Дисертації з теми "Liver Ischemia Repercussion Injury"
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1
Winbladh, Anders. "Microdialysis in Liver Ischemia and Reperfusion injury." Doctoral thesis, Linköpings universitet, Kirurgi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-68651.
Повний текст джерелаАнотація:
Introduction: New chemotherapy regimens and improvements in surgical technique have increased the number of patients with liver tumours eligible for curative liver resection. There is a significant risk of bleeding during liver surgery, but this risk can be reduced if the portal inflow is temporarily closed; i.e. the Pringles maneuver (PM). If the PM is used, the liver will suffer from ischemia and reperfusion injury (IRI). If the liver remnant is too small or if the patient has chronic liver disease, the IRI may inhibit the regeneration of the liver remnant. The patient may then die from postoperative liver failure. Several strategies have been tried to protect the liver from IRI. For instance can the PM be applied in short intervals or reactive oxygen species can be scavenged by antioxidants. There are no sensitive methods available for studying IRI in patients and little is known how IRI affects the metabolism in the liver. Microdialysis is a technique that allows for continuous sampling of interstitial fluid in the organ of interest Aim: To investigate the effects of ischemia and reperfusion on glucose metabolism in the liver using the microdialysis technique. Method: A porcine model of segmental ischemia and reperfusion was developed. The hepatic perfusion and glucose metabolism was followed for 6-8 hours by placing microdialysis catheters in the liver parenchyma (studies I-III). In study IV, 16 patients were randomized to have 10 minutes of ischemic preconditioning prior to the liver resection, which was performed with 15 minutes of ischemia and 5 minutes of reperfusion repetitively until the tumour(s) were resected. Results: During ischemia the glucose metabolism was anaerobic in the ischemic segment, while the perfused segment had normal glucose metabolism. Urea was added in the perfusate of the microdialysis catheters and was found to be a reliable marker of liver perfusion. The antioxidant NAcetylcystein (NAC) improved the hepatic aerobic glucose metabolism in the pig during the reperfusion, shown as reduced levels of lactate and improved glycogenesis in the hepatocytes. This can be explained by the scavenging of nitric oxide by NAC as nitric oxide otherwise would inhibit mitochondrial respiration. Also IP improved aerobic glucose metabolism resulting in lower hepatic lactate levels in patients having major liver resections. Conclusion: Microdialysis can monitor the glucose metabolism both in animal experimental models and in patients during and after hepatectomy. Both NAC and IP improves aerobic glucose metabolism, which can be of value in patients with compromised liver function postoperatively.
2
Björnsson, Bergþór. "Methods to Reduce Liver Ischemia/Reperfusion Injury." Doctoral thesis, Linköpings universitet, Institutionen för klinisk och experimentell medicin, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-110318.
Повний текст джерелаАнотація:
Introduction: During the last two decades, liver surgery has expanded enormously, partly due to improved surgical equipment and techniques as well as new and more powerful chemotherapy agents. As the liver is a very well-vascularized organ, there is an inherent risk of bleeding during liver resection. One of the most popular methods employed to reduce this risk is to close the vascular inflow to the liver using the Pringle’s maneuver (PM). However, this procedure has been recognized to cause ischemia/reperfusion injury (IRI) to the future liver remnant (FLR). In cases of extensive resection where the FLR is small and in cases when the liver suffers from chronic diseases, such as cirrhosis, IRI can greatly increase the risk of post-operative liver failure (POLF). Ischemic preconditioning (IPC) and, more recently, remote ischemic preconditioning (R-IPC) are methods that have been employed to reduce IRI. Aim: 1) To compare the effects of IPC and R-IPC in a rat model; 2) to investigate the clinical effect of IPC during modern liver surgery; 3) to investigate the role of the nitric oxide (NO) system in IRI, IPC and R-IPC; and 4) to explore the possible protective effects of nitrite administration before IRI. Methods: A rat model of segmental ischemia followed by 4 hours of reperfusion including microdialysis (μD) was developed from earlier models. The effects of IPC and R-IPC were compared using transaminases and histology as well as continuous μD sampling for glucose, pyruvate, lactate and glycerol. The role of the NO system was examined by serum and μD measurements of NOx as well as tissue measurements of iNOS mRNA and IL-1R mRNA. In study II, patients were randomized to IPC or no IPC prior to liver resection, where intermittent PM was used to decrease bleeding. Results: IPC was more effective in protecting the liver against IRI than R-IPC, as indicated by the levels of transaminases. Lower lactate levels were detected in patients treated with IPC before major liver resections than in controls. IPC reduced iNOS mRNA transcription during reperfusion; this result may be related to the early but not sustained increases in IL-1R transcription observed in the IPC group. Nitrite administered before ischemia reduced AST and ALT levels in the level after 4 hours of reperfusion; in addition, necrosis and glycerol release from the ischemic liver were reduced as well. Conclusion: IPC is more effective than R-IPC in animal models; however, this effect is unlikely to be of clinical importance. NOx decreases in the ischemic liver and the administration of nitrite before ischemia reduces IRI in rats. This may have clinical implications in the future.
3
Duarte, Sérgio Miguel Coelho. "Matrix-leukocyte interactions in liver ischemia-reperfusion injury." Doctoral thesis, Instituto de Ciências Biomédicas Abel Salazar, 2011. http://hdl.handle.net/10216/63694.
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4
Duarte, Sérgio Miguel Coelho. "Matrix-leukocyte interactions in liver ischemia-reperfusion injury." Tese, Instituto de Ciências Biomédicas Abel Salazar, 2011. http://hdl.handle.net/10216/63694.
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5
Georgiev, Panco. "Normothermic ischemia reperfusion injury in the cholestatic mouse liver /." Zürich, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000256332.
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6
Müller, Christian. "α-Lipoic Acid Attenuates Ischemia Reperfusion Injury of the Rat Liver". Diss., lmu, 2002. http://nbn-resolving.de/urn:nbn:de:bvb:19-2394.
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7
Hartkorn, Andreas. "Different approaches to influence the ischemia/reperfusion injury of the liver." Diss., kostenfrei, 2008. http://edoc.ub.uni-muenchen.de/8918/.
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8
Okumura, Shinya. "Oral administration of polyamines ameliorates liver ischemia-reperfusion injury and promotes liver regeneration in rats." 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225444.
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9
Richards, James Alexander. "The relative contribution of lymphocytes to hepatic ischemia reperfusion injury." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/25856.
Повний текст джерелаАнотація:
Background: Hepatic ischemia reperfusion injury (IRI) results from the interruption and then reinstatement of the liver’s blood supply. IRI involves both an ischemic and an immune-mediated reperfusion phase of tissue injury; similar inflammatory events are seen in other forms of acute (sterile) liver injury (ALI), including paracetamol toxicity. Hypothesis Irrespective of the primary insult, common pathways exist in the pathophysiology of the lymphocyte-mediated secondary liver injury. Natural mechanisms exist to limit lymphocyte function and these pathways can be targeted therapeutically by immunomodulatory agents. Aims: 1. To assess the relative importance of different lymphocyte subsets in IRI. 2. To correlate observations in IRI with other models of ALI. 3. To identify possible pharmacological targets. Materials and Methods Three experimental murine models of acute liver injury were utilised to test this hypothesis: murine model of warm hepatic IRI, concanavalin A (con A) hepatitis and paracetamol-induced liver injury. These models were interrogated with a combination of (transgenic and knockout) mouse lines, in vivo antibody depletion and small molecule inhibition. Injury was evaluated primarily in terms of the biochemical marker of liver injury alanine aminotransferase (ALT). Data were correlated with human tissue where possible. Results: T cells (CD3εKO vs WT p=0.010), but not other lymphocyte populations (B cells, NK cells, or other innate lymphoid cells), play a central role in warm hepatic IRI. Programmed Death Receptor-1 (PD-1) is a negative regulator of pro-inflammatory cytokine production by T cells and the absence of PD-1 was associated with significantly worse hepatic IRI (p=0.034), con A hepatitis (p=0.00020) and paracetamol-induced liver injury (p=0.0050). Interferon-γ (IFNγ) and T-box expressed in T cells (T-bet) are important mediators of hepatic IRI (p=0.017) and paracetamol induced liver injury (p=0.0007). The absence of IL-6 was associated with significant protection in paracetamol induced liver injury (p=0.006). The infiltrates within the recipient liver of patients transplanted following paracetamol overdose stain positively for PD-1, IFNγ and T-bet. The Janus family of kinases (JAK) play an important role in the common pathways of cytokine signal transduction. In vivo use of a selective JAK1/JAK2 inhibitor is protective in hepatic IRI (p=0.0014), con A hepatitis (p=0.019) and paracetamol-induced liver injury (p=0.0045). Conclusions: Common pathways appear to exist in the immune-mediated secondary phase of injury in ALI. Targeting these pathways will complement existing (cytoprotective) treatment strategies.
10
Bejaoui, Mohamed. "Polyethylene glycol conditioning: An effective strategy to protect against liver ischemia reperfusion injury." Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/385612.
Повний текст джерелаАнотація:
Ischemia is defined by the arrest of blood flow in the organ cutting thus oxygen and metabolite supply indispensable for its survival and function. Restoration of blood flow in hypoxic tissue, called reperfusion, can paradoxically result in more destructive than beneficial effects. Ischemia reperfusion injury (IRI) is an inevitable problem in many clinical situation of liver surgery such as organ transplantation, trauma and liver resection. Therapeutic strategies against IRI have been developed during the last 60 years and great advance into the mechanisms responsible of injuries have been achieved. However, efficient therapy against IRI is still lacking and few clinical studies in phase III have proven their effectiveness. This could be due in part to the complexity of the mechanisms responsible of IRI and to the specific drugs activity and their potential adverse effects.
Polyethylene glycols (PEGs) are water soluble nontoxic polymers that have been employed in many biomedical applications such as gastrointestinal disorders and drugs pegylation. Besides its usefulness as oncotic agents in preservation solutions, it has been shown that PEGs molecules protect against cold injury and ischemic damage.
In contrast to the current pharmacological strategies used against IRI, PEG presents the advantages of being a multi-target strategy. In fact, IRI is a multifactorial disease including oxidative stress, inflammation, endoplasmic reticulum stress, mitochondrial damage, and cytoskeleton alterations which lead to cell death and organ dysfunction. PEG has been associated with the majority of these events as it has been shown that PEG reduces reactive oxygen species, prevents cell death, maintains mitochondrial integrity, and reduces inflammation and endoplasmic reticulum stress. From this perspective, it is reasonable to expect that PEG administration may be an effective therapeutic strategy against liver IRI.
The aim of this thesis was to investigate the beneficial effects of PEG 35 in different models of IRI that mimic clinical situation of liver surgery. In the first study, we investigated the impact of the administration of intravenous PEG 35 before liver warm IRI. In the second one, we investigated whether intravenously administrated PEG 35 could protect against cold IRI in steatotic rat livers. Finally, we developed a new washout solution containing PEG 35 to prevent reperfusion injury after prolonged cold preservation.
The results of the present thesis demonstrated that:
- Intravenous administration of PEG 35 at 10 mg/kg protects the liver in an experimental model of warm IRI in rats. The protective mechanisms are associated with the activation of the pro survival pathways Akt and AMPK and the inhibition of apoptosis. PEG 35 also protects the hepatocyte morphology by increasing F/G-actin ratio and activating p-p38.
- Intravenous administration of PEG 35 at 10 mg/kg protects steatotic livers in an experimental model of cold IRI in obese rats. The protective effects of PEG 35 are mediated by the preservation of mitochondrial status, the stabilisation of the cytoskeleton and the regulation of the cytoprotective AMPK and Akt signalling pathways.
- Liver graft washout with a PEG 35-containing rinse solution increases the protection against IRI in a model of isolated perfused rat liver. .Protection was due to the inhibition of metalloproteinases, the activation of cytoprotective AMPK and eNOS signalling pathways and the preservation of cytoskeleton integrity.La lesión por isquemia reperfusión (I/R) es un proceso complejo que tiene lugar cuando un órgano se ve privado del aporte sanguíneo (isquemia) y se manifiesta de forma predominante después del posterior restablecimiento del flujo sanguíneo (reperfusión). Existen numerosas situaciones en la práctica clínica en las que el hígado se ve sometido a una situación de I/R, entre ellas, la resección hepática y el trasplante hepático. Los polietilenglicoles (PEGs) son polímeros solubles en agua, no tóxicos y con diferentes pesos moleculares. Algunos de ellos, con un peso molecular de 20 kDa (PEG 20) y de 35 kDa (PEG 35) forman parte de la composición de soluciones de preservación de órganos (SCOT e IGL-1). Además, en varios modelos experimentales de in vivo e in vitro se ha reportado que varios PEGs ejercen efectos beneficiosos. Atendiendo a lo anteriormente expuesto, la utilización de PEGs puede constituir una excelente herramienta para prevenir el daño hepático por I/R. El objetivo de esta tesis es investigar los efectos beneficiosos del PEG 35 en diferentes modelos de lesión por I/R, que imitan una cirugía hepática. Nuestros resultados demuestran que: - EL PEG 35 administrado por vía intravenosa protege eficientemente el hígado de ratas contra la I/R caliente. Los mecanismos de protección están asociados con la activación de la supervivencia vía Akt y AMPK y la inhibición de la apoptosis. El PEG 35 también protege la morfología de los hepatocitos mediante el aumento de la F/G-actina y la activación de p-p38. - La administración intravenosa de PEG 35 protege los hígados esteatósicos en un modelo de I/R fría en ratas obesas. Los efectos protectores de PEG 35 están mediados por la preservación del estado mitocondrial, la estabilización del citoesqueleto y la regulación de las vías de señalización citoprotectoras AMPK y AKT. - La adición de PEG 35 a una nueva solucione de lavado aumenta la protección contra la lesión por I/R en un modelo de hígado de rata aislado y perfundido a través de la inhibición de las metaloproteinasas, la activación de vías de señalización citoprotectoras AMPK y eNOS y la preservación de la integridad del citoesqueleto.
11
Gerwig, Tobias. "Prevention of Ischemia-Reperfusion Injury in the Rat Liver by Atrial Natriuretic Peptide." Diss., lmu, 2002. http://nbn-resolving.de/urn:nbn:de:bvb:19-888.
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12
Li, Xianliang, and 李先亮. "Insulin in UW solution exacerbates the ischemia/reperfusion injury in rat liver transplantation." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2003. http://hub.hku.hk/bib/B27785257.
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13
Wada, Seidai. "CAAT/Enhancer Binding Protein-Homologous Protein Deficiency Attenuates Liver Ischemia/Reperfusion Injury in Mice." Kyoto University, 2018. http://hdl.handle.net/2433/235981.
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14
Miyachi, Yosuke. "Causes of liver steatosis influence the severity of ischemia reperfusion injury and survival after liver transplantation in rats." Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/263516.
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15
Yamagami, Kazuhiko. "Heat shock preconditioning ameliorates liver injury following normothermic ischemia-reperfusion in steatotic rat livers." Kyoto University, 1999. http://hdl.handle.net/2433/181689.
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16
Hirao, Hirofumi. "The Protective Function of Galectin-9 in Liver Ischemia and Reperfusion Injury in Mice." 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225476.
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17
Miyauchi, Tomoyuki. "Preventive Effect of Antioxidative Nutrient‐Rich Enteral Diet Against Liver Ischemia and Reperfusion Injury." Kyoto University, 2019. http://hdl.handle.net/2433/242381.
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18
Kageyama, Shoichi. "Graft Reconditioning With Nitric Oxide Gas in Rat Liver Transplantation From Cardiac Death Donors." Kyoto University, 2014. http://hdl.handle.net/2433/193570.
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19
Hide, Alférez Diana. "Advances in ischemia and reperfusion injury: effects on liver microcirculation and therapeutic strategies for sinusoidal protection." Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/399454.
Повний текст джерелаАнотація:
Ischemia/reperfusion (IR) injury is a pathological condition caused by an initial interruption of blood, its biomechanical stimulus, and O2 supply followed by the restoration of perfusion and the accompanying oxygen, nutrient supply and shear stress. Clinically, ischemia/reperfusion injury is almost unavoidable in liver resection surgery, transplantation, and in blood transfusion after hemorrhagic shock. This pathology, associated with microvascular dysfunction and the “no reflow phenomenon” causes a wide range of derangements in the liver, which may finally lead to hepatic failure in case of severe injury. Sinusoidal dysfunction is, in part, due to the reduction in vasodilator molecules, such as nitric oxide. The decrease in NO bioavailability is due to both, a reduction in its production by eNOS in endothelial cells and an increase of its - scavenging by ROS like O2 . Thus, therapies focused on increasing eNOS expression or reducing ROS production may be useful in preventing microcirculatory derangements associated with IR injury.
Despite the importance of the liver sinusoid in health and disease scarce reports investigated the pathophysiological consequences of sinusoidal cell deregulation on hepatic IR injury. This has conduced to the erroneous idea that hepatocytes should be the main target for protection and therefore most of the therapies have focused on this cell type. Although IR injury has a clear negative impact in clinical practice, nowadays no pharmacological treatment is available, possibly due to the lack of microcirculatory protection of the tested drugs. Thus, we hypothesize that therapies focused in preserving the sinusoidal endothelial phenotype during IR will conduce not only to a better microcirculation but also to a global improvement of the whole liver.
With this background, the global aim of the present PhD thesis was to characterize the liver microcirculation in the setting of ischemia-reperfusion injury and evaluate possible drugs that, through an improvement in the hepatic sinusoid, could maintain a correct hepatic phenotype during IR.
The results derived from this doctoral thesis demonstrate the deleterious effects of ischemia/reperfusion injury on hepatic microcirculation both in cold and warm ischemia situations. In particular, the in vivo effects of warm IR include acute microcirculatory injury associated with an increase in intrahepatic vascular resistance, portal hypertension and reduced hepatic perfusion. To prevent this damage affecting all cell types in the liver sinusoid two therapeutic strategies have been evaluated: a recombinant form of the antioxidant human manganese superoxide dismutase (rMnSOD) in the context of cold storage for transplantation and the vasoprotective drug simvastatin in a model of partial warm ischemia. The papers included in this doctoral thesis demonstrate how both drugs are effective in improving liver endothelial function. Those effects are due, in part, to the maintenance of KLF2 expression and the vasoprotective pathways derived of this transcription factor; the maintenance of nitric oxide bioavailability and the reduction in superoxide levels. The endothelial and microcirculatory hepatic protection achieved by those drugs further conduces to a prevention of liver inflammation mediated by adhesion molecules, and thus to a reduction in hepatic parenchymal injury and a global decrease in cell death.
In conclusion, all the findings here described support the idea that preservation of the hepatic sinusoidal phenotype and function in essential to prevent ischemia/reperfusion injury and therefore to maintain liver function.En la present tesi doctoral es demostren els efectes deleteris del dany per isquèmia-reperfusió sobre la microcirculació hepàtica tant en condicions de preservació en fred com d’isquèmia calenta. En particular, els efectes in vivo de l’isquèmia-reperfusió en calent inclouen dany microcirculatori agut associat amb un increment de la resistència vascular intrahepàtica, hipertensió portal i reducció de la perfusió hepàtica. Per prevenir aquests danys que afecten als diferents tipus cel·lulars del sinusoid hepàtic s’han avaluat dues estratègies terapèutiques: l’antioxidant rMnSOD en el context de la preservació en fred per transplantament i el vasoprotector simvastatina en un model d’isquèmia calenta. Els articles inclosos en la present tesi doctoral demostren com ambdós fàrmacs són efectius millorant la funció endotelial hepàtica. Aquests efectes es deuen, en part, al manteniment de les vies vasoprotectores derivades del factor de transcripció KLF2 , al manteniment de la biodisponibilitat d’òxid nítric i a la reducció dels nivells del radical lliure superòxid. Aquesta protecció de l’endoteli i la microcirculació hepàtica s’associa amb una prevenció de l’inflamació mitjançada per mol·lècules d’adhesió i finalment condueix a una reducció del dany hepàtic i una menor mort cel·lular.
20
Kavanagh, Dean Philip John. "Molecular events governing hematopoietic stem cell recruitment in Vivo in murine liver following Ischemia-reperfusion injury." Thesis, University of Birmingham, 2010. http://etheses.bham.ac.uk//id/eprint/363/.
Повний текст джерелаАнотація:
Evidence suggests haematopoietic stem cells (HSCs) can migrate to injured liver and influence tissue repair. However, the molecular adhesive mechanisms governing HSC recruitment to injured hepatic microcirculation are poorly understood. These mechanisms were investigated in vivo following murine hepatic ischemia-reperfusion (IR) injury. HSC adhesion was significantly enhanced in injured livers and could be reduced by blocking CD49d on HSCs or VCAM-1 in vivo. Blockade of HSC CD18, CD31 or CD44 did not alter adhesion. HSC adhesion in sham treated CD31-/- animals was raised compared to wild-type animals and IR injury did not further raise this adhesion. Studies in vitro demonstrated that HSC treatment with inflammatory cytokines or conditioned media/plasma did not upregulate adhesion molecule expression but CXCL12 and CXCL1 did significantly enhance HSC adhesion to endothelium. However, blockade of CXCR4 (CXCL12 receptor) failed to reduce HSC adhesion in vivo following IR injury. Furthermore, we demonstrated exogenous HSCs were identified primarily in the pulmonary circulation and intraportal injection raised recruitment within the liver irrespective of the presence of injury. This study provides novel evidence for the importance of the VLA-4/VCAM-1 pathway in HSC recruitment to IR injured liver, a pathway that may be manipulated in order to enhance hepatic engraftment of these cells clinically.
21
Harada, Nobuko. "Inactivation of the small GTPase Rac1 protects the liver from ischemia/reperfusion injury in the rat." Kyoto University, 2004. http://hdl.handle.net/2433/145269.
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22
Shimabukuro, Takashi. "Can Heat Shock Pretreatment Protect the Rat Liver with Carbon Tetrachrolide-induced Fibrosis form Ischemia-reperfusion Injury?" Kyoto University, 1998. http://hdl.handle.net/2433/182256.
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23
Tamaki, Ichiro. "Hydrogen Flush After Cold Storage (HyFACS), as a new end-ischemic ex vivo treatment for liver grafts against ischemia/reperfusion injury." Kyoto University, 2019. http://hdl.handle.net/2433/242357.
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24
Wang, Yuan, and 王苑. "The effect of intravenous and intrathecal morphine preconditioning on hepatic ischaemia-reperfusion injury in normal and cirrhotic livers." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B47849848.
Повний текст джерелаАнотація:
Hepatic ischaemia-reperfusion injury occurs when patients undergoing liver
operations such as liver transplantation, tumour resection and shock. Intravenous and
intrathecal administration of morphine can be used to provide analgesia prior or after
liver surgery. It has been reported that systemically administered morphine conferred
protective effect on numerous organs, including heart, brain and kidney. The focus of
my research is to investigate the effect of intravenous and intrathecal morphine
preconditioning on normal and cirrhotic livers. Further, PI3K/Akt, STAT3 and
HO-1/iNOS pathways had been shown to ameliorate hepatic ischemia-reperfusion
injury. Hence, we aim to investigate these possible signaling pathways associated with
morphine mediated hepato-protection.
A partial hepatic ischaemia reperfusion injury model in rats was used. The
experiments were divided into two series: one involved in normal livers and the other
one involved in cirrhotic livers. For the normal livers, morphine at different doses
were administrated intravenously or intrathecally prior the onset of ischaemia, and the
experiments were repeated with previous intravenous administration of naloxone
methiodide (opioid receptor antagonist), or wortmannin (Akt inhibitor), respectively.
For the cirrhotic livers, morphine at optimal doses were injected intravenously or
intrathecally prior the onset of ischaemia. Those rats with only induced hepatic
ischaemia-reperfusion injury only were marked as control groups. The effect of
morphine preconditioning on hepatic architecture, apoptosis and liver function were
evaluated respectively by hematoxylin-eosin (H&E) staining, Terminal
deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) staining, the
expression of cleaved Caspase-3, and serum levels of alanine aminotransferase (ALT)
and aspartate aminotransferase (AST). Meanwhile, the expression of phosphorylated
Akt, phosphorylated JAK2, phosphorylated STAT3, HO-1 and iNOS were detected by
Western Blot to determine the signaling pathways involved by intravenous and
intrathecal morphine preconditioning.
The normal livers series presented intravenous and intrathecal morphine
preconditioning at the 100μg/kg, 10μg/kg, respectively, better persevered hepatic
architecture when compared with control groups. The degree of liver cell apoptosis
and expression of cleaved caspase-3 were also reduced by intravenous and intrathecal
morphine preconditioning. In additional, intravenous and intrathecal morphine
preconditioning ameliorated hepatocellular damage by reducing ALT&AST release.
Moreover, the expressions of phosphorylated Akt and its downstream protein STAT3
were significantly increased by intravenous and intrathecal morphine preconditioning,
compared with their respective control groups. The hepato-protective effect of
intravenous and intrathecal morphine preconditioning was reversed by naloxone
methiodide or wortmannin pretreatment. The similar pattern of protection was
observed in cirrhotic livers. Both intravenous and intrathecal morphine
preconditioning protected hepatic architecture much better than control groups. They
also attenuated hepatic apoptosis degree and hepatocellular enzyme release.
Furthermore, the expression of HO-1 was up-regulated, whereas the expression of
iNOS was down-regulated by intravenous and intrathecal morphine preconditioning.
In summary, this study provided evidence that intravenous and intrathecal
morphine preconditioning could attenuate hepatic ischaemia-reperfusion injury in
normal and cirrhotic livers. The involvement of opioid receptors, Akt/STAT3 pathway
and HO-1 pathway might be the underlying mechanisms of morphine
hepato-protection. Finally, the protective effect of morphine preconditioning might
provide a potential therapeutic approach for clinical usage.published_or_final_version
Anaesthesiology
Master
Master of Philosophy
25
Okamura, Yusuke. "Impact of Subnormothermic Machine Perfusion Preservation in Severely Steatotic Rat Livers: A Detailed Assessment in an Isolated Setting." 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225499.
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26
Kusakabe, Jiro. "Complement 5 inhibition ameliorates hepatic ischemia/reperfusion injury in mice, dominantly via the C5a-mediated cascade." Kyoto University, 2020. http://hdl.handle.net/2433/254516.
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27
Westman, Bo. "Studies of ischemia and reperfusion in muscle and liver on glutathione and amino acid metabolism in man /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-406-8/.
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28
Yonezawa, Kei. "Suppression of TNF-α production and neutrophil infiltration during ischemia-reperfusion injury of the liver after heat shock preconditioning". Kyoto University, 2002. http://hdl.handle.net/2433/149667.
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29
Uchinami, Hiroshi. "Effect of heat shock preconditioning on NF-κB/I-κB pathway during ischemia-reperfusion injury of the rat liver". Kyoto University, 2002. http://hdl.handle.net/2433/149733.
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30
Pantazi, Eirini. "New strategies to reduce liver ischemia – reperfusion injury in fatty and non-fatty livers: a focus on sirtuin 1 implication." Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/299797.
Повний текст джерелаАнотація:
Ischemia-reperfusion injury (IRI) is an inevitable situation in clinical settings such as liver transplantation and hepatic resection. It develops when blood flow is interrupted for a long period of time (ischemia) and then it restarts (reperfusion). IRI pathophysiology is highly complex and includes a number of mechanisms, such as oxidative stress, inflammation, apoptosis, microcirculatory disturbances, that contribute to organ damage and limit the clinical outcome. In addition, in order to reduce the gap between the need and availability of donors, many transplantation teams now use liver grafts, that previously have been considered unsuitable for transplantation, such as the steatotic livers. Steatotic livers are characterized by an excessive lipid accumulation and present higher vulnerability against IRI in comparison to normal ones. Subsequently, the use of steatotic liver grafts has been associated with poorest transplantation outcome and higher incidence of dysfunction.
In spite of the extensive investigations, IRI remains an unsolved problem and it is necessary the identification of new targets that could mitigate its adverse effects. Recently, sirtuin 1, (SIRT1) a nicotinamide adenosine dinucleotide (NAD+)-dependent deacetylase has gained increasing attention from researchers, due to its involvement in various cellular functions, including cell response to stress, cell cycle and metabolism. Although SIRT1 has been associated with beneficial effects against IRI in heart and brain, no data have been reported concerning its potential implication in hepatic IRI and liver transplantation.
Consequently, the present thesis aims to investigate the potential role of SIRT1 in rat liver IRI in a model of warm ischemia-reperfusion in steatotic livers (first study), in a model of rat orthotopic liver transplantation, OLT, (second study) and in reduced-size orthotopic liver transplantation, ROLT, (third study). In the first study, SIRT1 has been associated with the beneficial effects of ischemic preconditioning (a well-known surgical strategy to prevent IRI). In rat OLT SIRT1 has been correlated with the activation of autophagic pathway. In ROLT SIRT1 has been shown to contribute to the beneficial effects exerted by angiotensin II inhibition. According these results, the present thesis concludes that SIRT1 is implicated in the hepatic IRI and that strategies that enhance its activity can be a promising approach to reduce liver IRI.La lesión por isquemia-reperfusion (LIR) hepática es causa de una significativa mortalidad en caso de resecciones hepáticas y en el trasplante hepático. La LIR está relacionada con el desarrollo de fallo primario y con la disfunción primaria del injerto. Ella se está desarrollando por la privación del oxígeno durante la fase de isquemia y la nueva entrada de oxígeno, durante la reperfusión, la cual daña más el órgano sometido a isquemia. La LIR es un proceso muy complejo y varias investigaciones intensivas se han llevado a cabo para explorar los mecanismos de su patogénesis. Entre los más estudiados son el estrés oxidativo, la inflamación y la apoptosis. Además, debido a la gran demanda por órganos, muchos centros de trasplante se han visto obligados a utilizar injertos que anteriormente eran considerados inapropiados para trasplantar. Los hígados esteatósicos son un ejemplo; se caracterizan de una acumulación exagerada de lípidos y son más vulnerables frente la LIR. Además, están correlacionados con una incidencia elevada de disfunción después del trasplante. Consecuentemente, es necesario la identificación de nuevas estrategias que confieren una protección eficaz frente la LIR y especialmente en caso de hígados esteatósicos. La sirtuina 1 (SIRT1) es una enzima que elimina el grupo acetilo en varias proteínas y así regula varios procesos celulares, como la respuesta frente varios tipos de estrés, el ciclo celular y el metabolismo. Estudios recientes en el corazón y el cerebro han asociado la activación de la SIRT1 con una aumentada resistencia frente la LIR. No obstante, no se ha reportado todavía una posible implicación de la SIRT1 en la LIR hepática o en el trasplante. La presenta tesis tiene como objetivo investigar la implicación de la SIRT1 en la isquemia-reperfusión caliente en hígados esteatósicos de rata y su correlación con el precondicionamiento isquémico, una estrategia previamente reportada para prevenir la LIR. Además, se ha investigado la implicación de la SIRT1 en un modelo de trasplante ortotópico y en un modelo de trasplante con tamaño reducido en la rata. Así, el presente estudio demuestra que SIRT1 está involucrada en la LIR hepática y su activación podría ser una estrategia prometedora para disminuir los efectos adversos de la LIR.
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Kume, Makoto. "Ischemic preconditioning of the liver in rats : Implications of heat shock protein induction to increase tolerance of ischemia-reperfusion injury." Kyoto University, 1999. http://hdl.handle.net/2433/181688.
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Kadono, Kentaro. "Thrombomodulin Attenuates Inflammatory Damage Due to Liver Ischemia and Reperfusion Injury in Mice in Toll-Like Receptor 4-Dependent Manner." 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225492.
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Levesque, Eric. "Interactions entre le foie et le poumon en transplantation hépatique : conséquences pulmonaires des lésions hépatiques d’ischémie/reperfusion : travaux expérimentaux et cliniques." Thesis, Paris Est, 2017. http://www.theses.fr/2017PESC0024.
Повний текст джерелаАнотація:
Le foie et le poumon sont deux organes intimement liés et les atteintes pulmonaires sont fréquentes dans les pathologies hépatiques. En transplantation hépatique, les atteintes pulmonaires, les complications et la morbi-mortalité qu’elles engendrent, peuvent être en lien avec la pathologie hépatique du receveur mais aussi avec le donneur via le greffon, sa qualité et sa préservation. L’objectif de cette thèse était d’étudier deux aspects de cette interaction : 1- l’impact de l’insuffisance respiratoire aigüe (définie par le recours à la ventilation mécanique) sur le devenir post-transplantation ii) les conséquences des phénomènes d’ischémie-reperfusion du greffon hépatique sur les paramètres cardio-pulmonaires du receveur.Dans le premier travail, nous avons étudié, sur une cohorte de patients transplantés hépatiques à l’Hopital Henri Mondor (n=350 patients), le devenir post-opératoire en fonction de la présence ou non d’une ou plusieurs défaillances d’organe (neurologique, respiratoire, rénale, hémodynamique, hépatique et de la coagulation). Les patients avec au moins une défaillance d’organe ont une diminution significative de la survie post-LT à 90 jours (79% contre 96%) et 1 an (70% contre 91%) comparés aux patients cirrhotiques sans défaillance. Dans un deuxième travail issu de la même cohorte, nous développons un modèle permettant de prédire la mortalité à court terme et composé de 6 facteurs dont l’existence d’une défaillance d’organe. Le 3e travail, avec un effectif plus important (cohorte de l’Agence de la Biomédecine, PHRC « Optimatch »), a cherché à confirmer nos premiers résultats et à étudier le poids de chacune des défaillances d’organe et en particulier de la défaillance pulmonaire. Non seulement la présence d’une défaillance mais le nombre de défaillances au moment de la TH influence négativement le devenir à 3 mois des transplantés hépatiques. De plus, les défaillances pulmonaire et rénale sont des facteurs de risque indépendant de mortalité à 3 mois post-transplantation. Ces travaux montrent aussi que l’influence de ces défaillances d’organe peut être modulée en fonction du type de greffon, i.e. des critères du donneur.En plus de la qualité du greffon hépatique, la conservation de celui-ci a un impact sur la fonction du greffon et sur les paramètres cardio-pulmonaires chez le receveur. En effet dans un modèle de transplantation hépatique chez le gros animal (cochon), nous avons montré que les lésions d’ischémie/reperfusion du greffon engendrées entre le prélèvement et l’implantation ont des conséquences sur la fonction du greffon, le myocarde et le poumon. Ces lésions sont modulables selon la technique de préservation, notamment via l’utilisation de machine de perfusion.Ces travaux démontrent qu’au cours de la transplantation hépatique l’atteinte du parenchyme pulmonaire a un rôle clinique majeur chez le receveur et est médiée en partie par des phénomènes d’ischémie-reperfusion du greffon potentiellement modifiables par des améliorations des pratiques médicalesLiver and lung are two closely related organs. In liver transplantation, lung damage, complications, morbidity and mortality can be related to the liver disease of the recipient but also to the donor via the graft, its quality and its preservation. The aim of this manuscript was to study two aspects of these interactions: 1- the impact of acute respiratory failure (defined by the use of mechanical ventilation) on the post-transplantation outcome ii) the consequences of the ischemia-reperfusion injury of the graft on cardiopulmonary parameters in the recipient.In the first study, we investigated the impact of one or more organ failure (cerebral, lungs, kidney, circulation, hepatic and coagulation) on the 90-day mortality post LT. Patients with at least one organ failure had a significant decrease in post LT survival at 90-day (79% versus 96%) and 1 year (70% versus 91%) compared with cirrhotic patients without failure. In a second study, from the same cohort, we developed a model to predict short-term mortality. This model is composed of 6 factors including the existence of organ failure. In the third study, with a largest cohort (Agence de Biomedicine, PHRC “Optimatch”), we have confirmed these first results and we observe that the number at the LT influences the outcome. Decision tree-modeling identified 6 subgroups further classified in 4 increasing risk classes, highlighting the prognostic importance of respiratory failure and renal failure at the LT as well as complex interactions between donor and recipient features.In addition to the quality of the graft, its preservation has an impact on the graft function and on the cardiopulmonary parameters in the recipient. Indeed, in a model of LT in the large animal (pig) we show that the ischemia / reperfusion injuries, generated between the sampling and the implantation, have consequences on graft function, myocardium and lung. These lesions could be subdued according to the preservation technique.These studies demonstrate that during LT the recipient's pulmonary complications and its morbidity are related to the recipient’s pre-existing hepatic disease and to the donor via the graft through ischemia-reperfusion phenomena of the graft
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Panisello, Roselló Arnau. "Noves estratègies en la prevenció de la lesió hepàtica per isquèmia reperfusió = New strategies in the prevention of liver ischemia reperfusion injury." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/664647.
Повний текст джерелаАнотація:
Avui en dia, la única solució per a pacients que es troben en una situació de fase terminal de malaltia hepàtica o en una lesió hepàtica aguda es el transplantament. La demanda d’òrgans per a aquesta finalitat supera àmpliament la oferta disponible. Dintre d’aquest context, l’optimització de totes les etapes que engloba el procés de transplantament és indispensable. En el nostre cas ens centrem en tres conceptes d’aquest procés.
Una de les principals causes per les quals un transplantament de fetge no tingui èxit es degut a les complicacions derivades de la lesió per isquèmia-reperfusió. La lesió per isquèmia-reperfusió (IRI) es un fenomen complex i multifactorial que comença per la restricció total o parcial de reg sanguini a l’òrgan (isquèmia) i per la seva reinstauració després de un temps més o menys perllongat (reperfusió). Com a conseqüència d’aquesta privació de reg sanguini, l’òrgan sofreix una sèrie de reaccions i canvis metabòlics que afectaran a la seva viabilitat funcional. Per tant, la comprensió de la IRI ens pot donar eines per pal·liar els seus efectes.
Per altra banda, donada la desequilibrada ràtio oferta-demanda d’òrgans, es imprescindible incrementar el pool d’òrgans disponibles. Actualment i com a conseqüència de l’estil de vida occidental, molts dels possibles òrgans donants son descartats per la presència de greix infiltrat, és a dir, esteatosis. La comprensió i millora de les condicions d’aquests òrgans obre una porta a la seva utilització i a incrementar el pool de donants, amb la derivada d’incrementar el nombre de vides salvades.
Un dels altres aspectes claus en el transplantament és la preservació de l’òrgan prèvia a dit transplantament. En aquest context, la millora de les solucions de preservació és un factor vital per a incrementar la viabilitat dels òrgans i per tant tenir un major nombre d’ells disponible amb major funcionalitat.
Es per això que la tesis titulada “Noves estratègies en la prevenció de la lesió hepàtica per isquèmia reperfusió” empra els conceptes IRI, fetges esteatòtics i solucions de preservació com a eixos fonamentals en els seus estudis per a la millora de la qualitat i quantitat en els transplantaments hepàtics.Nowadays, the only solution for patients that are diagnosed with a terminal hepatic disease or that suffer from an acute hepatic injury is transplantation. However, the demand of organs for transplantation far exceeds the offer. In this context, the optimization of all the stages that englobes the process of transplantation is indispensable. In this case we mainly focus in three key concepts. One of the main reasons for which a liver transplant is not successful is due the complications derived from the ischemia-reperfusion injury. The ischemia-reperfusion injury (IRI) is a complex and multifactorial phenomenon that starts with the total or partial blood flow deprivation (ischemia) and its restoration after a more or less long time. As a consequence of blood flow deprivation, the organ suffers a series of reactions and metabolic changes which will affect its functional viability. For this reason, the understanding of the ischemia-reperfusion injury will supply us with the tools to counter its negative effects. In another vein, given the unbalanced ratio offer-demand of organs, it is mandatory to increase the available donor’s pool. Nowadays, and as a consequence of the occidental lifestyle, lots of possible donors are discarded due the presence of fat infiltration in their organs, that’s it, steatosis. The understanding and the improvement of this steatotic livers, opens a door to their usage and to increase the donor’s pool, with the derivative to increase the number of lives saved. Another key aspect in liver transplantation is the organ preservation prior to transplantation. In this sense, the improvement of the preservation solutions for livers is a crucial factor to increase livers viability, and therefore, achieving more availability with increased functionality. For this reason, the thesis entitled “new strategies in the prevention of liver ischemia reperfusion injury” uses the concepts IRI, liver steatosis and preservation solutions as fundamental axes in its studies to improve the quality and quantity of liver transplantation.
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Kan, Chunyi [Verfasser], Uta [Gutachter] Dahmen, Jun Gutachter] Li, and Silvio [Gutachter] [Nadalin. "Ischemia reperfusion injury of the marginal liver : identification and evaluation of novel therapeutic strategies / Chunyi Kan ; Gutachter: Uta Dahmen, Jun Li, Silvio Nadalin." Jena : Friedrich-Schiller-Universität Jena, 2018. http://d-nb.info/1170587232/34.
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Kawasoe, Junya. "The lectin-like domain of thrombomodulin is a drug candidate for both prophylaxis and treatment of liver ischemia and reperfusion injury in mice." Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/263533.
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Gringeri, Enrico. "Un nuovo sistema di perfusione parenchimale per la preservazione del graft epatico per trapianto: valutazione sperimentale sul piccolo e grande animale." Doctoral thesis, Università degli studi di Padova, 2008. http://hdl.handle.net/11577/3425544.
Повний текст джерелаАнотація:
Background
In liver transplantation one of the most important promblem which has not a solution yet is the large discrepancy between supply and demand for liver transplantation. To expand the pool of organs we should find the way to utilize marginal livers like the Non-heart-beating-donors ones and the fatty grafts. The use of these livers is associated with high incidence of post-operative primary dysfunction caused by the damage due to the Cold Storage preservation in the context of the process of ischaemia- reperfusion in extreme hypothermia (4° C). The utilization of new methods in the conservation of hepatic grafts like Machine Perfusion becomes necessary, especially for its ability to reduce the damage of ischaemia-reperfusion in hypothermia.
The great potentiality of this Machine in sane and marginal organ preservation and the number of works which took place about it, stimulated us to the deepen this argument.
Purpose
We decided to create a experimental model of Machine Perfusion for pigs and to test it with different temperatures to obtain the best condition of perfusion and graft preservation. We based our study on the various works that can be find in literature and on the research developed by the Università di Pavia on rats.
Methods
We used in our experiments 15 Landrace pig of the weight of 22 kilos each. We divided them in three groups of study. Group C: after hepatectomy the pig liver was preserved in Cold Storage (4° C) for 8 hours. Group N: after hepatectomy the pig liver was perfused in Normothermic Machine Perfusion (37°C) for 8 hours. Group I: the pig liver was perfused in Moderate Hypothermic Machine (20°C). After the preservation, all the 15 livers were tested with a rewarming (37°C) of 2 hours. During the two hours of the experiment we performed samples of blood and biopsies and we also valuated the indocianine green clearance.
Results
The results obtained by the histology, the functional test and biochemical levels of AST, ALT and LDH, in the moderate hypothermic perfusion prove the superiority of this machine .
Conclusion
It is concluded after these experiments the great ability of 20°C Machine Perfusion in pig's liver transplantation. We think that this method of preservation will be able to improve the pool of donors using NHBD livers and fatty livers. In future our research will deepen the problematic connected with the preservation of marginal organs, in particular of steatotic livers.
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YERMEK, NIGMET. "Human Atrial Natriuretic Peptide in Cold Storage of Donation after Circulatory Death Rat Livers: An Old but New Agent for Protecting Vascular Endothelia?" Kyoto University, 2019. http://hdl.handle.net/2433/242391.
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Bonsignore, Pasquale. "Sviluppo di biomarkers per la determinazione e la valutazione prognostica della ripresa funzionale epatica post trapianto, nel fegato marginale e nel non heart beating donor." Doctoral thesis, Università degli studi di Padova, 2014. http://hdl.handle.net/11577/3423510.
Повний текст джерелаАнотація:
ABSTRACT
Background
One of the most crucial issues in liver transplantation is the gap between the increasing number of patients waiting for a transplant and the shortage of available grafts. This limitation has led many liver transplant units to include for surgery organs defined as “marginal” or “sub-optimal” due to hepatic steatosis or sourcing from non-heart-beating donors (NHBD). In turn, the marginality of these organ donors is proportional to a high incidence of liver dysfunction after transplantation due mainly to more severe ischemia-reperfusion injury events. The use of new methods of preservation of hepatic grafts like Machine Perfusion becomes necessary, especially for its ability to reduce the damage of ischaemia-reperfusion in hypothermia.
This opens an interest towards the use of alternative methods in preserving hepatic graft as Machine Perfusion, able to reduce this type of insults and allow the dosage of biomarkers that can predict the extent of damage ischemia-reperfusion injury and the quality of functional recovery of the graft after transplantation.
The great potential of this system in the context of organ preservation and the numerous studies in the literature led us to investigate this issue.
Purpose
The aim of our work was to carry out an experimental model of Machine Perfusion (MP) for the preservation of livers procured from non heart-beating donor, as a viable alternative to the traditional Cold storage (CS) at 4°C.
A further aim of our project was to identify biomarkers that can be used as predictors of postoperative graft damage.
Material and methods
We used 10 Landrace pigs of about 20 kg to which we performed, 60 minutes after cardiac arrest, total hepatectomy, thus harvesting the liver. The animals were divided into two groups: in the first group (Group A) 5 livers was preserved for 6 hours in MP at 20° C. In the second group (Group B) 5 livers was stored for 6 hours in CS. In all study groups the period of preservation was followed by reperfusion in normothermic MP (37 °) with whole oxygenated blood previously collected from the donor animal for 2 hours to assess the response to reperfusion. During the experiment blood samples and histological specimens were collected.
Results
Graft preservation by Machin perfusion at 20°C is superior compared to the Cold Storage, both from biochemical (AST, ALT, LDH, lactate) and histological standpoint (necrosis and congestion).
The dose of AST, ALT, LDH and lactate has proven be a reliable parameter for the assessment of organ damage and functional recovery of the graft liver. The dosage of cytokines such as IL1, IL6, TNF alpha showed no significance.
Conclusion
These experimental evidences highlight the effectiveness of a preservation with continuous perfusion at 20° C on a large animal model. Both from biochemical that histological standpoint, we have observed that Machine Perfusion in moderate hypothermia is beneficial in the preservation of the graft and offers the considerable advantage of being able to test, during perfusion, biomarkers that can predict hepatic graft recovery, before transplant, in order to reduce the incidence of post-transplant graft disfunction.Riassunto Premesse generali Nell’ambito del trapianto di fegato, uno dei problemi più importanti non ancora risolti è la grande discrepanza tra la richiesta di organi e la risorsa di donazioni. Il ricorso ai così detti organi “marginali”, come quelli dei donatori a cuore non battente e con steatosi maggiore del 60%, potrebbe consentire di ampliare in maniera sensibile il pool degli organi disponibili per trapianto. L’impiego di questi fegati però è associato ad un’alta frequenza di Primary Disfunction postoperatoria a causa del danno che si sviluppa nel corso della preservazione in Cold Storage, nel contesto del processo di ischemia-riperfusione in ipotermia estrema (4°C). Si apre un’area di interesse di ricerca verso l’utilizzo di metodiche alternative nella conservazione del graft epatico come la Machine Perfusion, in grado di ridurre questo tipo di insulti e di consentire il dosaggio di biomarkers in grado di predire l’entità del danno da ischemia-riperfusione e la qualità della ripresa funzionale del graft dopo trapianto. Le grandi potenzialità di questo sistema nell’ambito della preservazione d’organo e i numerosi lavori in letteratura ci hanno spinto ad approfondire questa tematica. Scopo dello studio L’obiettivo del nostro lavoro è stato quello di realizzare un modello sperimentale di Machine Perfusion per la preservazione di fegati prelevati da donatore a cuore non battente, come valida alternativa alla preservazione tradizionale in Cold storage a 4°C. Ulteriore scopo del nostro progetto è stato quello di identificare eventuali biomarcatori in grado di predire l’entità del danno da ischemia-riperfusione e la qualità della ripresa funzionale del graft dopo trapianto di fegato da donatore a cuore non battente. Materiali e metodi Per questi esperimenti abbiamo utilizzato 10 maiali Landrace di circa 20 Kg ai quali abbiamo praticato, 60 minuti dopo l’arresto cardiaco, un’epatectomia totale, prelevando così il fegato. Gli animali sono stati suddivisi in due gruppi di 5 ciascuno: nel primo gruppo (Gruppo A) il fegato prelevato è stato perfuso in MP (Machine perfusion) per sei ore con soluzione di Celsior a 20°C. Nel secondo gruppo (Gruppo B) il fegato prelevato nei 5 animali è stato conservato per 6 ore in CS (Cold storage). In tutti i gruppi di studio il periodo di preservazione è stato seguito da un periodo di rewarming inteso come riperfusione dell’organo con sangue autologo in normotermia (37°) per due ore per valutare la risposta alla riperfusione. Durante tutte le otto ore dell’esperimento sono stati raccolti campioni ematici e istologici. Risultati Dal punto di vista biochimico (AST, ALT, LDH) e istologico (necrosi e congestione) la preservazione mediante perfusione a 20°C si è dimostrata superiore rispetto al Cold Storage. Il dosaggio di AST, ALT, Acido lattico ed LDH si è dimostrato essere un parametro attendibile per la valutazione del danno d’organo e della ripresa funzionale del graft epatico. Il dosaggio di citochine quali IL1, IL6, TNf alfa non ha mostrato alcuna significatività. Conclusioni Queste evidenze sperimentali mettono in rilievo l’efficacia di una preservazione con macchina a perfusione continua a 20°C sul grande animale. Sia dal punto di vista biochimico che istologico, infatti, abbiamo osservato che la Machine Perfusion in moderata ipotermia è di beneficio nella preservazione del graft ed offre il notevole vantaggio di poter testare, durante la perfusione, biomarcatori che possono predire l’eventuale ripresa funzione dell’organo, prima dell’esecuzione del trapianto, al fine di ridurre l’incidenza di disfunction del graft post trapianto.
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Filho, Marco Antonio Corrêa Guimarães. "Efeito do pré-condicionamento isquêmico remoto em modelo de lesão hepática por isquemia-reperfusão em ratos." Universidade do Estado do Rio de Janeiro, 2013. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=7368.
Повний текст джерелаАнотація:
A lesão por isquemia-reperfusão (I/R) é o mecanismo fisiopatológico central no desenvolvimento da insuficiência hepática pós-operatória. Diversas estratégias para minimizar suas consequências estão sendo desenvolvidas, mas ainda sem resultados satisfatórios. Recentemente o pré-condicionamento isquêmico remoto (PCIR), método em que ciclos breves de I/R aplicados em um órgão ou membro é capaz de atenuar os resultados da I/R em um órgão distante, vem sendo utilizado, em modelos experimentais, com resultados promissores. No entanto seu mecanismo de ação ainda não foi esclarecido. Um dos mecanismos propostos é a modulação na expressão das citocinas sintetizadas durante a resposta inflamatória que acompanha o processo de I/R. Foram utilizados 36 ratos (Rattus norvegicus), machos, com peso entre 250 e 280 g, divididos em três grupos: Grupo Sham, cirurgia simulada; Grupo IR, isquemia de 70% do fígado por 45 minutos e reperfusão; e Grupo PCIR, pré-condicionamento isquêmico remoto do fígado através de seis ciclos de isquemia-reperfusão da pata do animal, com quatro minutos de isquemia e quatro minutos de reperfusão em cada ciclo, seguido de isquemia hepática semelhante ao do Grupo IR. Terminado os procedimentos cirúrgicos, metade dos animais foi morta decorridos 60 minutos de reperfusão, e a outra metade após 180 minutos. Foi coletado tecido hepático do lobo submetido à isquemia, para estudo histopatológico, utilizando o índice de injúria hepática modificado; e sangue, para dosagem plasmática de TNF-α, IL-6, IL-10 e ALT. A análise histopatológica mostrou que a necrose celular foi significativamente reduzida no Grupo PCIR quando comparado com Grupo IR (p <0,0001). As transaminases mostraram o mesmo padrão com redução significativa dos seus valores no Grupo PCIR quando comparados com o Grupo I-R (p <0,0001). A dosagem das interleucinas mostrou redução significativa na expressão da IL-6 no Grupo PCIR quando comparado com o Grupo IR (p<0,001). Houve aumento da expressão de IL-10 nos grupo PCIR, porém não atingiu significância estatística. Não foi identificada diferença na dosagem de TNF-α nos grupos estudados. O PCI-R foi eficaz na redução na necrose celular resultante da lesão por I-R nos grupos estudados. A redução na síntese de IL-6 segue o padrão observado em outros estudos.Ischemia/Reperfusion (I/R) injury is an important pathophysiological mechanism in the postoperative liver failure. Different strategies to minimize the I/R liver injury have been developed during the last decades but the results had been disappointing. Recently, the remote ischemic preconditioning (RIPC), a method that involves a brief ischemic episode on an organ or tissue that subsequently affords protection to a remote organ or tissue, have been use in various experimental models with promising results. The precise pathway activated by the RIPC isnt clear, but cytokine release modulation has been proposed as a candidate mechanism. Thirty-six male rats (Rattus norvegicus) were divided in 3 groups: Sham; I/R injury, a 45 minutes lobar (70%) liver ischemia and reperfusion; and RIPC, 6 cycles of 4 minutes of ischemia and 4 minutes of reperfusion of the right hindlimb followed by a 45 minutes lobar (70%) liver ischemia and reperfusion. Liver tissue in the affected lobe and blood samples were collected after 60 minutes and 180 minutes of reperfusion for histopathological study of liver I/R, plasma cytokines (TNF-α, IL-6 and IL-10) and liver aminotransferases measurement (ALT). The histopathological study demonstrated a significant lesser degree of liver necrosis in the RIPC group (p <0,001). The aminotransferases levels followed the same pattern, with significant lower levels in the RIPC group (p <0,001). The cytokines assessment showed a reduction in the expression of IL-6 in the RIPC when compared with the I/R group (p <0,01). Interleukin-10 levels were higher in the RIPC group, but the difference wasnt significant. The TNF-α measurement didnt show any difference in the groups. The RIPC model presented consistently reduced the I/R injury to the liver and the IL-6 expression was similar to the reported in other studies.
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Lehmann, Thorsten. "Die Bedeutung der toxischen Sauerstoffradikale beim Ischämie/Reperfusionsschaden nach Lebertransplantation in der Ratte." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2004. http://dx.doi.org/10.18452/13953.
Повний текст джерелаАнотація:
Einleitung: Der Ischämie/Reperfusionsschaden (I/R) ist die wesentliche Ursache des frühen Transplantatversagens nach Lebertransplantation (LTx). Fettlebern sind dabei besonders betroffen. Freie Sauerstoffradikale spielen bei der Pathogenese eine zentrale Rolle. Die Morphologie der so versagenden Transplantatleber ist charakterisiert durch Entzündung, Nekrose und Apoptose. Endogene Radikalfänger wie die Superoxiddismutase (SOD), nicht aber exogen zugefuhrte, bauen freie Radikale ab. Das Ziel der vorgelegten Studien war es, im Modell der LTx von gesunden und verfetteten Lebern in der Ratte mittels adenoviralem Gentransfer von SOD den I/R zu vermindern, die Überlebensrate zu erhöhen und zugrunde liegende Mechanismen aufzuzeigen. Methoden: Bei Experimenten mit verfetteten Lebern wurde eine ausgeprägte Steatose der Spenderlebern durch Füttern einer Ethanol- und fettreichen Diät (Lieber-DiCarli) erzeugt. Explantierte Lebern wurden für 24 h konserviert und orthotop transplantiert. Einigen Spendern wurde 72 h vor Organentnahme Cu/Zn-SOD enthaltendes Adenovirus (Ad.SOD1) i.v. appliziert. Als Kontrollen dienten Fettlebern, welche mit dem Gen von b-Galaktosidase (Ad.lacZ) transfiziert wurden, oder aber gesunde Lebern. Untersuchungsparameter waren neben Transfektionsparametern die Transaminasen, histopathologische Morphologie, Überlebensraten, sowie die Aktivierung von Transkriptionsfaktoren und deren Kinasen. Freie Radikale wurden in der Galle mittels Elektronenspin-Resonanz-Spektroskopie nachgewiesen. In weiteren Experimenten wurden auch die mitochondriale und die extrazelluläre Isoform hinsichtlich ihrer protektiven Wirkung untersucht. Ebenso wurde die Auswirkung der freien Radikale auf die Regeneration nach Teillebertransplantation untersucht. Ergebnisse: 72 h nach Injektion von Ad.lacZ exprimierten etwa 80% aller Hepatozyten die b-Galaktosidase. In der Ad.SOD1 Gruppe war die Genexpression 3-fach, die Aktivität 12-fach erhöht. Im Vergleich zu den unbehandelten oder Ad.lacZ infizierten Empfängern von Fettlebern, stiegen die Transaminasen um etwa 50% bei der Ad.SOD1 Gruppe an. Alle Empfänger von Ad-SOD1 behandelten Fettlebern überlebten, hingegen nur 10% der Ad.lacZ Gruppe. Etwa 35% der Hepatozyten von Fettlebern waren nekrotisch, jedoch nur 10% in Ad.SOD1-behandelten Fettlebern. Ad.SOD1 halbierte die Freisetzung von freien Radikalen und minimierte die Aktivierung von NF-kB. Die Aktivität der Kinase IKK wurde nicht reduziert, der Anstieg der Aktivität von JNK jedoch komplett inhibiert. Die Freisetzung von TNFa wurde nicht beeinflußt. Als wirksamste Isoform hat sich die zytosolische erwiesen, die extrazelluläre ist nach Überexpression ohne protektive Wirkung. Die Leberregeneration läßt sich nach Transplantation durch SOD-Überexpression massiv anregen und das Organversagen bei kritischer Leberzellmasse vermeiden. Schlußfolgerung: Diese Studie zeigt erstmals die Wirksamkeit einer neuen Strategie zur Organprotektion fur gesunde Lebern und Fettlebern. Die Eliminierung von Sauerstoffradikalen spielt bei der Pathogenese eine Schlüsselrolle. Der adenoviraler Gentransfer von SOD stellt ein gangbares therapeutisches Verfahren für die Zukunft dar, um auch marginale, verfettete Organe vor reperfusionsbedingtem Versagen zu schützen. Dabei ist die zytosolische SOD am effektivsten. Auch bei der Teilleber-Transplantation ist diese Therapieform erfolgversprechend.Background: Oxygen-derived free radicals play a central role in pathomechanisms of reperfusion injury after organ transplantation, and fatty livers are particularly susceptible. Endogenous radical scavenger systems such as superoxide dismutase (SOD) degrade toxic radicals; however, SOD is degraded rapidly when given exogenously. Therefore, the hypothesis that treatment of the donor liver with an adenoviral vector encoding the Cu/Zn-SOD gene (Ad.SOD1), or the Mn-SOD gene or the ec-SOD gene would lead to permanent gene expression and therefore protect the organ against injury and increase survival in a rat model of liver transplantation including fatty livers was tested. Transplantation of reduced-size livers may lead to a hypermetabolic state and increased production of oxygen radicals. Since oxygen radicals may cause liver injury and impair liver regeneration, we tested the hypothesis that overexpression of superoxide dismutase (SOD) in reduced-size livers (RSL) would accelerate regeneration and reduce injury in a rat model of transplantation of RSL. Methods: Donors received chow diet (untreated), high-fat diet, or ethanol-containing high-fat diet. Some donors were infected with Ad-SOD1, while untreated grafts and livers infected with the indicator gene lacZ encoding bacterial b-galactosidase (Ad.lacZ) served as controls. Some livers were harvested 72 hours later, reduced to 45% of weight, and transplanted. After liver transplantation, SOD activity and protein expression in liver, survival, histopathology, release of transaminases, free radical adducts in bile and activation of NF-kB, IkB kinase (IKK), Jun-N-terminal kinase (JNK) and TNFa were evaluated. Moreover, in transplanted split-livers regeneration was evaluated by Brdu-staining, and measurement of cyclinD1 and p21. Results: Approximately 80% of hepatocytes expressed b-galactosidase 72h after injection of Ad-lacZ. Moreover, SOD1 gene expression and activity were increased 3- and 10-fold in the Ad-SOD1 group, respectively. Following transplantation, 20-25% of rats treated with Ad.lacZ survived. In contrast, all SOD1-treated animals survived. Transaminases measured 8h after transplantation in Ad-SOD1 rats were only 40% of those in controls which increased 40-fold above normal values. Approximately 20% of hepatocytes in untreated and Ad.lacZ-infected organs were necrotic 8h after reperfusion, whereas necrosis was nearly undetectable in grafts from rats treated with Ad.SOD1. Free radical adducts were increased 2-fold in the ethanol group compared to untreated controls. Ad.SOD1 blunted this increase and reduced the activation of NF-kB, which was similar in untreated and ethanol-treated groups. Ad.SOD1 did not affect activity of IKK, but JNK activity was blunted. Release of TNFa was not affected. In recipients of Ad.SOD1-RSL survival was dramatically increased (100% vs. 20% in Ad.lacZ-RSL), and peak levels of AST/ALT and bilirubin levels were reduced by 75% and 87.5%, respectively (p
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Glanemann, Matthias. "Mechanische und pharmakologische Organkonditionierung im Rahmen warmer Leberischämie." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2005. http://dx.doi.org/10.18452/13969.
Повний текст джерелаАнотація:
In der vorliegenden Arbeit wurden zwei Verfahren untersucht, die eine erfolgreiche Protektion vor hepatischer Ischämie/Reperfusionsschädigung versprachen: ischämische Präkonditionierung (IP) und pharmakologische Konditionierung mit Methylprednisolon (MP). Dabei wurde zunächst das Ausmaß der hepatozellulären Schädigung nach warmer Leberischämie durch Abklemmen der blutzuführenden Gefäße im Ligamentum hepatoduodenale (Pringle-Manöver) analysiert, wobei beide Behandlungsstrategien eine vergleichbar starke Gewebsprotektion erzielten. Nach 70%-iger Leberteilresektion mit Pringle-Manöver war jedoch trotz reduzierter Ischämie/Reperfusionsschädigung die Leberregeneration nach IP-Behandlung nachhaltig eingeschränkt. Im Gegensatz dazu waren die regenerativen Vorgänge nach MP-Behandlung nicht schneller, aber doch mit einer vergleichbaren Kinetik zu unbehandelten, ischämischen Kontrollen abgelaufen. Zusammenfassend gilt, daß sowohl IP- als auch MP-Behandlung die Ischämie/Reperfusionsschädigung deutlich reduzieren. Dies hat jedoch keinen positiven Einfluß auf die nachfolgende Regeneration nach Leberteilresektion mit Pringle-Manöver.The present study analyses two strategies to protect from hepatic ischemia-reperfusion injury: ischemic preconditioning (IP) and pharmacologic administration of methylprednisolone (MP). First, the extent of hepatocellular damage after warm liver ischemia induced by cross clamping of the hepatic vessels in the hepatoduodenal ligament (Pringle manöver) was analysed demonstrating comparable tissue protection by both treatment modalities. After 70% partial hepatectomy including Pringle manöver however, the hepatocellular regerneration was markedly decreased after IP treatment, despite reduced ischemia-reperfusion injury. Moreover, MP treatment did not improve hepatic regeneration since it showed a comparable timing to untreated, ischemic controls. In conclusion, both IP and MP significantly reduced hepatic ischemia-reperfusion injury. However, no beneficial effects on hepatocellular regeneration after partial hepatectomy including pringle manöver were observed.
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Morais, Lúcio Kenny. "Efeito do pré-condicionamento isquêmico remoto no transplante ortotópico de fígado de doadores em parada cardíaca. Estudo experimental em suínos." Universidade Federal de Goiás, 2012. http://repositorio.bc.ufg.br/tede/handle/tede/8061.
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Introduction: Improved liver function from non-heart-beating donors seems to be related to short periods of warm ischemia; hence ischemia-reperfusion injury is a critical unsolved issue. Remote Ischemic preconditioning (PC) has been shown to protect the liver from ischemia-reperfusion injury. However little is known about the usefulness of ischemic precondition as a strategy to improve tolerance of non-heart-beating liver grafts to warm ischemia. Therefore we designed an experimental study aiming the effects of ischemic preconditioning on liver transplantation from non-heart-beating donors. Methods: Protocol was approved by Federal University of Goias Ethics Committee. Twentyfour Landrace pigs were assigned into 4 groups: I: after cardiac arrest livers were procured and transplanted; II: after PC and cardiac arrest livers were procured and transplanted; III: after PC and cardiac arrest, a 15 minutes period of warm ischemia was observed before livers were procured and transplanted; IV: after PC and cardiac arrest, a 30 minutes period of warm ischemia was observed before livers were procured and transplanted. Donors: cardiac arrest was obtained by ligation of coronary arteries and interruption of ventilation. PC (10` x 10`) and warm ischemia waiting time were observed accordingly. Livers were flushed with 4°C HTK solution cooled and procured. Recipients: standard technique was used. After one hour of reperfusion, blood and liver samples were collected and euthanasia was carried out. Non-parametrical statistical tests were applied. Results were expressed as medians. A value of p<0.05 was considered statistically significant. Results: AST, ALT, lactic acid and factor V levels were similar for the different studied groups by the end of one hour of reperfusion. A trend towards a deteriorated liver function was observed in group IV. When histological variables were addressed, vacuolization of hepatocytes and cell dropout scores were similar in all groups. Congestion score, vacuolization of hepatocytes and cell dropout scores tended to be higher in animals from group IV, but with no statistical significance. Conclusions: Remote ischemic preconditioning showed no benefits to liver grafts from nonheart- beating donors. Even though it did not result in benefits, no prejudice could be noticed in this research, as well.
Introdução: A melhora na função hepática em doadores de coração parado parece estar relacionada a curtos períodos de isquemia normotérmica, logo a lesão de isquemia e reperfusão é uma questão crucial não resolvida. O pré-condicionamento isquémico remoto (PC), promove proteção ao fígado da lesão de isquemia e reperfusão. No entanto, pouco se sabe sobre a utilidade do PC como uma estratégia para melhorar a tolerância de enxertos de doadores em parada cardíaca frente à isquemia normotérmica. Portanto, foi desenvolvido um estudo experimental visando os efeitos do pré-condicionamento isquêmico no transplante de fígado de doadores em parada cardíaca.Métodos: O protocolo do estudo foi aprovado na Universidade Federal de Goiás pelo Comitê de Ética em Pesquisa. Vinte e quatro suínos da raça Landrace foram divididos em 4 grupos: I: após parada cardíaca, o fígado foi captado e transplantado; II: após o PC, promoveu-se a parada cardíaca, seguida de captação e transplante hepático; III: após o PC, promoveu-se a parada cardíaca, seguida de um período de 15 minutos de isquemia normotérmica, com captação e transplante hepático em seguida; IV: após o PC, promoveu-se a parada cardíaca, seguida de um período de 30 minutos de isquemia normotérmica, com captação e transplante hepático em seguida. Nos doadores, a parada cardíaca foi obtida pela ligadura das artérias coronárias e interrupção do suporte ventilatório. O PC (10 'x 10') e o tempo de isquemia normotérmica foram observados em conformidade com a padronização. O fígado foi perfundido com solução HTK resfriada a 4 ° C e posteriormente captado. Para o receptor foi utilizada a técnica padrão. Após uma hora de reperfusão, amostras de sangue e de tecido hepático foram coletadas, seguida da realização da eutanásia. Foram aplicados testes estatísticos não-paramétricos. Os resultados foram expressos em medianas. O valor de p <0,05 foi considerado estatisticamente significativo. Resultados: Os valores encontrados de AST, ALT, lactato e fator V foram semelhantes para os diferentes grupos estudados até o fim do experimento. No entanto, foi observado uma tendência para piora da função hepática no grupo IV. Em relação às variáveis histológicas, a vacuolização dos hepatócitos e a desestruturação celular foram semelhantes em todos os grupos; houve uma tendência de aumento da congestão no grupo IV, sem significância estatística. Conclusões: O pré-condicionamento isquêmico remoto não mostrou benefício para enxertos de fígado de parada cardíaca. Mesmo que o PC não tenha promovido benefícios nesta pesquisa, também não foram observados danos.
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He, Zhong-De, and 何鐘德. "PROTECTIVE EFFECT OF HONOKIOL ON RAT LIVER AGAINST ISCHEMIA- REPERFUSION INJURY." Thesis, 1996. http://ndltd.ncl.edu.tw/handle/94304226894410364954.
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Chiu, En-Yu, and 邱恩郁. "Protective Effect of KMUP-1 Against Ischemia-Reperfusion Injury In Liver." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/88699181037702214022.
Повний текст джерелаАнотація:
碩士高雄醫學大學
藥理學研究所
98
Hepatic ischemia-reperfusion (I/R) -induced injury is a major cause of morbidity and mortality associated with liver transplantation and resectional surgery as well as septic and hemorrhagic shock. Indeed, there is a large body of experimental and clinical evidence suggesting that I/R induced by these surgical procedures or pathophysiological events injures the liver and may ultimately lead to tissue dysfunction and possibly liver failure. These surgical procedures or pathophysiological events usually results in oxidative stress, hepatocyte death, endothelial cell damage and microcirculatory disturbances, leading to liver dysfunction. Previous reports have defined this injury as bi-phasic, having both an acute and a sub-acute phase. The acute phase occurs within the first 6 h of reperfusion and is characterized by the activation of resident Kupffer cells, resulting in enhanced production of reactive oxygen species (ROS). Historically, enhanced ROS production has been thought to generate severe oxidative stress to the tissue by virtue of its ability to degrade membrane lipids and/or proteins. A growing body of experimental evidence suggests that nitric oxide (NO) may also modulate I/R-induced tissue injury in various organ systems. In vitro and in vivo data suggest that endothelial nitric oxide synthase (eNOS)-derived NO may act to protect tissue by virtue of its ability to react with and decompose ROS, and interfere with Caspase activation. Guanosine 3’,5’cyclic momnophosphate (cGMP), a key intracellular second messenger molecule, has been shown to up-regulate Bcl-2 expression in some cells. Phosphodiesterase 5 (PDE5) inhibition results in raising the intracellular cGMP concentration which subsequently activates cytosolic cGMP-dependent protein kinase (PKG). Previous studies demonstrated that PKG expression increased the protective effect against necrosis and apoptosis following simulated ischemia and reoxygenation. KMUP-1, a xanthine derivative, was demonstrated to promote vasodilation, inhibition of PDEs, enhancement of cGMP, and activation of K+ channels. In this study, we investigated the protective effects and pharmacological mechanism of action of KMUP-1 in liver after I/R. Male Wistar rats were randomly divided into five groups, as follows: Sham-operated group, I/R with Vehicle group, I/R with KMUP-1 0.25 mg/kg group, I/R with KMUP-1 0.5 mg/kg group, and I/R with KMUP-1 1 mg/kg group. They underwent 70% partial hepatic ischemia for 45 minutes and subsequent reperfusion for 240 miniutes. Sham-operated group underwent all surgical procedure except ligation of portal triad. All rats were treated by bolus injection via femoral vein (i.v.) 10 min before partial ischemia. They were sacrificed at 240 minutes after reperfusion. In a rat model of acute hepatic ischemia-reperfusion, administration of KMUP-1 inhibited I/R-induced apoptosis, as detected by ladder-pattern fragmentation of genomic DNA. KMUP-1 improved parameters of liver function, enhanced protein expressions of eNOS/ cGMP/ PKG pathway, and ratio of Bcl-2/ Bax and decreased ROS production and caspase-3 activation. In conclusion, these results suggest that KMUP-1 may protect liver from I/R-induced apoptosis by scavenging free radicals and regulating the protein expression of Bcl-2 family and eNOS/ cGMP/ PKG pathway. Thus, KMUP-1 will be useful clinically in the prevention of acute hepatic ischemia-reperfusion injury.
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Pommey, Sandra Aude Isabelle. "Over-expression of human CD39 in mouse liver protects against ischemia reperfusion injury in a model of liver transplantation." 2009. http://repository.unimelb.edu.au/10187/5625.
Повний текст джерелаАнотація:
Primary graft non-function is one of the major limitations of organ transplantation increasing the risk of rejection and early graft failure. A major cause of primary non-function is ischemia reperfusion injury (IRI), an obligatory insult in transplantation. During procurement, the donor is subjected to a period of ischemia inducing the release of tissue-damaging factors such as nitric oxide and reactive oxygen species. Upon engraftment and reperfusion with the recipient blood, these ischemia-induced factors cause rapid cell death and amplification of the inflammatory response leading to further tissue damage.CD39 is an integral vascular and immune ectonucleotidase. CD39 hydrolyses extracellular nucleotides ATP and ADP into AMP, which is then hydrolysed into adenosine by CD73. Extracellular adenosine produced by the concerted action of CD39 and CD73 has potent anti-inflammatory and anti-coagulation effects acting principally via the purinergic adenosine receptor A2a.
NKT cells have only recently been recognised and constitute an important subset of T lymphocytes that display both effector and suppressive functions. NKT cells are found in high proportion in the liver of mice and are implicated by depletion studies in protection against hepatic IRI.
We have generated mice transgenic for human CD39 (hCD39) and have shown they have an anti-coagulant phenotype. As CD39 is also critical to immune regulation we hypothesised that transgenic expression of hCD39 would modify lymphocyte development and/or function and consequently impact on ischemia reperfusion injury.
Flow cytometric analysis was used to assess the number and phenotype of lymphocytes within the thymus and in the periphery of hCD39 transgenic mice. In vitro and in vivo assays were used to test the function of CD4+ T cells and invariant NKT cells from hCD39 transgenic mice. Bone marrow adoptive transfers experiments defined the role of hCD39 expression on bone marrow progenitor cells in comparison to tissue expression. The importance of adenosine signalling through the A2a receptor was studied by crossing hCD39 transgenic mice with A2a receptor knock-out (KO) mice. The effect of hCD39 expression on ischemia reperfusion injury was evaluated in a model of murine liver transplantation
A high level of hCD39 expression in the transgenic thymus resulted in lymphocyte maturation blockade and peripheral lymphopenia of CD4+ T cells and invariant NKT cells. Both lymphocyte populations were functionally deficient. The observed phenotype resulted from the expression of hCD39 on bone marrow progenitor cells but was independent of A2a receptor signalling. Over-expression of hCD39 in transgenic livers was protective against ischemia reperfusion injury induced by cold storage and liver transplantation.
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Lin, Han-Chen, and 林含貞. "The Protective Effects of Ischemic Postconditioning on Liver Ischemia-reperfusion Injury Among Rats." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/06248672235876015037.
Повний текст джерелаАнотація:
碩士國立臺灣大學
解剖學暨生物細胞學研究所
98
Introduction: Ischemic postconditioning (iPoC), a repetitive, brief ischemia- reperfusion maneuver performed at or before the initiation of tissue reperfusion, has been shown to mitigate reperfusion injury in heart and brain. The aim of this study is to investigate the effects of iPoC on liver ischemia- reperfusion injury. Methods: Partial liver ischemia-reperfusion injury is induced by clamping the left lobes of liver for 45 minutes on male Wistar rats (160 g- 180 g). Three cycles of one-minute’s ischemia-reperfusion of the liver, performed by clamping and de-clamping of the liver, are applied before the commencement of reperfusion as the iPoC maneuver. Blood and liver samples are harvested at 240 minutes after reperfusion for end-point assessments which include serum GPT, H&E staining, TUNEL staining, and electron microscopy (EM) study. The results are compared between the sham, sham+ATR(atractyloside), control , postconditioning (iPoC) and postconditioning+ATR (iPoC+ATR) groups. Results: Our data shows that there are no differences in the basal GPT levels of the five groups, but ischemic postconditioning could reduce the elevation of serum GPT level after reperfusion for 240 minutes (174.0±28.3 U/L v.s 416.3±16.7 U/L, p <0.05), and decrease the percentage of apoptotic hepatocytes(44.9±9.9 % v.s 81.1±13.8 %，p<0.05). The co-treatment with iPoC and ATR (iPoC+ATR) could increase the elevation of serum GPT and the number of apoptotic hepatocytes. There are no differences between iPoC+ATR and control groups in serum GPT level after reperfusion for 240 minutes (557.0±86.7 U/L v.s 416.3±16.7 U/L, p=0.18) and the percentage of apoptotic hepatocytes ((63.2±4.0 % v.s 81.1±13.8 %，p=0.09). EM study showed the morphology of mitochondria is more intact after reperfusion when compared to those in control group. Western blot shows increased cytochrome c expression in cytosol portion after reperfusion injury of liver, and postconditioning decreased the expression of cytochrome c after reperfusion. The co-treatment with iPoC and ATR could increase the expression of cytochrome c after reperfusion. Conclusions: This study shows that ischemic postconditioning can attenuate cell deaths after reperfusion injury of liver. The mechanism of protection conferred by postconditioning is related to reduced cytochrome c release, and mediation of mitochondrial permeability transition pore (mPTP).
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Hartkorn, Andreas [Verfasser]. "Different approaches to influence the ischemia, reperfusion injury of the liver / Andreas Hartkorn." 2008. http://d-nb.info/990802906/34.
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Müller, Christian. "Alpha-Lipoic acid attenuates Ischemia reperfusion injury of the Rat Liver : mechanisms of protection." 2002. http://edoc.ub.uni-muenchen.de/239/.
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Tian, Yu-Feng, and 田宇峯. "Effects of Antrodia camphorate precondition against ischemia-reperfusion injury of the liver in rats." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/14121268590174437433.
Повний текст джерелаАнотація:
碩士南台科技大學
生物科技系
98
It has been found that in recent years the incidence of liver diseases has been increasing greatly in Taiwan. Chronic liver diseases and liver cirrhosis are at the sixth among the top ten causes of death recently. Furthermore, liver cancer is the leading cause of cancer mortality. Liver resection and liver transplantation are the main therapy. Ischemia-reperfusion injury plays an important role during liver resection or liver transplantation. Ischemia-reperfusion (I/R) injury of the liver may occur under many clinical conditions, such as hepatic trauma, hepatic transplantation, hypoperfusion shock or partial hepatectomy for liver tumors. Until now, the actual mechanisms remain unknown. There is evidenced that the sequence of hepatic I/R injury may cause severe liver injury. It was suggested that the increase of Kupffer cells activation induced reaction oxygen species involves the possible mechanisms. Activation of Kupffer cells results in production and release of proinflammatory cytokins, including tumor necrosis factor α (TNF-α) and interleukin 1(IL-1β), chemokines, and neutrophil activation, lead to sinusoid endothelial cell death and hepatic cell damage. The period of hepatic ischemia associated with this technique and the resultant reperfusion can lead to liver injury and dysfunction, which is the main cause of death after hepatectomy. Thus, hepatic I/R injury has been actively investigated, and recently, protective strategies consisting of surgical interventions, pharmacological agents, and gene therapy have been reported. Therefore, enhancing the safety of hepatic surgery and diminishing the significant rates of morbidity and mortality are the most important task in clinical therapy. In Taiwan, Antrodia camphorate(AC) is an exclusive fungus parasitic on the inner cavity of the endemic species Cinnamomum kanehirai Hayata and an important traditional Chinese medicinal fungus(Basidiomycetes) for the treatment of human disease such as food and drug intoxication, abdominal pain, hypertension and liver cancer. Recently, polysaccharides extracted from fruiting bodies and mycelial cultures of Antrodia camphorate are reported to provide several therapeutic benefits including anti-inflammation, antioxidation, vasorelaxation and anti-hepatitis B virus activities, but the underlying molecular mechanisms are obscure. Our study had four groups which included ischemia reperfusion group、0.2 g/kg AC + I/R group、AC sham group and normal control group. The I/R rats are treated with 0.2 g/kg Antrodia camphorate (AC) 30 minute before ischemia (IR, ischemia 30min + 0.2 g/kg A.C.), than reperfusion 6h or reperfusion 7 day. Rat serums which were assayed TNF-αquantity by ELISA were extrated before ischemia、after reperfusion 2h and 6h. The serums which were assayed IL-6 and IL-10 quantity by ELISA were extrated before ischemia、after reperfusion 1h, 2h, 3h, 4h, 5h and 6h. After reperfusion 6h the serums were also assayed glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT) quantity. Liver tissue【left lateral lobe(ischemia liver) and right lateral lobe(nonischemia liver】will be taken for measuring lipid peroxidation(MDA assay).liver tissue will also be taken for paraffin-embedded tissue sections which were respectively stained by H&E or TUNEL, and observed histopathology and liver cell apoptosis. In these results, the ischemia reperfusion animal modal was successful，when MBP decreased at ischemia stage and increased gradually at reperfusion stage. Furthermore the liver was black and necrosis during reperfusion 6h. Pretreated Antrodia camphorate, we detected that rat GPT concentration was improved at reperfusion 6h stage, contrasted with IR control (P＜0.05), but GOT concentration was decreased slighter in pretreated Antrodia camphorate. The paraffin-emmbedded tissue sections which were stained by H&E showed that AC could diminish hepatocyte vacuolar degeneration, vascular congestion and less severe hepatic necrosis in liver grafts at reperfusion 6 hours. The physiology monitory result showed : 1. After ischemia injury, AC could avoid high body temperature. 2. At ischemia stage, AC could maintain heart rate stability. 3. Contrasted with IR control, AC could maintain blood pressure stability at reperfusion 3~6 h. Under other hand, AC could reduce the TNF-α、IL-6 quantity of liver ischemia reperfusion injury rat serum, and suppress inflammation reaction. In AC therapy group, because inflammation reaction were be suppressed, IL-10 quantity range on the rise were be down regulating in serum. When we assayed MDA level., which was decreased at Antrodia camphorate pretreatment, compared with IR control after reperfusion 6h. In the result of TUNEL stain, AC reduced severe hapatic cell DNA fragmentation and apoptosis in liver at reperfusion 6 hours. At reperfusion 7 day, we found AC which could increase the survival rate to 80％。 In this study, we had established rat liver ischemia reperfusion modal. The results suggested, effect of Antrodia camphorate precondition to protect was good, which could reduce liver ischemia reperfusion injury. In the future, we will investigate the mechanism of protection with Antrodia camphorate, and add other medicine or therapy method which can increase the curative effect of liver ischemia reperfusion injury.