WNT Agonist Attenuates Liver Injury and Improves Survival After Hepatic Ischemia/Reperfusion

Kuncewitch, Michael; Yang, Weng Lang; Molmenti, Ernesto P.; Nicastro, Jeffrey; Coppa, Gene F.; Wang, Haichao

doi:10.1097/shk.0b013e3182764fe8

Cited by 43 publications

(49 citation statements)

References 34 publications

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“…Hepatic ischemia-reperfusion (I/R) injury can occur in a variety of clinical settings that include but not limited to trauma, liver resections, orthotopic transplantation, or prolonged shock states (1, 2). In the setting of liver transplantation, hepatic I/R contributes up to 10% of early organ failure as well as creating a higher incidence of both acute and chronic rejection (3).…”

Section: Introductionmentioning

confidence: 99%

Blocking Cold-Inducible RNA-Binding Protein Protects Liver From Ischemia-Reperfusion Injury

Godwin

Yang

Sharma

et al. 2015

Shock

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Cold inducible RNA-binding protein (CIRP) is a nuclear protein which has been recently identified as a novel inflammatory mediator in hemorrhagic shock and sepsis. We hypothesized that CIRP acts as a potent inflammatory mediator in hepatic ischemia-reperfusion (I/R), and thus blocking CIRP protects against I/R-induced liver injury. Male C57BL/6 mice were subjected to 70% hepatic ischemia by microvascular clamping of the hilum of the left and median liver lobes for 60 min, followed by reperfusion. Anti-CIRP antibody (1 mg/kg body weight) or vehicle (normal saline) in 0.2 mL was injected via the internal jugular vein at the beginning of the reperfusion. Blood and liver tissues were collected 24 h after I/R for various measurements and a 10-day survival study was performed. CIRP released into the circulation was significantly increased 24 h after hepatic I/R. Anti-CIRP antibody treatment markedly reduced hepatocellular damage markers and significantly improved the liver microarchitecture. Anti-CIRP also reduced the systemic and local inflammation demonstrated by attenuation in both serum and hepatic levels of interleukin 6. The expression of neutrophil-attracting chemokine as well as liver neutrophil infiltration was reduced by anti-CIRP treatment. Anti-CIRP also dramatically decreased the amount of apoptosis and nitrosative stress, evidenced by decrease in TUNEL staining and inducible nitric oxide synthase and cyclooxygenase-2 levels, respectively. Finally, the 10-day survival rate was increased from 37.5% in the vehicle group to 75% in the anti-CIRP treatment group. Thus, targeting CIRP offers potential therapeutic implications in the treatment of hepatic I/R injury.

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Section: Introductionmentioning

confidence: 99%

Blocking Cold-Inducible RNA-Binding Protein Protects Liver From Ischemia-Reperfusion Injury

Godwin

Yang

Sharma

et al. 2015

Shock

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“…Both sets of injections were administered once a day for 11 days. Rats in the HIR and the HIR þ NaHS group underwent 70% hepatic I/R according to a previously described protocol on the fourth day; 20 the rats were subjected to midline laparotomy after they were anesthetized with pentobarbital (50 mg/kg, intraperitoneally, i.p. ), and then a microaneurysm clamp was used to occlude the portal vein and hepatic artery to induce ischemia of the hepatic left lateral and median lobes, then liver was reperfused by removing the clamp after 60 min.…”

Section: Experimental Design and Hepatic I/r Modelmentioning

confidence: 99%

Hydrogen sulfide protects against cognitive impairment induced by hepatic ischemia and reperfusion via attenuating neuroinflammation

Wang

et al. 2016

Exp Biol Med (Maywood)

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Previously, hepatic ischemia followed by reperfusion (hepatic I/R) has been found to cause cognitive impairment. Hydrogen sulfide (H 2 S) attenuates hepatectomy induced cognitive deficits and also protects against cognitive dysfunction induced by neurodegenerative diseases. In this study, we aim to determine whether sodium hydrosulfide (NaHS), a H 2 S donor, could alleviate hepatic I/R-induced cognitive impairment and the underlying mechanisms. Rats were injected intraperitoneally with NaHS (5 mg/kg/d) for 11 days. A segmental hepatic I/R model was established on the fourth day. Cognitive function, proinflammatory cytokines levels, and hippocampal ionized calcium-binding adaptor molecule 1 (Iba1) expression was analyzed. We found hepatic I/R increased proinflammatory cytokines levels in serum and hippocampus, up-regulated Iba1 expression, leading to cognitive impairment in rats. However, treatment with NaHS alleviated hepatic I/R induced these neuroinflammatory changes and effectively improved cognitive function. Thus, NaHS appears to protect against cognitive impairment in rats undergoing hepatic I/R by attenuating neuroinflammation in the hippocampus.

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“…DKK-1 is known to be a secreted protein that functions as a negative regulator of Wnt signaling and plays a crucial role in inducing various tumor cells apoptosis. A previous study showed that the Wnt agonist protects against hepatic I/R injury through its known proliferative and anti-apoptotic properties (23).…”

Section: Discussionmentioning

confidence: 99%

Minocycline protects against hepatic ischemia/reperfusion injury in a rat model

et al. 2014

Biomedical Reports

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Hepatic ischemia/reperfusion (I/R) injury is a common clinical problem. The present study was conducted to investigate the protective effect and mechanism of minocycline (Mino), a tetracycline with anti-inflammatory and antioxidant properties, on I/R injury of liver in rats. In total, 54 male Sprague-Dawley rats were randomly divided into 3 groups with 18 rats in each: Sham-operated (control group), I/R model (I/R group) and Mino preconditioning groups (Mino group). The rats of the Mino group were administered Mino (45 mg/kg) by gastric irrigation at 36 h before surgery and were subsequently administered with 22.5 mg/kg every 12 h for the 36 h before surgery. The rats were sacrificed at 2, 6 and 24 h after reperfusion, and the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were measured. Hematoxylin/eosin staining of liver tissues was performed to detect the rat liver histological changes and the grade of liver I/R injury (Suzuki's criteria); the levels of malondialdehyde (MDA) and myeloperoxidase (MPO) were determined by spectrophotometry; hepatic tumor necrosis factor-α (-α) and interleukin-1β (β) mRNA were measured by quantitative polymerase chain reaction; the Dickkopf-1 (DKK-1) and β-catenin gene products of the liver were detected by western blot analysis. Mino treatment significantly ameliorated the I/R injury of the liver, as shown by decreased Suzuki scores and liver function (ALT, AST and LDH). After 2, 6 and 24 h reperfusion, compared to the I/R group the MDA and MPO levels of the Mino group decreased in the liver tissues and the levels of hepatic -α and-1β mRNA were decreased too. The protein expression of hepatic DKK-1 decreased, whereas β-catenin increased, which indicates that the Wnt/β-catenin pathway has been activated. In conclusion, Mino protects the liver from I/R injury mainly through reducing oxidative stress and inhibiting the release of pro-inflammatory cytokines by activating the Wnt/β-catenin signaling pathway in the liver.

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WNT Agonist Attenuates Liver Injury and Improves Survival After Hepatic Ischemia/Reperfusion

Cited by 43 publications

References 34 publications

Blocking Cold-Inducible RNA-Binding Protein Protects Liver From Ischemia-Reperfusion Injury

Blocking Cold-Inducible RNA-Binding Protein Protects Liver From Ischemia-Reperfusion Injury

Hydrogen sulfide protects against cognitive impairment induced by hepatic ischemia and reperfusion via attenuating neuroinflammation

Minocycline protects against hepatic ischemia/reperfusion injury in a rat model

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