Modulation of Prostanoids Profile and Counter-Regulation of SDF-1α/CXCR4 and VIP/VPAC2 Expression by Sitagliptin in Non-Diabetic Rat Model of Hepatic Ischemia-Reperfusion Injury

Molecular mechanisms underlying the beneficial effect of sitagliptin repurposed for hepatic ischemia-reperfusion injury (IRI) are poorly understood. We aimed to evaluate the impact of IRI and sitagliptin on the hepatic profile of eicosanoids (LC-MS/MS) and expression/concentration (RTqPCR/ELISA) of GLP-1/GLP-1R, SDF-1α/CXCR4 and VIP/VPAC1, VPAC2, and PAC1 in 36 rats. Animals were divided into four groups and subjected to ischemia (60 min) and reperfusion (24 h) with or without pretreatment with sitagliptin (5 mg/kg) (IR and SIR) or sham-operated with or without sitagliptin pretreatment (controls and sitagliptin). PGI2, PGE2, and 13,14-dihydro-PGE1 were significantly upregulated in IR but not SIR, while sitagliptin upregulated PGD2 and 15-deoxy-12,14-PGJ2. IR and sitagliptin non-significantly upregulated GLP-1 while Glp1r expression was borderline detectable. VIP concentration and Vpac2 expression were downregulated in IR but not SIR, while Vpac1 was significantly downregulated solely in SIR. IRI upregulated both CXCR4 expression and concentration, and sitagliptin pretreatment abrogated receptor overexpression and downregulated Sdf1. In conclusion, hepatic IRI is accompanied by an elevation in proinflammatory prostanoids and overexpression of CXCR4, combined with downregulation of VIP/VPAC2. Beneficial effects of sitagliptin during hepatic IRI might be mediated by drug-induced normalization of proinflammatory prostanoids and upregulation of PGD2 and by concomitant downregulation of SDF-1α/CXCR4 and reinstating VIP/VCAP2 signaling.

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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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Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00342.2002 ◽

2003 ◽

Vol 284 (1) ◽

pp. G15-G26 ◽

Cited By ~ 556

Author(s):

Hartmut Jaeschke

Keyword(s):

Reperfusion Injury ◽

Liver Surgery ◽

Molecular Mechanisms ◽

Ischemia Reperfusion Injury ◽

Current Knowledge ◽

Ischemia Reperfusion ◽

Oxidant Stress ◽

Cellular Mechanisms ◽

Hepatic Ischemia ◽

Hepatic Ischemia Reperfusion

Ischemia-reperfusion injury is, at least in part, responsible for the morbidity associated with liver surgery under total vascular exclusion or after liver transplantation. The pathophysiology of hepatic ischemia-reperfusion includes a number of mechanisms that contribute to various degrees in the overall injury. Some of the topics discussed in this review include cellular mechanisms of injury, formation of pro- and anti-inflammatory mediators, expression of adhesion molecules, and the role of oxidant stress during the inflammatory response. Furthermore, the roles of nitric oxide in preventing microcirculatory disturbances and as a substrate for peroxynitrite formation are reviewed. In addition, emerging mechanisms of protection by ischemic preconditioning are discussed. On the basis of current knowledge, preconditioning or pharmacological interventions that mimic these effects have the greatest potential to improve clinical outcome in liver surgery involving ischemic stress and reperfusion.

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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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Beneficial effects of gaseous hydrogen sulfide in hepatic ischemia/reperfusion injury

Transplant International ◽

10.1111/j.1432-2277.2012.01514.x ◽

2012 ◽

Vol 25 (8) ◽

pp. 897-908 ◽

Cited By ~ 23

Author(s):

Eelke M. Bos ◽

Pauline M. Snijder ◽

Henrike Jekel ◽

Michel Weij ◽

Jaklien C. Leemans ◽

...

Keyword(s):

Hydrogen Sulfide ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Gaseous Hydrogen ◽

Hepatic Ischemia ◽

Beneficial Effects ◽

Hepatic Ischemia Reperfusion

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The Impact of Dabigatran Treatment on Sinusoidal Protection Against Hepatic Ischemia/Reperfusion Injury in Mice

Liver Transplantation ◽

10.1002/lt.25929 ◽

2020 ◽

Author(s):

Daisuke Noguchi ◽

Naohisa Kuriyama ◽

Taemi Hibi ◽

Koki Maeda ◽

Toru Shinkai ◽

...

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Hepatic Ischemia ◽

Hepatic Ischemia Reperfusion ◽

The Impact

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The Impact of Hepatic Steatosis on Hepatic Ischemia-Reperfusion Injury in Experimental Studies: A Systematic Review

BioMed Research International ◽

10.1155/2013/192029 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 25

Author(s):

Michael J. J. Chu ◽

Anthony J. R. Hickey ◽

Anthony R. J. Phillips ◽

Adam S. J. R. Bartlett

Keyword(s):

Systematic Review ◽

Reperfusion Injury ◽

Hepatic Steatosis ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Experimental Studies ◽

Hepatic Ischemia ◽

Hepatic Ischemia Reperfusion ◽

The Impact ◽

Macrovesicular Steatosis

Background. The impact of hepatic steatosis on outcome following hepatic ischemia-reperfusion injury (IRI) remains controversial with conflicting clinical results. A number of experimental studies have been published examining the relationship between hepatic steatosis and IRI. This systematic review evaluates these experimental studies.Methods. An electronic search of the Medline and Embase databases (January 1946 to June 2012) was performed to identify studies that reported relevant outcomes in animal models of hepatic steatosis subjected to IRI.Results. A total of 1314 articles were identified, of which 33 met the predefined criteria and were included in the study. There was large variation in the type of animal model, duration, and type of IRI and reporting of histological findings. Increased macrovesicular steatosis (>30%) was associated with increased histological damage, liver function derangement, and reduced survival. Increased duration of warm or cold ischemia had a negative impact on all outcomes measured. Microvesicular steatosis did not influence outcome.Conclusions. Findings from this systemic review support the hypothesis that livers with >30% macrovesicular steatosis are less tolerant of IRI. Clinically, it is likely that these findings are applicable to patients undergoing hepatic resection, but further studies are required to confirm these data.

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