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      Prostacyclin mimetics afford protection against lipopolysaccharide/d-galactosamine-induced acute liver injury in mice.

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          Abstract

          Prostacyclin (PGI2) serves as a protective, anti-inflammatory mediator and PGI2 mimetics may be useful as a hepatoprotective agent. We examined whether two PGI2 mimetics, ONO-1301 and beraprost, are beneficial in acute liver injury and attempted to delineate the possible mechanism underlying the hepatoprotective effect. Acute liver injury was induced by lipopolysaccharide/d-galactosamine (LPS/GalN) in mice. Mice were given an intraperitoneal injection of PGI2 mimetics 1h before LPS/GalN challenge. Both ONO-1301 and beraprost significantly declined the LPS/GalN-induced increase in serum aminotransferase activity. ONO-1301 and, to a lesser extent, beraprost inhibited hepatic gene expression levels of pro-inflammatory cytokines, which were sharply elevated by LPS/GalN. The hepatoprotective effects of ONO-1301, to a lesser extent, of beraprost were also supported by liver histopathological examinations. The PGI2 receptor antagonist CAY10441 abrogated their hepatoprotective effects. The mechanisms behind the benefit of PGI2 mimetics in reducing LPS/GalN-induced liver injury involved, in part, their suppressive effects on increased generation of reactive oxygen species (ROS), since their ability to prevent LPS/GalN-induced hepatic apoptosis was mimicked by the antioxidant N-acetyl-l-cysteine. They significantly diminished LPS/GalN-induced activation of signal transducers and activators of transcription 3 (STAT3) in liver tissues, an effect which was highly associated with their hepatoprotective effects. We indicate that IP receptor activation with PGI2 mimetics can rescue the damage in the liver induced by LPS/GalN by undermining activation of STAT3 and leading to a lower production of ROS. Our findings point to PGI2 mimetics, especially ONO-1301, as a potential novel therapeutic modality for the treatment of acute liver injury.

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          Author and article information

          Journal
          Toxicol. Appl. Pharmacol.
          Toxicology and applied pharmacology
          Elsevier BV
          1096-0333
          0041-008X
          November 01 2017
          : 334
          Affiliations
          [1 ] Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan; Department of Japanese Oriental Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
          [2 ] Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
          [3 ] Department of Anesthesiology and Pain Relief Center, The University of Tokyo Hospital, Tokyo, Japan.
          [4 ] Department of Japanese Oriental Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
          [5 ] Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. Electronic address: yhattori@med.u-toyama.ac.jp.
          Article
          S0041-008X(17)30369-1
          10.1016/j.taap.2017.09.003
          28887131
          242f757b-4f56-4ce0-8da1-4c60ee79358c
          History

          Signal transducers and activators of transcription,Hepatoprotection,IP receptor,Reactive oxygen species,Acute liver failure

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