Recombinant human soluble thrombomodulin decreases the plasma high-mobility group box-1 protein levels, whereas improving the acute liver injury and survival rates in experimental endotoxemia

Nagato, Masaru; Okamoto, Kohji; Abe, Yukio; Higure, Aiichiro; Yamaguchi, Koji

doi:10.1097/ccm.0b013e3181a55184

Cited by 94 publications

(75 citation statements)

References 40 publications

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“…The therapeutic potentials of rTM in different inflammatory diseases have been noted in various animal models such as lipopolysaccharide-challenged sepsis and arthritis. 14,21 Importantly, the use of rTM significantly improves the survival of mechanically ventilated patients with severe sepsis when compared with patients who have not received rTM, further supporting the clinical benefit of rTM as an anti-inflammatory agent. 22 Interestingly, the use of rTM increased the proportion of CD4 + / CD25 + /Foxp3 + Treg cells in the spleens isolated from HSCTrecipient mice in association with an increase in the production of IL-10 compared with control diluent-treated mice (Figures 1c, d and 4), suggesting a novel mechanism by which rTM acts as an immunosuppressive agent.…”

Section: Discussionmentioning

confidence: 83%

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Thrombomodulin alleviates murine GVHD in association with an increase in the proportion of regulatory T cells in the spleen

Ikezoe

Yang

Nishioka

et al. 2014

Bone Marrow Transplant

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Recombinant human soluble thrombomodulin (rTM), a potent anticoagulant, has been used for the treatment of disseminated intravascular coagulation in Japan since 2008. Interestingly, rTM possesses anti-inflammatory and cytoprotective functions. This study examined whether rTM alleviates GVHD in a murine hematopoietic SCT (HSCT) model. Use of rTM significantly improved the survival of mice on day 28 of transplantation (survival rate 70% in rTM -treated mice vs 35% in control, P o0.05) in association with a significant decrease in plasma levels of IL-6, IFN-γ and high-mobility group B1 DNA-binding protein on day 7 of HSCT. Intriguingly, the proportion of regulatory T cells in the spleen was significantly increased in rTM-treated mice on day 7 of transplantation compared with control diluent-treated mice. In addition, elevated plasma levels of TM and fibrin/fibrinogen degradation product were noted in HSCT-recipient mice, suggesting coagulopathy caused by endothelial cell damage in this GVHD model. The use of rTM potently decreased these levels. Importantly, rTM did not hamper the anti-GVL and engraftment of hematopoietic cells. Taken together, the use of rTM may prevent GVHD and serve as a potential therapeutic strategy to improve clinical outcomes in individuals who receive HSCT.

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Section: Discussionmentioning

confidence: 83%

“…The dose of rTM was decided according to previous studies. 14 The mortality of mice was evaluated until day 28 after HSCT. The experiments were repeated twice independently.…”

Section: Induction Of Gvhd and Treatment With Rtmmentioning

confidence: 99%

Thrombomodulin alleviates murine GVHD in association with an increase in the proportion of regulatory T cells in the spleen

Ikezoe

Yang

Nishioka

et al. 2014

Bone Marrow Transplant

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“…Recently, thrombomodulin (TM) administration has been shown to rescue septic shock animals [14]. The enhanced activity of thrombin when complexed with TM should have caused activation of thrombin activatable fibrinolysis inhibitor (TAFI) which then inactivates C5a anaphylatoxin by removing the C-terminal arginine [15,16] Six cynomolgus monkeys intravenously infused with a lethal dose of bacterial LPS (4mg/kg) destined to death were treated with intravenous administration of 2 mg/kg/h of AcPepA for 3 h starting 30 min after the lethal LPS injection (#5 and #8).. Control monkeys (#1 and #10) were infused only saline instead of AcPepA following LPS injection.…”

Section: Resultsmentioning

confidence: 99%

HMGB1 Release by C5a Anaphylatoxin is an Effective Target for Sepsis Treatment

Okada¹,

Imai

Okada

et al. 2012

Clin Exp Pharmacol

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Antibodies to C5a have proven to be effective in treating experimental septic primate models. A 17 amino acid peptide (ASGAPAPGPAGPLRPMF) named PepA binds to C5a and prevents complement-mediated lethal shock in rats. AcPepA harboring an acetyl group at the N-terminal alanine showed increased inhibitory activity against C5a. Cynomolgus monkeys destined to expire from a lethal dose of bacterial endotoxin (4 mg/kg) were rescued by intravenous administration of AcPepA. AcPepA could have interfered with the ability of C5a to stimulate C5L2 which is responsible for HMGB1 release and stimulation of TLR4 as an endogeneous ligand with LPS behavior. The suppression of HMGB1 release by AcPepA administration to LPS-shock monkeys is likely responsible for rescuing the animals.

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“…The pretreated CD groups were termed 1 mg ART (1 mg/kg ART-123) and 5 mg ART (5 mg/kg ART-123). The dose of 1 mg/kg ART-123 was selected based on previous studies (Mohri et al 1994;Nagato et al 2009), and 5 mg/kg ART-123 was used for the high-dose group. All livers were preserved in University of Wisconsin (UW) solution (DuPont Pharmaceuticals Co., Wilmington, DE, USA) for 6 h at 4°C.…”

Section: Experimental Designmentioning

confidence: 99%

“…Previous studies reported that thrombomodulin binds to HMGB1 and is capable of preventing the amplification of inflammatory responses (Abeyama et al 2005;Ito et al 2008). Nagato et al (2009) reported that ART-123 binds to HMGB1 from a necrotic cell and decreases plasma HMGB1 levels in rats. Miyagi et al (2004) suggested that warm IR injury causes a feedback loop involving microcirculatory disturbances and cytokine storms, indicating that warm IR injury is similar to DIC.…”

Section: Introductionmentioning

confidence: 99%

Soluble Thrombomodulin Ameliorates Ischemia-Reperfusion Injury of Liver Grafts by Modulating the Proinflammatory Role of High-Mobility Group Box 1

Kashiwadate

Miyagi

Hara

et al. 2016

Tohoku J. Exp. Med.

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Transplantation using grafts obtained after cardiac death (CD) is considered a promising solution for graft shortages. However, no standard criteria for organ preservation have been established for CD donors. High-mobility group box 1 (HMGB1) is a DNA-binding protein that is released from dying hepatocytes as an early mediator of inflammation and organ tissue damage. HMGB1 stimulates immunocytes to produce inflammatory cytokines, thereby amplifying the inflammatory response. Thrombomodulin is an integral membrane protein that functions as an endothelial anticoagulant cofactor, and it binds HMGB1 through the extracellular domain. We investigated the effects of ART-123, recombinant human soluble thrombomodulin, on warm ischemia-reperfusion injury in liver grafts. Male Wistar rats were divided into four ex vivo groups: heart-beating (HB) group, in which livers were isolated from HB donors; CD group, in which livers were isolated from CD donors exposed to apnea-induced conditions and warm ischemic conditions for 30 min after cardiac arrest; and two CD groups pretreated with ART-123 (1 or 5 mg/kg). Each isolated liver was reperfused for 1 h after cold preservation for 6 h. The perfusate levels of HMGB1, LDH, TNF-α, and IL-6 were significantly lower in the CD group pretreated with ART-123 (5 mg/kg) than in the CD group. Bile production was significantly higher in the CD group pretreated with ART-123 (5 mg/kg) than in the CD group. The sinusoidal spaces were significantly narrower in the CD group than in the other groups. We propose that ART-123 maintains sinusoidal microcirculation by reducing endothelial cell damage during warm ischemia-reperfusion injury.

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Recombinant human soluble thrombomodulin decreases the plasma high-mobility group box-1 protein levels, whereas improving the acute liver injury and survival rates in experimental endotoxemia

Cited by 94 publications

References 40 publications

Thrombomodulin alleviates murine GVHD in association with an increase in the proportion of regulatory T cells in the spleen

Thrombomodulin alleviates murine GVHD in association with an increase in the proportion of regulatory T cells in the spleen

HMGB1 Release by C5a Anaphylatoxin is an Effective Target for Sepsis Treatment

Soluble Thrombomodulin Ameliorates Ischemia-Reperfusion Injury of Liver Grafts by Modulating the Proinflammatory Role of High-Mobility Group Box 1

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