Effects of warm ischemia and reperfusion on the liver microcirculatory phenotype of rats: underlying mechanisms and pharmacological therapy.
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SUBMITTER: Hide D
PROVIDER: S-EPMC4764954 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hepatic ischemia-reperfusion injury (IRI) is a multifactorial phenomenon which has been associated with adverse clinical outcomes. IRI related tissue damage is characterized by various chronological events depending on the experimental model or clinical setting. Despite the fact that IRI research has been in the spotlight of scientific interest for over three decades with a significant and continuous increase in publication activity over the years and the large number of pharmacological and surgical therapeutic attempts introduced, not many of these strategies have made their way into everyday clinical practice. Furthermore, the pathomechanism of hepatic IRI has not been fully elucidated yet. In the complex process of the IRI, flow properties of blood are not neglectable. Hemorheological factors play an important role in determining tissue perfusion and orchestrating mechanical shear stress-dependent endothelial functions. Antioxidant and anti-inflammatory agents, ischemic conditioning protocols, dynamic organ preservation techniques may improve rheological properties of the post-reperfusion hepatic blood flow and target endothelial cells, exerting a potent protection against hepatic IRI. In this review paper we give a comprehensive overview of microcirculatory, rheological and molecular-pathophysiological aspects of hepatic circulation in the context of IRI and hepatoprotective approaches.
| S-EPMC7918617 | biostudies-literature
Project description:A fatty liver is known to have impairment of microcirculation, which is worsened after ischemia reperfusion injury (IRI). This makes most fatty grafts unsuitable for transplantation, and in the absence of real time assessment of microcirculation this selection has been at best, random. The aim of this study was to demonstrate the utility of a contrast enhanced ultrasound model in quantitative assessment of the microcirculation of a fatty liver.We subjected fatty mice to IRI, and blood flow dynamics were assessed before and after the injury.There was a significant increase in the resistive and pulsatility index of the extrahepatic artery and a significant decrease in velocity of the portal vein. There was also a quantifiable decrease in the intrahepatic blood volume, blood flow, time to peak flow, and perfusion index of mice with fatty liver, suggesting that a fatty liver develops hemodynamic abnormalities after IRI, leading to increased hepatocellular injury.Hemodynamic abnormalities in liver can be reliably quantified using a contrast, enhanced Doppler ultrasound, which is an inexpensive technique with multiple clinical applications. It can be used to assess the quality of the fatty liver donor graft before organ retrieval; for determining live donor candidacy, for making post-IRI recovery prognosis, and for assessing the effectiveness of therapeutic interventions.
| S-EPMC4768725 | biostudies-literature
Project description:Cholestasis is a significant risk factor for immediate hepatic failure due to ischemia reperfusion (I/R) injury in patients undergoing liver surgery or transplantation. We recently demonstrated that inhibition of Hedgehog (Hh) signaling with cyclopamine (CYA) before I/R prevents liver injury. In this study we hypothesized that Hh signaling may modulate I/R injury in cholestatic rat liver. Cholestasis was induced by bile duct ligation (BDL). Seven days after BDL, rats were exposed to either CYA or vehicle for 7 days daily before being subjected to 30 min of ischemia and 4 h of reperfusion. Expression of Hh ligands (Sonic Hedgehog, Patched-1 and Glioblastoma-1), assessment of liver injury, neutrophil infiltration, cytokines, lipid peroxidation, cell proliferation and apoptosis were determined. Significant upregulation of Hh ligands was seen in vehicle treated BDL rats. I/R injury superimposed on these animals resulted in markedly elevated serum alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin accompanied with increased neutrophil recruitment and lipid peroxidation. Preconditioning with CYA reduced the histological damage and serum liver injury markers. CYA also reduced neutrophil infiltration, proinflammatory cytokines such as TNF-α and IL-1β expression of α-smooth muscle actin and type 1 collagen resulting in reduced fibrosis. Furthermore CYA treated animals showed reduced cholangiocyte proliferation, and apoptosis. Hepatoprotection by CYA was conferred by reduced activation of protein kinase B (Akt) and extracellular signal regulated kinase (ERK). Endogenous Hh signaling in cholestasis exacerbates inflammatory injury during liver I/R. Blockade of Hh pathway represents a clinically relevant novel approach to limit I/R injury in cholestatic marginal liver.
| S-EPMC3121156 | biostudies-literature
Project description:BackgroundAlthough Danhong injection (DHI) has been proved to be curative, the mechanism of its action against ischemia stroke (IS) is not clear. Here, we explored the therapeutic basis of DHI by network pharmacology.MethodsPutative targets and activity scores for each compound in DHI were obtained from the Traditional Chinese Medicine System Pharmacology Database, Encyclopedia of Traditional Chinese Medicine, and Quantitative Structure Activity Relationships. Next, target proteins of IS were identified on GeneCards and CTD. Overlapping targets of DHI associated with IS were acquired via Venn diagram. GO and KEGG pathway analyses were done using WebGestalt. Cytoscape software was used for PPI network construction and hub nodes screening. Several validation studies were carried out by using AutoDock-Vina, label-free mass spectrometry, and transcriptome RNA-sequencing.ResultsThe 37 active compounds and 66 targets were identified. Of these, 26 compounds and 41 targets belonged to diterpenoid quinones (DQs), which is the predominant category based on chemical structure. The results of enrichments analysis show that 8 DQs target proteins associated with IS were involved in several biological processes and signaling pathway such as apoptotic, cell cycle, cellular response to xenobiotic stimulus process, and the PI3K-Akt signaling. Moreover, 3 nodes in core module involved in PI3K-Akt signaling and 1 hub node were identified by PPI network analysis. Finally, the results of molecular docking and label-free mass spectrometry display good effect on hub node regulation in DHI treatment.ConclusionsDQs is the predominant category of DHI and play an important role in antiapoptotic activity mediated by modulating PI3K-Akt signaling. Our findings offer insight into future research and clinical applications in IS therapy.
| S-EPMC8163534 | biostudies-literature
Project description:Liver ischemia-reperfusion injury (IRI) is a known risk factor for the postoperative outcome of patients undergoing liver surgery/transplantation. Attempts to protect from organ damage require multidisciplinary strategies and are of emerging interest in view of patients with higher age and American Society of Anesthesiology status. Ischemic preconditioning has been successfully applied to prevent from IRI during liver resection/transplantation. Because even short periods of ischemia during preconditioning inevitably lead to hypoxia and formation of anti-inflammatory/cytoprotective acting adenosine, we reasoned that short nonischemic hypoxia also protects against hepatic IRI.Mice underwent hypoxic preconditioning (HPC) by breathing 10% oxygen for 10 min followed by 10 min of 21% oxygen before left liver lobe ischemia (45 min) and reperfusion (4 hr). The interactions of hypoxia?adenosine?adenosine receptors were tested by pharmacologic antagonism at adenosine receptor (AR) sites in wild-type mice and in mice with genetic deletions at the A1, A2A, A2B, and A3 ARs. Hepatocellular damage, inflammation, and metabolic effects were quantified by enzyme activities, cytokines, liver myeloperoxidase, blood adenosine, and tissue AMP, respectively.Hepatoprotection by HPC was significant in wild-type and A1, A2A, and A3 AR knockout mice as quantified by lower alanine aminotransferase serum activities, cytokine levels, histologic damage scores, tissue myeloperoxidase concentrations, and preserved AMP concentrations. Protection by HPC was blunted in mice pretreated with the A2B AR antagonist MRS1754 or in A2B AR knockout mice.Because liver protective effects of HPC are negated when the A2B receptor is nonfunctional, the hypoxia?adenosine?A2B receptor pathway plays a critical role in the prevention of warm IRI in vivo. Hypoxic activation of this pathway warrants use of selective A2B AR agonists or even intermittent hypoxia (e.g., in deceased organ donors) to protect from liver IRI.
| S-EPMC3491139 | biostudies-literature
Project description:BACKGROUND Intestinal ischemia/reperfusion (I/R) injury is a serious clinical complication. This study aimed to explore the hub genes and pathways of intestinal I/R injury. MATERIAL AND METHODS GSE96733 from the GEO website was extracted to analyze the differentially expressed genes (DEGs) of intestinal I/R injured and sham-operated mice at 3 h and 6 h after surgery. The DAVID and STRING databases were used to construct functional enrichment analyses of DEGs and the protein-protein interaction (PPI) network. In Cytoscape software, cytoHubba was used to identify hub genes, and MCODE was used for module analysis. Testing by qRT-PCR detected the expression of hub genes in intestinal I/R injury. Western blot analysis detected the key proteins involved with the important pathways of intestinal I/R injury. RESULTS IL-6, IL-10, CXCL1, CXCL2, and IL-1ß were identified as critical upregulated genes, while IRF7, IFIT3, IFIT1, Herc6, and Oasl2 were identified as hub genes among the downregulated genes. The qRT-PCR testing showed the expression of critical upregulated genes was significantly increased in intestinal I/R injury (P<0.05), while the expression of hub downregulated genes was notably reduced (P<0.05). The proteins of CXCL1 and CXCR2 were upregulated following intestinal I/R injury (P<0.05) and the CXCL1/CXCR2 axis was involved with intestinal I/R injury. CONCLUSIONS The results of the present study identified IL-6, IL-10, CXCL1, CXCL2, IL-1ß, IRF7, IFIT3, IFIT1, Herc6, and Oasl2 as hub genes in intestinal I/R injury and identified the involvement of the CXCL1/CXCR2 axis in intestinal I/R injury.
| S-EPMC7733309 | biostudies-literature
Project description:Acute ischemia/reperfusion (I/R) liver injury is a clinical condition challenging to treat. Meldonium is an anti-ischemic agent that shifts energy production from fatty acid oxidation to less oxygen-consuming glycolysis. Thus, we investigated the effects of a 4-week meldonium pre-treatment (300 mg/kg b.m./day) on the acute I/R liver injury in Wistar strain male rats. Our results showed that meldonium ameliorates I/R-induced liver inflammation and injury, as confirmed by liver histology, and by attenuation of serum alanine- and aspartate aminotransferase activity, serum and liver high mobility group box 1 protein expression, and liver expression of Bax/Bcl2, haptoglobin, and the phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells. Through the increased hepatic activation of the nuclear factor erythroid 2-related factor 2, meldonium improves the antioxidative defence in the liver of animals subjected to I/R, as proved by an increase in serum and liver ascorbic/dehydroascorbic acid ratio, hepatic haem oxygenase 1 expression, glutathione and free thiol groups content, and hepatic copper-zinc superoxide dismutase, manganese superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activity. Based on our results, it can be concluded that meldonium represent a protective agent against I/R-induced liver injury, with a clinical significance in surgical procedures.
| S-EPMC7809046 | biostudies-literature
Project description:Ischemia/reperfusion injury (IRI) remains a significant problem to be solved in uterus transplantation (UTx). Melatonin and glycine have been shown to possess direct cytoprotective activities, mainly due to their antioxidative and anti-inflammatory properties. The aim of this study was to investigate the protective effects of melatonin and glycine and their combination on IRI in a rat model of warm ischemia. In this study, Sprague-Dawley rats were assigned to eight groups, including sham and IRI (n = 80). Melatonin and glycine alone or their combination were administered prior to 1 h of uterus ischemia followed by 1 h of reperfusion. Melatonin (50 mg/kg) was administered via gavage 2 h before IRI and glycine in an enriched diet for 5 days prior to intervention. Uterus IRI was estimated by histology, including immunohistochemistry, and biochemical tissue analyses. Histology revealed that uterus IRI was significantly attenuated by pretreatment with melatonin (p = 0.019) and glycine (p = 0.044) alone as well as their combination (p = 0.003). Uterus IRI led to increased myeloperoxidase expression, which was significantly reduced by melatonin (p = 0.004), glycine (p < 0.001) or their combination (p < 0.001). The decline in superoxide dismutase activity was significantly reduced in the melatonin (p = 0.027), glycine (p = 0.038) and combined treatment groups (p = 0.015) when compared to the IRI control group. In conclusion, melatonin, glycine and their combination significantly reduced oxidative stress-induced cell damage after IRI in a small animal warm ischemia model, and, therefore, clinical studies are required to evaluate the protective effects of these well-characterized substances in uterus IRI.
| S-EPMC8394613 | biostudies-literature
Project description:Diabetes mellitus (DM) exhibits a higher sensitivity to myocardial ischemia/reperfusion (I/R) injury and may compromise the effectiveness of cardioprotective interventions, including ischemic preconditioning. We previously found that liver ischemic preconditioning (RLIPC) could limit infarct size post I/R in non-diabetic rat hearts and further exerted anti-arrhythmic effects in diabetic or non-diabetic rats after myocardial I/R, however, little is known regarding the effect of RLIPC on infarct-sparing in diabetic hearts. In this study, we evaluated the protective effects of RLIPC on I/R injury in streptozotocin-induced type 1 diabetic rats. Type 1 diabetes mellitus was induced by one-time intraperitoneal injection of streptozotocin in Sprague-Dawley rats. Rats were exposed to 45 min of left anterior descend in (LAD) coronary artery occlusion, followed by 3 h of reperfusion. For liver ischemic preconditioning, four cycles of 5 min of liver I/R stimuli were performed before LAD occlusion. The cardioprotective effect of RLIPC was determined in diabetic rats. Compared to non-RLIPC treated DM rats, RLIPC treatment significantly reduced infarct size and cardiac tissue damage, inhibited apoptosis in diabetic hearts post I/R. RLIPC also improved cardiac functions including LVESP, LVEDP, dp/dtmax, and - dp/dtmax. In addition, RLIPC preserved cardiac morphology by reducing the pathological score post I/R in diabetic hearts. Finally, Westernblotting showed that RLIPC stimulated phosphorylation of ventricular GSK-3β and STAT-5, which are key components of RISK and SAFE signaling pathways. Our study showed that liver ischemic preconditioning retains strong cardioprotective properties in diabetic hearts against myocardial I/R injury via GSK-3β/STAT5 signaling pathway.
| S-EPMC7820418 | biostudies-literature
Project description:Wnt-induced secreted protein-1 (WISP1) is an extracellular matrix protein that has been reported in cancer researches. Our previous studies on WISP1 implied it could be a harmful mediator in septic mice. However, its role in liver ischemia reperfusion (I/R) injury is unknown. This study investigated the effects of WISP1 on liver I/R damage. Male C57BL/6 wild-type mice were used to undergo 60?min segmental (70%) ischemia. WISP1 expression was measured after indicated time points of reperfusion. Anti-WISP1 antibody was injected intraperitoneally to mice. Toll-like receptor 4 (TLR4) knockout mice and TIR-domain-containing adaptor inducing interferon-? (TRIF) knockout mice were adopted in this study. WISP1 was significantly enhanced after 6?h of reperfusion when compared with sham treated mice and significantly decreased either by TLR4 knockout mice or TRIF knockout mice. Anti-WISP1 antibody significantly decreased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), pathological changes and pro-inflammatory cytokine levels in the mice following I/R. Furthermore, significantly increased serum transaminase levels were found in C57 wild-type mice treated with recombinant WISP1 protein, but not found in TLR4 knockout or TRIF knockout mice subjected to liver I/R. Taken together, WISP1 might contribute to hepatic ischemia reperfusion injury in mice and possibly depends on TLR4/TRIF signaling.
| S-EPMC4731767 | biostudies-literature