Expression of Inflammatory and Regenerative Genes in a Model of Liver Ischemia/Reperfusion and Partial Hepatectomy

Athanasopoulos, Panagiotis; Mastoraki, Aikaterini; Papalois, Αpostolos; Nastos, Constantinos; Kondi-Pafiti, Agathi; Kostopanagiotou, Georgia; Smyrniotis, Vassilios; Arkadopoulos, Nikolaos

doi:10.3109/08941939.2015.1060280

Cited by 10 publications

(12 citation statements)

References 45 publications

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“…Previous studies have shown that IR‐stressed livers can activate the acute inflammation response, which increases hepatocellular injury . A complex inflammatory program is engaged in liver IR injury, which is always accompanied with a large increase in cytokines.…”

Section: Resultsmentioning

confidence: 99%

Plasma membrane‐bound G protein–coupled bile acid receptor attenuates liver ischemia/reperfusion injury via the inhibition of toll‐like receptor 4 signaling in mice

et al. 2016

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The plasma membrane-bound G protein-coupled bile acid receptor (TGR5) displays varied levels of expression in different tissues. TGR5-induced liver protection has been demonstrated during several liver diseases, except during ischemia/reperfusion injury (IRI). Male adult wild-type and TGR5 knockout (KO) mice were subjected to liver partial warm ischemia/reperfusion. Hepatic injury was evaluated based on serum alanine aminotransferase and serum aspartate aminotransferase. Liver histological injury and inflammatory cell infiltration were evaluated in tissue sections using liver immunohistochemical analysis. We used quantitative realtime polymerase chain reaction to analyze the liver expression of inflammatory cytokines. The toll-like receptor 4 (TLR4) signaling pathway and its related apoptotic molecules were investigated after reperfusion. Moreover, the effect of TGR5 on inflammation was determined with TGR5 1/1 or TGR5 2/2 primary bone marrow-derived macrophages in vitro. TGR5 significantly attenuated liver damage after IRI. As demonstrated by in vivo experiments, TGR5 significantly reduced the up-regulation of the TLR4-nuclear factor kappa B (NF-jB) pathway and inhibited caspase 8 activation after IRI. Later experiments showed that TGR5 KO significantly increased the expression of TLR4-NF-jB signaling molecules and promoted hepatocellular apoptosis. In addition, in vitro experiments showed that overexpression of 6alpha-ethyl-23(S)-methylcholic acid (INT-777)-activated TGR5 directly downregulated tumor necrosis factor a (TNF-a) and interleukin (IL) 6 expression but up-regulated IL10 expression in hypoxia/reoxygenation-induced primary TGR5 1/1 macrophages. Moreover, the expression of TLR4-NF-jB signaling molecules was significantly inhibited by the activation of TGR5. Importantly, these results were completely reversed in primary TGR5 2/2 macrophages. This work is the first to provide evidence for a TGR5-inhibited inflammatory response in IRI through suppression of the TLR4-NFjB pathway, which may be critical in reducing related inflammatory molecules and modulating innate inflammation. The plasma membrane-bound G protein-coupled bile acid receptor (TGR5) displays varied levels of expression in different tissues. (1)(2)(3) Growing evidence has shown that TGR5 can regulate bile acid homeostasis, increase energy expenditure in brown adipose tissue, and contribute to glucose metabolism. (4)(5)(6) In addition, another novel function of TGR5 is its potent anti-inflammatory effect. In hepatic tissue, TGR5 expression is detected in macrophages, including Kupffer cells. (2) An in vivo study has demonstrated that activation of TGR5 decreases lipopolysaccharide (LPS)-induced inflammation in the liver (7) and inflammation in atherosclerotic plaques. (8) InAbbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMDM, bone marrow-derived macrophage; ELISA, enzyme-linked immunosorbent assay; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GPCR, G protein-coupled receptor; HPRT, hypoxanthine-guanine phos...

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Section: Resultsmentioning

confidence: 99%

Plasma membrane‐bound G protein–coupled bile acid receptor attenuates liver ischemia/reperfusion injury via the inhibition of toll‐like receptor 4 signaling in mice

et al. 2016

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“…A rat model of segmental (70%) hepatic ischemia/ reperfusion was established as previously described (Shen et al, 2002;Athanasopoulos et al, 2016). Rats were anesthetized with pentobarbital sodium (40 mg/kg) through intraperitoneal injection.…”

Section: Ischemia/reperfusion Injury Modelmentioning

confidence: 99%

Propofol protects against hepatic ischemia/reperfusion injury via miR‐133a‐5p regulating the expression of MAPK6

Zhao

Meng

et al. 2017

Cell Biology International

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Propofol has been found to play an important role in hepatic ischemia/reperfusion (I/R) injury with the antioxidant effects. However, the molecular mechanism of propofol in hepatic I/R injury has not been fully understood. Male Sprague-Dawley rats were randomly assigned into Sham group, hepatic I/R group, and propofol treatment group. I/R injury was attained by ischemia for 1 h and reperfusion for 2 h. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity were detected. QSG-7701 cells were cultured in hypoxia condition for 15 h and then in reoxygenation condition for 6 h to imitate hypoxia/reoxygenation (H/R) injury in vitro. Real-time RT-PCR and Western blot were performed to determine the expression of miR-133a-5p and MAPK6. Luciferase reporter assay was used to determine the regulation of miR-133a-5p on MAPK6. Propofol significantly reduced the activities of serum AST and ALT induced by hepatic I/R injury in rats. Propofol increased the level of miR-133a-5p and decreased the expression of MAPK6 in vivo and in vitro. Luciferase reporter assay showed that MAPK6 was a target of miR-133a-5p. Knockdown of miR-133a-5p abrogated the effect of propofol on the upregulation of MAPK6 induced by H/R. MAPK6 overexpression promoted the cell apoptosis induced by H/R which could be attenuated by propofol. Finally, we found that miR-133a-5p reversed the protective effect of propofol in rats with hepatic I/R injury. Propofol showed protective roles for hepatic I/R injury in vivo and H/R injury in vitro, which involved with miR-133a-5p regulating the expression of MAPK6.

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“…Despite the unanimity of data in rats and mice that both pre-and postconditioning will have a beneficial effect to the liver I/R injury via modifications of the NO pathway (24)(25)(26)(27), there are conflicting data in the literature in regard to iNOS and eNOS expression in pigs during the early hours of reperfusion. These conflicting data consist to either failure to identify significant differences in the expression of iNOS during the early hours of reperfusion following hepatectomy in pigs (28) or even reports of minimal protection of the ischemic preconditioning all together (29). A significant experimental difference between studies undertaken in pigs and rodents (e.g., mice and rats) is the need of venous decompression of the intrabdominal viscera in pigs during the occlusion of the porta hepatis; this can be achieved either by a portocaval shunt (28) or veno-venous bypass (29,30).…”

Section: Discussionmentioning

confidence: 99%

“…These conflicting data consist to either failure to identify significant differences in the expression of iNOS during the early hours of reperfusion following hepatectomy in pigs (28) or even reports of minimal protection of the ischemic preconditioning all together (29). A significant experimental difference between studies undertaken in pigs and rodents (e.g., mice and rats) is the need of venous decompression of the intrabdominal viscera in pigs during the occlusion of the porta hepatis; this can be achieved either by a portocaval shunt (28) or veno-venous bypass (29,30). Pigs are unable to tolerate continuous prolonged occlusion of the portal vein as they develop quickly significant intestinal congestion with subsequent severe haemodynamic instability (30).…”

Section: Discussionmentioning

confidence: 99%

Ischemic postconditioning decreases iNOS gene expression but ischemic preconditioning ameliorates histological injury in a swine model of extended liver resection

Kontis

Pantiora

Melemeni

et al. 2019

Transl. Gastroenterol. Hepatol

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Background: Both pre-and postconditioning have been shown to protect the liver parenchyma from ischemia/ reperfusion (I/R) injury during hepatectomy by altering the production of NO. However, to date there is no study to compare their effect on the inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) gene expression, who are the main modulators in the pathway of NO during the acute phase of I/R injury. Methods: We designed a prospective experimental cohort comprising of three groups (sham group-SG, preconditioning-PrG and postconditioning group-PoG) and consisting of 10 animals per group. All animals underwent extended hepatectomy (70%) under prolonged warm ischemia either after preconditioning or followed by postconditioning or without any protective maneuver (SG). Following reperfusion blood samples and liver biopsies were obtained at the start of reperfusion (0 hours), at 6 and 12 hours post reperfusion. iNOS and eNOS gene expression was assessed on liver tissue by polymerase chain reaction (PCR); in addition, the extent of hepatocellular injury was histologically assessed. Results: At the beginning of reperfusion iNOS expression was significantly reduced in the PoG in comparison to the SG (Kruskal-Wallis test, P=0.012; Mann-Whitney U test, P<0.0005 Bonferroni correction) and continued to remain at low levels until 6 hours post reperfusion (Kruskal-Wallis test, P=0.01; Mann-Whitney U test, P<0.0005-Bonferroni correction) This difference was eliminated by 12 hours. No significant differences were found in the expression of eNOS between groups and within time measurements. Aspartate aminotransferase (AST) and Alkaline phosphatase (ALP) were found increased at the start of reperfusion; their levels continued to increase by 6 hours in all groups, however only in the PoG the increase attended statistical significance at 12 hours after reperfusion. ALT levels presented only minor alterations during the course of reperfusion. The PrG was found to have more intense hepatocellular injury at the start of reperfusion than the PoG however, that appeared to gradually settle by 12 hours in contrast to PoG where the hepatocellular injury continued to deteriorate. Conclusions: PoG appeared to decrease iNOS overexpression more effectively than PrG in comparison to animals who have undergone no protective maneuver (SG). However, PrG was more effective than PoG in ameliorating the hepatocellular injury observed at 12 hours after the ischemic insult.

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Expression of Inflammatory and Regenerative Genes in a Model of Liver Ischemia/Reperfusion and Partial Hepatectomy

Abstract: In the present survey, a new I/R swine model was proposed and specific parameters were analyzed, revealing differences between the study groups.

Cited by 10 publications

References 45 publications

Plasma membrane‐bound G protein–coupled bile acid receptor attenuates liver ischemia/reperfusion injury via the inhibition of toll‐like receptor 4 signaling in mice

Plasma membrane‐bound G protein–coupled bile acid receptor attenuates liver ischemia/reperfusion injury via the inhibition of toll‐like receptor 4 signaling in mice

Propofol protects against hepatic ischemia/reperfusion injury via miR‐133a‐5p regulating the expression of MAPK6

Ischemic postconditioning decreases iNOS gene expression but ischemic preconditioning ameliorates histological injury in a swine model of extended liver resection

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