N-Acetylcysteine Reduced Ischemia and Reperfusion Damage Associated with Steatohepatitis in Mice

N-acetylcysteine (NAC) is a pharmacological alternative with great potential for reducing the deleterious effects of surgical procedures on patients with steatohepatitis. We evaluated the effect of NAC on hepatic ischemia/reperfusion (I/R) injury in C57BL/6J mice, 8 weeks-old, weighing 25–30 g, with steatohepatitis induced by a methionine- and choline-deficient (MCD) diet. Groups: MCD group (steatohepatitis), MCD-I/R group (steatohepatitis plus 30 min of 70% liver ischemia and 24 h of reperfusion), MCD-I/R+NAC group (same as MCD-I/R group plus 150 mg/kg NAC 15 min before ischemia), and control group (normal AIN-93M diet). Liver enzymes and histopathology; nitrite and TBARS (thiobarbituric acid reactive substances) levels; pro-inflammatory cytokines; antioxidants enzymes; Nrf2 (nuclear factor erythroid-2-related factor 2) expression; and apoptosis were evaluated. In the group treated with NAC, reductions in inflammatory infiltration; AST (aspartate aminotransferase), nitrite, and TBARS levels; GPx (gutathione peroxidase) activity; cytokines synthesis; and number of apoptotic cells were observed while the GR (glutathione reductase) activity was increased. No differences were observed in Nfr2 expression or in SOD (superoxide dismutase), CAT (catalase), and GST (glutathione S-transferase) activities. Thus, it may be concluded that NAC exerts beneficial effects on mice livers with steatohepatitis submitted to I/R by reducing oxidative stress, inflammatory response, and cell death.

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Preconditioning with L-alanyl-glutamine reduces hepatic ischemia-reperfusion injury in rats

Acta Cirurgica Brasileira ◽

10.1590/s0102-86502011000700003 ◽

2011 ◽

Vol 26 (suppl 1) ◽

pp. 8-13 ◽

Cited By ~ 7

Author(s):

Raimundo José Cunha Araújo Júnior ◽

Raimundo Gerônimo da Silva Júnior ◽

Marcelo Pinho Pessoa de Vasconcelos ◽

Sérgio Botelho Guimarães ◽

Paulo Roberto Leitão de Vasconcelos ◽

...

Keyword(s):

Caspase 3 ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Control Group ◽

Average Weight ◽

Sham Operation ◽

Hepatic Ischemia ◽

Portal Triad ◽

Hepatic Ischemia Reperfusion ◽

Control Sham

PURPOSE: To evaluate the effects of pre-conditioning with L-alanyl- glutamine (L-Ala-Gln) in rats subjected to total hepatic ischemia. METHODS: Thirty Wistar rats, average weight 300g, were randomly assigned to 3 groups (n=10): G-1 - Saline, G-2- L-Ala-Gln, G-3-control (Sham). G-1 and G-3 groups were treated with saline 2.0 ml or L-Ala-Gln (0.75mg/Kg) intraperitoneally (ip) respectively, 2 hours before laparotomy. Anesthetized rats were subjected to laparotomy and total hepatic ischemia (30 minutes) induced by by clamping of portal triad. Control group underwent peritoneal puncture, two hours before the sham operation (laparotomy only). At the end of ischemia (G1 and G2), the liver was reperfused for 60 minutes. Following reperfusion blood samples were collected for evaluation of alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels. Liver (medium lobe) was removed for immunohistochemistry study with antibody for Caspase-3. RESULTS: It was found a significant decrease (p<0.05) of ALT levels (270.6 +40.8 vs 83.3 +5.5 - p <0.05), LDH (2079.0 +262.4 vs. 206.6 +16.2 - p <0.05) and Caspase-3 expression (6.72 +1.35 vs. 2.19 +1.14, p <0.05) in rats subjected to I / R, comparing the group treated with L-Ala -Gln with G-2. Also, the ALT level was significantly lower (P<0.05) in G-1 and G-2 groups than in G-3 (control group). CONCLUSION: L-Ala-Gln preconditioning in rats submitted to hepatic I/R significantly reduces ALT, LDH and Caspase-3 expression, suggesting hepatic protection.

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Protective Effects of Human Liver Stem Cell-Derived Extracellular Vesicles in a Mouse Model of Hepatic Ischemia-Reperfusion Injury

Stem Cell Reviews and Reports ◽

10.1007/s12015-020-10078-7 ◽

2020 ◽

Author(s):

Alberto Calleri ◽

Dorotea Roggio ◽

Victor Navarro-Tableros ◽

Nicola De Stefano ◽

Chiara Pasquino ◽

...

Keyword(s):

Stem Cell ◽

Reperfusion Injury ◽

Extracellular Vesicles ◽

Human Liver ◽

Imaging System ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Control Group ◽

Hepatic Ischemia ◽

Hepatic Ischemia Reperfusion

AbstractHepatic ischemia-reperfusion injury (IRI) is observed in liver transplantation and hepato-biliary surgery and is associated with an inflammatory response. Human liver stem cell-derived extracellular vesicles (HLSC-EV) have been demonstrated to reduce liver damage in different experimental settings by accelerating regeneration and by modulating inflammation. The aim of the present study was to investigate whether HLSC-EV may protect liver from IRI in a mouse experimental model. Segmental IRI was obtained by selective clamping of intrahepatic pedicles for 90 min followed by 6 h of reperfusion. HLSC-EV were administered intravenously at the end of the ischemic period and histopathological and biochemical alterations were evaluated in comparison with controls injected with vehicle alone. Intra liver localization of labeled HLSC-EV was assessed by in in vivo Imaging System (IVIS) and the internalization into hepatocytes was confirmed by fluorescence analyses. As compared to the control group, administration of 3 × 109 particles (EV1 group) significantly reduced alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) release, necrosis extension and cytokines expression (TNF-α, CCL-2 and CXCL-10). However, the administration of an increased dose of HLSC-EV (7.5 × 109 particles, EV2 group) showed no significant improvement in respect to controls at enzyme and histology levels, despite a significantly lower cytokine expression. In conclusion, this study demonstrated that 3 × 109 HLSC-EV were able to modulate hepatic IRI by preserving tissue integrity and by reducing transaminases release and inflammatory cytokines expression. By contrast, a higher dose was ineffective suggesting a restricted window of biological activity.

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Intraportal versus Systemic Pentoxifylline Infusion after Normothermic Liver Ischemia: Effects on Regional Blood Flow Redistribution and Hepatic Ischemia-Reperfusion Injury

HPB Surgery ◽

10.1155/2013/689835 ◽

2013 ◽

Vol 2013 ◽

pp. 1-6 ◽

Cited By ~ 2

Author(s):

Edson A. Ribeiro ◽

Luiz F. Poli-de-Figueiredo ◽

Rodrigo Vincenzi ◽

Flavio H. F. Galvao ◽

Nelson Margarido ◽

...

Keyword(s):

Blood Flow ◽

Ischemia Reperfusion Injury ◽

Regional Blood Flow ◽

Ischemia Reperfusion ◽

Microcirculatory Blood Flow ◽

Hepatic Ischemia ◽

Portal Triad ◽

Beneficial Effects ◽

Hepatic Ischemia Reperfusion ◽

Blood Flow Redistribution

Pentoxifylline (PTX) has been shown to have beneficial effects on microcirculatory blood flow. In this study we evaluate the potential hemodynamic and metabolic benefits of PTX during hepatic ischemia. We also test the hypothesis that portal PTX infusion can minimize the I/R injury when compared to systemic infusion. Methods. Twenty-four dogs ( kg) were subjected to portal triad occlusion (PTO) for 45 min. The animals were assigned to 3 groups: CT (control, PTO, ), PTX-syst (PTO + 25 mg/Kg of PTX IV, ), and PTX-pv (PTO + 25 mg/Kg of PTX in the portal vein, ). Animals were followed for 120 min. Systemic hemodynamics, gastrointestinal tract perfusion, oxygen-derived variables, and liver enzymes were evaluated throughout the experiment. Results. Animals treated with PTX presented significantly higher CO in the first hour after reperfusion, when compared to the CT (~3.7 vs. 2.1 L/min, ). Alanine aminotransferase (ALT) was similar in the PTX groups two hours after reperfusion but significantly higher in the CT (227 vs. ~64 U/L, ). Conclusion. PTX infusion was associated with hemodynamic benefits and was able to minimize liver injury during normothermic hepatic I/R. However, local PTX infusion was not associated with any significant advantage over systemic route.

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Mo1837 Beneficial Effects of Diazoxide on Hepatic Ischemia/Reperfusion Injury

Gastroenterology ◽

10.1016/s0016-5085(13)64147-5 ◽

2013 ◽

Vol 144 (5) ◽

pp. S-1112

Author(s):

Mateus A. Nogueira ◽

Ana Maria M. Coelho ◽

Sandra N. Sampietre ◽

Nilza A. Molan ◽

Rosely A. Patzina ◽

...

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Hepatic Ischemia ◽

Beneficial Effects ◽

Hepatic Ischemia Reperfusion

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Effect of heat shock preconditioning on NF-κB/I-κB pathway during I/R injury of the rat liver

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00466.2001 ◽

2002 ◽

Vol 282 (6) ◽

pp. G962-G971 ◽

Cited By ~ 38

Author(s):

Hiroshi Uchinami ◽

Yuzo Yamamoto ◽

Makoto Kume ◽

Kei Yonezawa ◽

Yasuhide Ishikawa ◽

...

Keyword(s):

Heat Shock ◽

Messenger Rna ◽

Ischemia Reperfusion ◽

Nuclear Factor Κb ◽

Control Group ◽

Nuclear Factor ◽

Fatal Complication ◽

Hepatic Ischemia ◽

Proinflammatory Mediators ◽

Hepatic Ischemia Reperfusion

Hepatic ischemia-reperfusion (I/R) injury continues to be a fatal complication after liver surgery. Heat shock (HS) preconditioning is an effective strategy for protecting the liver from I/R injury, but its exact mechanism is still unclear. Because the activation of nuclear factor-κB (NF-κB) is an important event in the hepatic I/R-induced inflammatory response, the effect of HS preconditioning on the pathway for NF-κB activation was investigated. In the control group, NF-κB was activated 60 min after reperfusion, but this activation was suppressed in the HS group. Messenger RNA expressions of proinflammatory mediators during reperfusion were also reduced with HS preconditioning. Concomitant with NF-κB activation, NF-κB inhibitor I-κB proteins were degraded in the control group, but this degradation was suppressed in the HS group. This study shows that HS preconditioning protected the liver from I/R injury by suppressing the activation of NF-κB and the subsequent expression of proinflammatory mediators through the stabilization of I-κB proteins.

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Fate and Effect of Intravenously Infused Mesenchymal Stem Cells in a Mouse Model of Hepatic Ischemia Reperfusion Injury and Resection

Stem Cells International ◽

10.1155/2016/5761487 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 14

Author(s):

T. C. Saat ◽

S. van den Engel ◽

W. Bijman-Lachger ◽

S. S. Korevaar ◽

M. J. Hoogduijn ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Weight Ratio ◽

Hepatocellular Injury ◽

Hepatic Ischemia ◽

Beneficial Effects ◽

Hepatic Ischemia Reperfusion

Liver ischemia reperfusion injury (IRI) is inevitable during transplantation and resection and is characterized by hepatocellular injury. Therapeutic strategies to reduce IRI and accelerate regeneration could offer major benefits. Mesenchymal stem cells (MSC) are reported to have anti-inflammatory and regeneration promoting properties. We investigated the effect of MSC in a model of combined IRI and partial resection in the mouse. Hepatic IRI was induced by occlusion of 70% of the blood flow during 60 minutes, followed by 30% hepatectomy. 2 × 105MSC or PBS were infused 2 hours before or 1 hour after IRI. Six, 48, and 120 hours postoperatively mice were sacrificed. Liver damage was evaluated by liver enzymes, histology, and inflammatory markers. Regeneration was determined by liver/body weight ratio, proliferating hepatocytes, and TGF-βlevels. Fate of MSC was visualized with 3D cryoimaging. Infusion of 2 × 105MSC 2 hours before or 1 hour after IRI and resection showed no beneficial effects. Tracking revealed that MSC were trapped in the lungs and did not migrate to the site of injury and many cells had already disappeared 2 hours after infusion. Based on these findings we conclude that intravenously infused MSC disappear rapidly and were unable to induce beneficial effects in a clinically relevant model of IRI and resection.

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Hepatic Ischemia-Reperfusion Induces Renal Heme Oxygenase-1 via NF-E2-Related Factor 2 in Rats and Mice

Molecular Pharmacology ◽

10.1124/mol.106.029033 ◽

2006 ◽

Vol 71 (3) ◽

pp. 817-825 ◽

Cited By ~ 47

Author(s):

Yuji Tanaka ◽

Jonathan M. Maher ◽

Chuan Chen ◽

Curtis D. Klaassen

Keyword(s):

Heme Oxygenase ◽

Ischemia Reperfusion ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Hepatic Ischemia ◽

Hepatic Ischemia Reperfusion ◽

Rats And Mice

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Cell-specific overactivation of nuclear erythroid 2 p45-related factor 2-mediated gene expression in myeloid cells decreases hepatic ischemia/reperfusion injury

Liver Transplantation ◽

10.1002/lt.24473 ◽

2016 ◽

Vol 22 (8) ◽

pp. 1115-1128 ◽

Cited By ~ 8

Author(s):

Lung-Yi Lee ◽

Calvin Harberg ◽

Kristina A. Matkowskyj ◽

Shelly Cook ◽

Drew Roenneburg ◽

...

Keyword(s):

Gene Expression ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Myeloid Cells ◽

Related Factor ◽

Hepatic Ischemia ◽

Hepatic Ischemia Reperfusion

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Effect of hydration with Ringer's solution submitted to magnetic field in an experimental model of hepatic ischemia-reperfusion injury in rats

JOURNAL OF SURGICAL AND CLINICAL RESEARCH ◽

10.20398/jscr.v9i2.15916 ◽

2018 ◽

Vol 9 (2) ◽

pp. 44-53

Author(s):

Juliana Mendonça Freire ◽

Jeovana Pinheiro Fernandes de Souza ◽

Italo Medeiros Azevedo ◽

Fabio Medeiros de Azevedo ◽

Artur Da Silva Carriço ◽

...

Keyword(s):

Magnetic Field ◽

Experimental Model ◽

Ischemia Reperfusion ◽

Test Group ◽

Control Group ◽

Hepatic Ischemia ◽

Left Liver ◽

Ringer’S Solution ◽

Significant Difference ◽

Hepatic Ischemia Reperfusion

Purpose: To evaluate the effect of hydration with Ringer's solution submitted to magnetic field in experimental model of hepatic ischemia/reperfusion in rats. Methods: Wistar rats weighing 389.58±46.88g were randomly allocated into 2 groups: control group (n = 6) - Hepatic ischemia/reperfusion and hydration with Ringer's solution; and test group (n = 6) - Hepatic ischemia/reperfusion and hydration with Ringer submitted to magnetic field of 20 mT during 2 hours. After anesthesia with ketamine 70 mg/kg and xylazine 7 mg/kg i.p., the animals were weighed and operated by aseptic technique. The ischemia of the median and left liver lobes was induced for 30 minutes using a vascular clip. Then, i.v. hydration with 3 ml of Ringer in the control group, and 3 ml of magnetized Ringer’s solution in the test group. After 24 hours, blood sample and fragment of the left liver lobe were collected for the determination of AST, ALT, ALP and albumin levels, and histopathological examination. Results: There was no significant difference in comparison of the rats weight loss, biochemical measurements and histopathological scores between the groups (p>0.05). Conclusion: The hydration with Ringer's solution submitted to magnetic field after hepatic ischemia/reperfusion in rats did not alter liver function tests neither histopathological scores, comparing with the control group.

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