Inhibition of microsomal prostaglandin E synthase-1 facilitates liver repair after hepatic injury in mice

Nishizawa, Nobuyuki; Yoshiya, Ikuto; Eshima, Koji; Ohkubo, Hirotoki; Kojo, Ken; Inoue, Takuya; Raouf, Joan; Jakobsson, Per Johan; Uematsu, Satoshi; Akira, Shizuo; Narumiya, Shuh; Watanabe, Masahiko; Murakami, Masataka

doi:10.1016/j.jhep.2018.02.009

Cited by 53 publications

(79 citation statements)

References 35 publications

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“…However, inhibition of inducible PGE 2 synthase attenuates reperfusion injury through inactivation of Kupffer cells and neutrophils, indicating a crucial role for prostaglandins in hepatic IRI. (37) In our experimental model, the results clearly support that constitutive expression of COX-2 in hepatic parenchymal cells leads to a diminished neutrophil infiltration in liver after IRI as indicated by Ly6G + immunostaining and MPO activity.…”

Section: Discussionsupporting

confidence: 80%

Protective Role of Hepatocyte Cyclooxygenase‐2 Expression Against Liver Ischemia–Reperfusion Injury in Mice

et al. 2019

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Section: Discussionsupporting

confidence: 80%

Protective Role of Hepatocyte Cyclooxygenase‐2 Expression Against Liver Ischemia–Reperfusion Injury in Mice

et al. 2019

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“…It is less clear which prostanoid receptors mediate the beneficial actions of PGE 2 : originally, G q -coupled E prostanoid receptors were shown to be more important for stimulating the proliferation of hepatocytes than G s -coupled receptors [30], but in ischemia-reperfusion injury, the protective effect was conveyed by stimulation of the EP 4 receptor [33]. However, more recently, the beneficial effects of PGE 2 and in particular of the EP 4 receptor have been questioned [34]: in fact, inhibition of PGE 2 synthesis—by deletion of the inducible microsomal PGE synthase-1 or by its inhibition with a small molecule—mitigated liver cell necrosis resulting from ischemia and reperfusion. Similarly, blockage of the EP 4 receptor—not of the EP 1 or of the EP 2 receptor—protected against hepatocyte damage and reduced necrotic areas in mice, in which the EP 4 receptor was absent due to genetic deletion [34].…”

Section: Discussionmentioning

confidence: 99%

“…However, more recently, the beneficial effects of PGE 2 and in particular of the EP 4 receptor have been questioned [34]: in fact, inhibition of PGE 2 synthesis—by deletion of the inducible microsomal PGE synthase-1 or by its inhibition with a small molecule—mitigated liver cell necrosis resulting from ischemia and reperfusion. Similarly, blockage of the EP 4 receptor—not of the EP 1 or of the EP 2 receptor—protected against hepatocyte damage and reduced necrotic areas in mice, in which the EP 4 receptor was absent due to genetic deletion [34]. Thus, the available evidence shows that the activation of G s -coupled prostaglandin receptors results in both enhanced and reduced hepatocyte necrosis depending on the nature of the injury and the time of the snapshot.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the available evidence shows that the activation of G s -coupled prostaglandin receptors results in both enhanced and reduced hepatocyte necrosis depending on the nature of the injury and the time of the snapshot. In fact, the conflicting results of Kuzumoto et al [33] and of Nishizawa et al [34] can be rationalized by considering that the time points sampled differed: Kuzumoto et al [33] examined early events (i.e., 2 h after reperfusion), while the observation period of Nishizawa et al [34] focused on changes occurring days after ischemia and reperfusion. The pathophysiology underlying damage caused by SOS is presumably more akin to that of ischemia and reperfusion than that of partial hepatectomy.…”

Section: Discussionmentioning

confidence: 99%

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Treprostinil reduces endothelial damage in murine sinusoidal obstruction syndrome

et al. 2018

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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.

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“…Indeed, Ly6C high /CD11b high /F4/80 high monocyte-derived macrophages are involved in liver repair after acetaminophen hepatotoxicity [29]. In addition, we recently reported that Ly6C high /CD11b high /F4/80 low cells recruited to the liver display a pro-inflammatory macrophage phenotype and delay liver repair after hepatic ischemia/reperfusion [20]. The phenotypes of macrophages recruited to injured livers at 24 h post-ConA treatment were different in WT and Ramp1 −/− mice, indicating that RAMP1 signaling is involved in macrophage polarization.…”

Section: Discussionmentioning

confidence: 99%

RAMP1 in Kupffer cells is a critical regulator in immune-mediated hepatitis

Inoue

Yoshiya

Nishizawa

et al. 2018

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The significanceF of the relationship between the nervous and immune systems with respect to disease course is increasingly apparent. Immune cells in the liver and spleen are responsible for the development of acute liver injury, yet the regulatory mechanisms of the interactions remain elusive. Calcitonin gene-related peptide (CGRP), which is released from the sensory nervous system, regulates innate immune activation via receptor activity-modifying protein 1 (RAMP1), a subunit of the CGRP receptor. Here, we show that RAMP1 in Kupffer cells (KCs) plays a critical role in the etiology of immune-mediated hepatitis. RAMP1-deficient mice with concanavalin A (ConA)-mediated hepatitis, characterized by severe liver injury accompanied by infiltration of immune cells and increased secretion of pro-inflammatory cytokines by KCs and splenic T cells, showed poor survival. Removing KCs ameliorated liver damage, while depleting T cells or splenectomy led to partial amelioration. Adoptive transfer of splenic T cells from RAMP1-deficient mice led to a modest increase in liver injury. Co-culture of KCs with splenic T cells led to increased cytokine expression by both cells in a RAMP1-dependent manner. Thus, immune-mediated hepatitis develops via crosstalk between immune cells. RAMP1 in KCs is a key regulator of immune responses.

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Inhibition of microsomal prostaglandin E synthase-1 facilitates liver repair after hepatic injury in mice

Cited by 53 publications

References 35 publications

Protective Role of Hepatocyte Cyclooxygenase‐2 Expression Against Liver Ischemia–Reperfusion Injury in Mice

Protective Role of Hepatocyte Cyclooxygenase‐2 Expression Against Liver Ischemia–Reperfusion Injury in Mice

Treprostinil reduces endothelial damage in murine sinusoidal obstruction syndrome

RAMP1 in Kupffer cells is a critical regulator in immune-mediated hepatitis

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