ALT) and coagulative necrosis. Extensive accumulation of platelets in the liver was observed in both WT and TP mice. TP expression co-localized with CD31-positive LSECs. MCT treatment caused LSEC destruction, concomitant with elevated expression of matrix metalloproteinases (MMPs) and adhesion molecules in WT mice, and LSEC damage was further exacerbated in TP mice. Viability of isolated LSECs was lower in cells from TP mice, whereas mRNA levels of MMPs and adhesion molecules were higher; U46619, a TxA agonist, reduced these levels in WT mice. These data suggest that TP signaling has no effect on platelet accumulation during MCT-induced liver injury, but instead prevents injury by suppressing LSEC damage.

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http://dx.doi.org/10.1016/j.taap.2019.114733DOI Listing

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