Chymase Inhibition Attenuates Lipopolysaccharide/ &lt;smlcap&gt;D&lt;/smlcap&gt;-Galactosamine-Induced Acute Liver Failure in Hamsters

Imai, Yoshiro; Jin, Denan; Koyama, Koji; Tashiro, Kunio; Li, Zhong‐Lian; Otsuki, Yoshinori; Okamura, Haruki; Hayashi, Michihiro; Uchiyama, Kazuhisa

doi:10.1159/000357684

Cited by 11 publications

(12 citation statements)

References 38 publications

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“…These phenomena have also been observed in the LPS/GalN-induced ALF model in MMP-9-deficient mice [ 53 ]. In a hamster ALF model, hepatic chymase activity was significantly increased after the administration of lipopolysaccharide and D-galactosamine [ 54 ]. Significant increases in hepatic MMP-9 activity and TNF-α concentration were also observed, but these increases were attenuated by treatment with a chymase inhibitor, TY-51469 [ 54 ].…”

Section: Experimental Evidences On Chymase Inhibitors In Nafld/nasmentioning

confidence: 99%

“…In a hamster ALF model, hepatic chymase activity was significantly increased after the administration of lipopolysaccharide and D-galactosamine [ 54 ]. Significant increases in hepatic MMP-9 activity and TNF-α concentration were also observed, but these increases were attenuated by treatment with a chymase inhibitor, TY-51469 [ 54 ]. Significant increases in plasma aspartate aminotransferase and alanine aminotransferase activities were significantly attenuated by chymase inhibition [ 54 ].…”

Section: Experimental Evidences On Chymase Inhibitors In Nafld/nasmentioning

confidence: 99%

“…Significant increases in hepatic MMP-9 activity and TNF-α concentration were also observed, but these increases were attenuated by treatment with a chymase inhibitor, TY-51469 [ 54 ]. Significant increases in plasma aspartate aminotransferase and alanine aminotransferase activities were significantly attenuated by chymase inhibition [ 54 ]. Chymase inhibition may provide a therapeutic strategy for attenuating the symptoms of hepatic inflammation.…”

Section: Experimental Evidences On Chymase Inhibitors In Nafld/nasmentioning

confidence: 99%

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Chymase as a Possible Therapeutic Target for Amelioration of Non-Alcoholic Steatohepatitis

Jin

2020

IJMS

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The development and progression of non-alcoholic steatohepatitis (NASH) are linked to oxidative stress, inflammation, and fibrosis of the liver. Chymase, a chymotrypsin-like enzyme produced in mast cells, has various enzymatic actions. These actions include activation of angiotensin II, matrix metalloproteinase (MMP)-9, and transforming growth factor (TGF)-β, which are associated with oxidative stress, inflammation, and fibrosis, respectively. Augmentation of chymase activity in the liver has been reported in various NASH models. Generation of hepatic angiotensin II and related oxidative stress is upregulated in NASH but attenuated by treatment with a chymase inhibitor. Additionally, increases in MMP-9 and accumulation of inflammatory cells are observed in NASH but are decreased by chymase inhibitor administration. TGF-β and collagen I upregulation in NASH is also attenuated by chymase inhibition. These results in experimental NASH models demonstrate that a chymase inhibitor can effectively ameliorate NASH via the reduction of oxidative stress, inflammation, and fibrosis. Thus, chymase may be a therapeutic target for amelioration of NASH.

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Section: Experimental Evidences On Chymase Inhibitors In Nafld/nasmentioning

confidence: 99%

Section: Experimental Evidences On Chymase Inhibitors In Nafld/nasmentioning

confidence: 99%

Section: Experimental Evidences On Chymase Inhibitors In Nafld/nasmentioning

confidence: 99%

See 1 more Smart Citation

Chymase as a Possible Therapeutic Target for Amelioration of Non-Alcoholic Steatohepatitis

Jin

2020

IJMS

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“…A significant increase of TNF-α level in the liver has been previously observed 1 h after LPS/GalN injection 34,35 . Furthermore, TNF-α levels in the liver showed an early peak at 1 h and then decreased 7 .…”

Section: Discussionmentioning

confidence: 67%

“…Escherichia coli, O111: B4) 4 µg/kg and D-galactosamine (GalN) 600 mg/kg intraperitoneally 16,17 . LPS and GalN were purchased from Sigma (St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

Enhanced effect of recombinant human soluble thrombomodulin by ultrasound irradiation in acute liver failure

Hoshino

Nakamura

Nakano

et al. 2020

Sci Rep

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The administration of recombinant human soluble thrombomodulin (rhsTM) significantly improves liver inflammation and increases the survival rate of patients with acute liver failure (ALF). However, rhsTM is dose-dependently correlated to the risk of bleeding. Recently, ultrasound (US) was found to enhance the effect of various drugs. Thus, the present study aimed to determine the enhancement effect of US irradiation on rhsTM in ALF. rhsTM (1 mg/kg) and US (1 MHz, 0.3 W/cm 2 ) were irradiated to the liver of lipopolysaccharide/D-galactosamine-induced ALF mice model. The post-treatment aspartate aminotransferase, alanine aminotransferase, and high-mobility group box 1 levels were significantly lower in the rhsTM + US group than in the rhsTM alone group. Histopathological findings revealed significantly reduced liver injury and apoptosis in the rhsTM + US group. By contrast, US irradiation had no effect on rhsTM and TNF-α concentration in the liver tissue. In conclusion, US irradiation enhanced the effect of rhsTM in the ALF mice model. However, further studies must be conducted to determine the exact mechanism of such enhancement effect.

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Recombinant human soluble thrombomodulin improved lipopolysaccharide/d-galactosamine-induced acute liver failure in mice

Osumi

Jin

Imai

et al. 2015

Journal of Pharmacological Sciences

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The effect of recombinant human soluble thrombomodulin (TM-α) on acute liver failure (ALF) is unclear, and we elucidated the effect of TM-α in lipopolysaccharide (LPS)/d-galactosamine (GalN)-induced ALF in mice. Placebo (saline) or TM-α (100 mg/kg) was administered 1 h after LPS/GalN administration. Survival rates were evaluated for 24 h after LPS/GalN administration. Plasma and liver samples were evaluated 1, 3, and 7 h after LPS/GalN administration. Survival rates were significantly higher in the TM-α-treated group than in the placebo group. A significant augmentation of plasma high-mobility group box 1 protein (HMGB1) was observed 7 h after LPS/GalN administration. In the TM-α-treated mice, plasma HMGB1 was significantly lower than in the placebo group. A significant augmentation of hepatic nuclear factor (NF)-κB p65 was observed in the placebo-treated group, whereas a significant reduction, relative to placebo, was observed in the TM-α-treated group. Hepatic expression of tumor necrosis factor (TNF)-α and myeloperoxidase were significantly increased in the placebo group, and were similarly significantly attenuated in the TM-α-treated group. TM-α treatment also produced a significant attenuation of liver neutrophil accumulation after LPS/GalN administration. Thus, TM-α may become a useful treatment strategy for reducing the symptoms of ALF via the attenuation of LPS/GalN-induced HMGB1 levels.

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Chymase Inhibition Attenuates Lipopolysaccharide/ <smlcap>D</smlcap>-Galactosamine-Induced Acute Liver Failure in Hamsters

Cited by 11 publications

References 38 publications

Chymase as a Possible Therapeutic Target for Amelioration of Non-Alcoholic Steatohepatitis

Chymase as a Possible Therapeutic Target for Amelioration of Non-Alcoholic Steatohepatitis

Enhanced effect of recombinant human soluble thrombomodulin by ultrasound irradiation in acute liver failure

Recombinant human soluble thrombomodulin improved lipopolysaccharide/d-galactosamine-induced acute liver failure in mice

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