Liver Reperfusion Research Articles

Baicalein Preconditioning Modulates Hepatocellular Injury following Liver Ischemia and Reperfusion in Rats via Anti-Inflammatory and Antioxidant Signaling

Background: Hepatic ischemia/reperfusion (I/R) is a frequent and major complication during liver transplantation. Baicalein, a plant flavonoid, has anti-inflammatory and antioxidant effects. However, whether these effects mediate its protective effects in liver I/R injury remains poorly understood. Objective: This study was designed to investigate the effects of baicalein preconditioning on liver I/R in rats and the underlying mechanisms. Methods: Baicalein (300 mg/kg) was intraperitoneally injected 30 min before 45 min of ischemia followed by 1 h of reperfusion. Results: Baicalein preconditioning attenuated liver I/R injury, as indicated by a reduction in serum aminotransferase activities and an improvement of histopathological abnormalities. Baicalein also significantly reduced the activity of the cellular hepatic proapoptotic enzyme caspase-3 in response to I/R injury. Moreover, baicalein significantly reduced nuclear factor kappa-B expression and the subsequent proinflammatory cytokine production, tumor necrosis factor alpha (TNF-α) level, increased interleukin-10 (IL-10), an anti-inflammatory cytokine, reduced the TNF-α/IL-10 ratio, and suppressed leukocyte infiltration. It increased hepatic antioxidants and reduced lipid peroxidation. Conclusion: Taken together, bai­calein preconditioning would seem to protect against liver I/R injury via antioxidant, antiapoptotic, and anti-inflam­matory effects.

Up-regulation of FOXO1 and reduced inflammation by β-hydroxybutyric acid are essential diet restriction benefits against liver injury

Liver ischemia and reperfusion injury (IRI) is a major challenge in liver surgery. Diet restriction reduces liver damage by increasing stress resistance; however, the underlying molecular mechanisms remain unclear. We investigated the preventive effect of 12-h fasting on mouse liver IRI. Partial warm hepatic IRI model in wild-type male C57BL/6 mice was used. The control ischemia and reperfusion (IR) group of mice was given food and water ad libitum, while the fasting IR group was given water but not food for 12 h before ischemic insult. In 12-h fasting mice, serum liver-derived enzyme level and tissue damages due to IR were strongly suppressed. Serum β-hydroxybutyric acid (BHB) was significantly raised before ischemia and during reperfusion. Up-regulated BHB induced an increment in the expression of FOXO1 transcription factor by raising the level of acetylated histone. Antioxidative enzyme heme oxigenase 1 (HO-1), a target gene of FOXO1, then increased. Autophagy activity was also enhanced. Serum high-mobility group box 1 was remarkably lowered by the 12-h fasting, and activation of NF-κB and NLRP3 inflammasome was suppressed. Consequently, inflammatory cytokine production and liver injury were reduced. Exogenous BHB administration or histone deacetylase inhibitor administration into the control fed mice ameliorated liver IRI, while FOXO1 inhibitor administration to the 12-h fasting group exacerbated liver IRI. The 12-h fasting exerted beneficial effects on the prevention of liver IRI by increasing BHB, thus up-regulating FOXO1 and HO-1, and by reducing the inflammatory responses and apoptotic cell death via the down-regulation of NF-κB and NLRP3 inflammasome.

Prophylactic Use of Laser Light and Methylene Blue on Ischemia and Liver Reperfusion Injury

ObjectiveThis study aimed to evaluate the effect of hepatic preconditioning with laser light in the presence of methylene blue (MB) in the liver ischemia-reperfusion injury process. MethodForty male Wistar rats were divided into 8 experimental groups (n = 5). Saline (.5 mL) or MB (15 mg/kg) was injected intravenously (inferior vena cava). After 2 minutes, 660 nm laser light was applied at a dose of 112.5 DE. Fifteen minutes after the application of saline or MB, 1 hour partial ischemia followed by 15 minutes of reperfusion was applied when the rats were sacrificed. The mitochondrial function parameters (O2 consumption rates in states 3 and 4 and the respiratory control ratio), osmotic swelling, and determination of malondialdehyde were evaluated. Hepatic function was studied using the serum determination of the alanine aminotransferase and aspartate aminotransferase enzymes. Results and ConclusionsMB therapy alone showed the capacity of preserving the rate of oxygen consumption in the mitochondrial respiratory state of the group submitted to ischemia compared to the sham group. However, when combined with low-intensity laser therapy, it failed to replicate the relevant protective effects in relation to oxidative phosphorylation or the mitochondrial membrane ischemia/reperfusion injury. Whether or not MB was combined with laser treatment, it was shown to be efficient in reducing oxidative stress. In relation to alanine aminotransferase enzymes, whether or not laser treatment was combined with MB had a protective effect on the hepatic lesion, whereas in relation to aspartate aminotransferase enzymes only laser treatment was able to provide this protection.

MOLECULAR MECHANISMS OF ISCHEMIC-REPERFUSION INJURY DURING LIVER RESECTION FOR COLORECTAL CANCER METASTASES- STUDY PROTOCOL

Bleeding during liver resection is a significant threat to the clinical outcome. Portal triad occlusion with complete ischemia of the liver flow of hepatoduodenal ligament is a well-documented, safe and useful way to reduce this problem. Although the technique is efficient in limiting blood loss, there is still controversy concerning potential disadvantages and subsequent reperfusion liver injury. A prospective analysis will include at least 30 patients 18-75 years old, who are undergoing liver resection due to metastases of the colorectal carcinoma. After signing the informed consent, the parameters will be analyzed in three phases, pre-, intra- and postoperatively. During surgery (indicated by a surgical/oncological team of doctors not related to our study) liver tissue samples will be taken of the “healthy liver” (not involved in the tumor process) in which after tissue homogenization, analysis of parameters will be done responsible for the development of liver injury. This research will not affect the clinical practice, course and outcome of the treatment in patients who are included. The study may be useful for future patients who will undergo liver resections. The application of modern research methods with scientific validity of statistical processing of data and the use of appropriate literature, significant data will be obtained about the character, i.e. intensity of damage of the liver tissue in patients undergoing liver resections.

Extracellular mitochondria Released from Hepatic Ischemia Reperfusion Induce Macrophage activation both in vitro and in vivo

Abstract Background During liver transplantation ischemia and reperfusion injury (IRI), an immune driven inflammatory response provoked by cellular oxygen deprivation, is unavoidable. The inflammatory responses, resulting from acute oxidative stress and consequent hepatocellular death during the early reperfusion phase, cause the release of endogenous danger signals. Recent studies show that the release of free mitochondria (FM) from deceased organ donors is directly linked with functionally important immune activation and early allograft dysfunction (Pollara, et al., 2018). Organs from donors after cardiocirculatory death (DCD) undergo a prolonged warm ischemia process compared with organs from donors after neurological determination of death (NDD), and therefore have more severe IRI. Herein, we investigated the roles of FM in liver IRI, particularly as related to macrophages. Methods Liver biopsies were assayed by TEM to assess for FM release. FM were co-cultured with macrophages (cell line, bone marrow derived macrophages, and primary Kupffer cells), and injected i.p. in vivo to explore the recruitment and activation of macrophages. Inflammatory mediators were tested by luminex. Results FM levels were significantly higher in IRI. Co-culture of FM with macrophages significantly increased inflammatory mediator release but this process was not Formyl Peptide Receptor 1 dependent. The injection of FM induced significant accumulation of monocyte-derived macrophages and activation of macrophages in the peritoneum. Conclusion Our results indicate that IRI can elicit significantly increased FM, and that FM from hepatic IRI can attract and activate macrophages, which may influence the outcome of liver transplantation.

Allograft Liver Biopsy

Although not ideal, liver biopsy is the best available method for evaluation of the liver and is considered the gold standard. The most common use of liver biopsies in the posttransplantation setting is for diagnosis of allograft dysfunction presenting with abnormal liver chemistry tests. The causes of allograft dysfunction differ according to time. Early on, preservation and reperfusion injury, infection, donor-related disease, and acute rejection are more common. Later, disease recurrence, de novo disease, and chronic rejection are seen more frequently. A complete history and physical examination are followed by ultrasonography with Doppler. If biliary or vascular causes are suspected, further imaging is performed and stents or surgery planned. If these tests are not diagnostic, a liver biopsy is performed. In addition to diagnosis of allograft dysfunction, protocol liver biopsy can be helpful particularly to diagnose disease recurrence, particularly the immune-mediated diseases, as well as to evaluate the patient for eligibility for immunosuppression minimization and possible withdrawal. Given the risks and cost associated with liver biopsy, several methods are used for evaluation of fibrosis and rejection in the liver allograft. Although very promising, these methods have not been widely validated and are not ready for clinical use. This review contains 9 figures, 2 tables, and 54 references. Key Words: biopsy to diagnose allograft liver dysfunction, disease recurrence after liver transplant, immunosuppression withdrawal after liver transplant, liver biopsy to guide immunosuppression minimization, noninvasive methods to evaluate liver allograft, posttransplant diagnostic liver biopsy, preservation and reperfusion injury, protocol liver biopsy after transplant

Allograft Liver Biopsy

Although not ideal, liver biopsy is the best available method for evaluation of the liver and is considered the gold standard. The most common use of liver biopsies in the posttransplantation setting is for diagnosis of allograft dysfunction presenting with abnormal liver chemistry tests. The causes of allograft dysfunction differ according to time. Early on, preservation and reperfusion injury, infection, donor-related disease, and acute rejection are more common. Later, disease recurrence, de novo disease, and chronic rejection are seen more frequently. A complete history and physical examination are followed by ultrasonography with Doppler. If biliary or vascular causes are suspected, further imaging is performed and stents or surgery planned. If these tests are not diagnostic, a liver biopsy is performed. In addition to diagnosis of allograft dysfunction, protocol liver biopsy can be helpful particularly to diagnose disease recurrence, particularly the immune-mediated diseases, as well as to evaluate the patient for eligibility for immunosuppression minimization and possible withdrawal. Given the risks and cost associated with liver biopsy, several methods are used for evaluation of fibrosis and rejection in the liver allograft. Although very promising, these methods have not been widely validated and are not ready for clinical use. This review contains 9 figures, 2 tables, and 54 references. Key Words: biopsy to diagnose allograft liver dysfunction, disease recurrence after liver transplant, immunosuppression withdrawal after liver transplant, liver biopsy to guide immunosuppression minimization, noninvasive methods to evaluate liver allograft, posttransplant diagnostic liver biopsy, preservation and reperfusion injury, protocol liver biopsy after transplant

Sevoflurane Preconditioning plus Postconditioning Decreases Inflammatory Response with Hemodynamic Recovery in Experimental Liver Ischemia Reperfusion.

Objective The inhalation anesthetic sevoflurane has presented numerous biological activities, including anti-inflammatory properties and protective effects against tissue ischemic injury. This study investigated the metabolic, hemodynamic, and inflammatory effects of sevoflurane pre- and postconditioning for short periods in the rescue of liver ischemia-reperfusion (IR) injury using a rat model. Materials and Methods Twenty Wistar rats were divided into four groups: sham group, control ischemia group (partial warm liver ischemia for 45 min followed by 4 h of reperfusion), SPC group (administration of sevoflurane 2.5% for 15 min with 5 min of washout before liver IR), and SPPoC group (administration of sevoflurane 2.5% for 15 min before ischemia and 20 min during reperfusion). Results All animals showed a decrease in the mean arterial pressure (MAP) and portal vein blood flow during ischemia. After 4 h of reperfusion, only the SPPoC group had MAP recovery. In both the SPC and SPPoC groups, there was a decrease in the ALT level and an increase in the bicarbonate and potassium serum levels. Only the SPPoC group showed an increase in the arterial blood ionized calcium level and a decrease in the IL-6 level after liver reperfusion. Therefore, this study demonstrated that sevoflurane preconditioning reduces hepatocellular injury and acid-base imbalance in liver ischemia. Furthermore, sevoflurane postconditioning promoted systemic hemodynamic recovery with a decrease in inflammatory response.

Inhibition of Cyclin-dependent Kinase 2 Signaling Prevents Liver Ischemia and Reperfusion Injury.

Liver ischemia and reperfusion injury (IRI) is a major complication of liver transplant, hepatectomy, and hemorrhagic shock. The cyclin-dependent kinase 2 (CDK2) acts as a pivotal regulator of cell cycle and proliferation. This study evaluated the modulation and therapeutic potential of CDK2 inhibition in a mouse model of partial liver warm IRI. Liver IR-triggered intrinsic CDK2 expression, peaking by 0.5 hour of reperfusion and maintaining a high-level throughout 1 to 24 hours. Roscovitine, a specific CDK2 inhibitor, prevented liver IR-mediated damage with abolished serum alanine aminotransferase levels and reserved liver pathology. CDK2 inhibition-mediated liver protection was accompanied by decreased macrophage/neutrophil infiltration, diminished hepatocyte apoptosis, abolished toll like receptor 4 signaling and downstream gene inductions (C-X-C motif ligand-10, Tumor necrosis factor-α, interleukin-1β, and interleukin-6), yet augmented interleukin-10 expression. In vitro, CDK2 inhibition by Roscovitine suppressed macrophage TLR4 activation and further depressed downstream inflammatory signaling (myeloid differentiation factor 88, interferon regulatory transcription factor 3, p38, c-Jun N-terminal kinase, and extracellular-regulated kinase). Our novel findings revealed the critical role of CDK2 in hepatic cytoprotection and homeostasis against liver IRI. As CDK2 inhibition regulated local immune response and prevented hepatocyte death, this study provided the evidence for new treatment approaches to combat IRI in liver transplant.

MicroRNA-449b-5p targets HMGB1 to attenuate hepatocyte injury in liver ischemia and reperfusion.

MicroRNAs (miRNAs) participate in the pathological process of liver ischemia/reperfusion (I/R) injury. MiR-449b-5p is the target miRNA of high mobility group box 1 (HMGB1). Its role and molecular mechanism in liver I/R injury remain unidentified. In this study, we found a protective effect of miR-449b-5p against hepatic I/R injury. HMGB1 expression significantly increased, whereas miR-449b-5p dramatically decreased in patients after liver transplant and in L02 cells exposed to hypoxia/reoxygenation (H/R). A dual-luciferase reporter assay confirmed the direct interaction between miR-449b-5p and the 3' untranslated region of HMGB1 messenger RNA. We also found that overexpression of miR-449b-5p significantly promoted cell viability and inhibited cell apoptosis of L02 cells exposed to H/R. Moreover, miR-449b-5p repressed HMGB1 protein expression and nuclear factor-κB (NF-κB) pathway activation in these L02 cells. In an in vivo rat model of hepatic I/R injury, overexpression of miR-449b-5p significantly decreased alanine aminotransferase and aspartate aminotransferase and inhibited the HMGB1/NF-κB pathway. Our study thus suggests that miR-449b-5p alleviated hepatic I/R injury by targeting HMGB1 and deactivating the NF-κB pathway, which may provide a novel and promising therapeutic target for hepatic I/R injury.

Protective Role of Hepatocyte Cyclooxygenase-2 Expression Against Liver Ischemia-Reperfusion Injury in Mice.

Liver ischemia and reperfusion injury (IRI) remains a serious clinical problem affecting liver transplantation outcomes. IRI causes up to 10% of early organ failure and predisposes to chronic rejection. Cyclooxygenase-2 (COX-2) is involved in different liver diseases, but the significance of COX-2 in IRI is a matter of controversy. This study was designed to elucidate the role of COX-2 induction in hepatocytes against liver IRI. In the present work, hepatocyte-specific COX-2 transgenic mice (hCOX-2-Tg) and their wild-type (Wt) littermates were subjected to IRI. hCOX-2-Tg mice exhibited lower grades of necrosis and inflammation than Wt mice, in part by reduced hepatic recruitment and infiltration of neutrophils, with a concomitant decrease in serum levels of proinflammatory cytokines. Moreover, hCOX-2-Tg mice showed a significant attenuation of the IRI-induced increase in oxidative stress and hepatic apoptosis, an increase in autophagic flux, and a decrease in endoplasmic reticulum stress compared to Wt mice. Interestingly, ischemic preconditioning of Wt mice resembles the beneficial effects observed in hCOX-2-Tg mice against IRI due to a preconditioning-derived increase in endogenous COX-2, which is mainly localized in hepatocytes. Furthermore, measurement of prostaglandin E2 (PGE2 ) levels in plasma from patients who underwent liver transplantation revealed a significantly positive correlation of PGE2 levels and graft function and an inverse correlation with the time of ischemia. Conclusion: These data support the view of a protective effect of hepatic COX-2 induction and the consequent rise of derived prostaglandins against IRI.

Increase in post-reperfusion sensitivity to tissue plasminogen activator-mediated fibrinolysis during liver transplantation is associated with abnormal metabolic changes and increased blood product utilisation.

Increased systemic fibrinolytic activity can occur in liver transplant recipients after the donor graft is reperfused. However, it remains unclear whether this is related solely to tissue plasminogen activator (t-PA) levels or whether unique metabolic changes can alter t-PA activity and enhance fibrinolytic activity. We hypothesise that an increase in sensitivity to t-PA-mediated fibrinolysis (StF) following liver reperfusion is associated with specific metabolic abnormalities. Liver transplant recipients had serial blood samples analysed with a modified thrombelastography assay using exogenous t-PA to measure sensitivity/resistance to fibrinolysis with the lysis 30 min after maximum clot strength (tLY30). Paired plasma samples were analysed with mass spectroscopy-based metabolomics. The tLY30 was correlated to metabolites using Spearman's rho. StF was defined as a tLY30 change of >8.5% from the anhepatic phase to 30 min after reperfusion based on the distribution of tLY30 in a healthy control population. StF occurred in 53% of patients. Cohorts had similar MELD scores (18 vs 16, p=0.876) and tLY30 at baseline (p=0.867) and anhepatic phase of surgery (p=0.463). Thirty min after reperfusion, the tLY30 was 73% in patient with StF vs 33% in those without StF 33% (p=0.006). StF was associated with increased red blood cell transfusions (p=0.035), during the first 2 hours of reperfusion. Nine metabolites demonstrated a correlation with tLY30 (p<0.05). StF is a transient event that resolves within 2 hours of graft reperfusion and is associated with increased blood product use. This phenomenon correlates with derangements in citric acid cycle, purine and amino acid metabolism. Future research is needed to determine whether these metabolites are biomarkers or mechanistically linked to increased sensitivity to t-PA-mediated fibrinolytic activity following graft reperfusion.

Overproduction of Tenascin-C Driven by Lipid Accumulation in the Liver Aggravates Hepatic Ischemia/Reperfusion Injury in Steatotic Mice.

The purpose of this study was to assess the significance of tenascin-C (Tnc) expression in steatotic liver ischemia/reperfusion injury (IRI). The critical shortage in donor organs has led to the use of steatotic livers in transplantation regardless of their elevated susceptibility to hepatic IRI. Tnc is an endogenous danger signal extracellular matrix molecule involved in various aspects of immunity and tissue injury. In the current study, mice were fed with a steatosis-inducing diet and developed approximately 50% hepatic steatosis, predominantly macrovesicular, before being subjected to hepatic IRI. We report here that lipid accumulation in hepatocytes inflated the production of Tnc in steatotic livers and in isolated hepatic stellate cells. Moreover, we show that the inability of Tnc-/- deficient steatotic mice to express Tnc significantly protected these mice from liver IRI. Compared with fatty controls, Tnc-/- steatotic mice showed significantly reduced serum transaminase levels and enhanced liver histological preservation at both 6 and 24 hours after hepatic IRI. The lack of Tnc expression resulted in impaired lymphocyte antigen 6 complex, locus (Ly6G) neutrophil and macrophage antigen-1 (Mac-1) leukocyte recruitment as well as in decreased expression of proinflammatory mediators (interleukin 1β, tumor necrosis factor α, and chemokine [C-X-C motif] ligand 2) after liver reperfusion. Myeloperoxidase (MPO) is the most abundant cytotoxic enzyme secreted by neutrophils and a key mediator of neutrophil-induced oxidative tissue injuries. Using an in vitro model of steatosis, we also show that Tnc markedly potentiated the effect of steatotic hepatocytes on neutrophil-derived MPO activity. In conclusion, our data support the view that inhibition of Tnc is a promising therapeutic approach to lessen inflammation in steatotic livers and to maximize their successful use in organ transplantation.

Изменения мембранного потенциала митохондрий в зависимости от длительности ишемии и реперфузии печени у крыс

Изменения мембранного потенциала митохондрий в зависимости от длительности ишемии и реперфузии печени у крыс

УЧАСТИЕ МОНООКСИД УГЛЕРОДА В КОРРЕКЦИИ РЕПЕРФУЗИОНЫХ ПОВРЕЖДЕНИЙ ПЕЧЕНИ

Reperfusion liver injuries are common in clinical practice during hepatic transplantation, resections or traumas&nbsp;when temporary occlusion of the main vessels (Pringle's maneuver) of the organ is necessary. The purpose of the&nbsp;review is to analyze and summarize our own and literature data about the role of carbon monoxide in the development&nbsp;and correction of hepatic ischemia-reperfusion syndrome in an experiment.

Opposite acute potassium and sodium shifts during transplantation of hypothermic machine perfused donor livers.

Liver transplantation is frequently associated with hyperkalemia, especially after graft reperfusion. Dual hypothermic oxygenated machine perfusion (DHOPE) reduces ischemia/reperfusion injury and improves graft function, compared to conventional static cold storage (SCS). We examined the effect of DHOPE on ex situ and in vivo shifts of potassium and sodium. Potassium and sodium shifts were derived from balance measurements in a preclinical study of livers that underwent DHOPE (n = 6) or SCS alone (n = 9), followed by ex situ normothermic reperfusion. Similar measurements were performed in a clinical study of DHOPE‐preserved livers (n = 10) and control livers that were transplanted after SCS only (n = 9). During DHOPE, preclinical and clinical livers released a mean of 17 ± 2 and 34 ± 6 mmol potassium and took up 25 ± 9 and 24 ± 14 mmol sodium, respectively. After subsequent normothermic reperfusion, DHOPE‐preserved livers took up a mean of 19 ± 3 mmol potassium, while controls released 8 ± 5 mmol potassium. During liver transplantation, blood potassium levels decreased upon reperfusion of DHOPE‐preserved livers while levels increased after reperfusion of SCS‐preserved liver, delta potassium levels were ‐0.77 ± 0.20 vs. +0.64 ± 0.37 mmol/L, respectively (P = .002). While hyperkalemia is generally anticipated during transplantation of SCS‐preserved livers, reperfusion of hypothermic machine perfused livers can lead to decreased blood potassium or even hypokalemia in the recipient.

Multimodality imaging of the Meso-Rex bypass.

Extrahepatic portal vein obstruction (EHPVO) is the most common cause of upper gastrointestinal bleeding in children. It is defined as thrombosis of the extrahepatic portal vein with or without extension to the intrahepatic portal veins. The Meso-Rex shunt is the gold standard treatment in children with favorable anatomy since it restores physiological portal liver reperfusion. This is achieved by rerouting the splanchnic venous blood through an autologous graft from the superior mesenteric vein (SMV) into the Rex recess of the left portal vein, curing portal hypertension by doing so. General and hepatobiliary radiologists must be familiar with multimodality imaging appearances of EHPVO and with the role of imaging in identifying suitable candidates for Meso-Rex bypass surgery. Imaging might also detect complications of this procedure, some of which might be treated via interventional radiology.

Topical hepatic hypothermia associated with ischemic preconditioning. Histopathological and biochemical analysis of ischemia reperfusion damage in a 24 hour model 1.

To develop a new 24 hour extended liver ischemia and reperfusion (LIR) model analyzing the late biochemical and histopathological results of the isolated and combined application of recognized hepatoprotective mechanisms. In addition, we used a new stratification with zoning to classify the histological lesion. A modified animal model of severe hepatic damage produced through 90 minutes of segmental ischemia (70% of the organ) and posterior observation for 24 hours of reperfusion, submitted to ischemic preconditioning (IPC) and topical hypothermia (TH) at 26ºC, in isolation or in combination, during the procedure. Data from intraoperative biometric parameters, besides of late biochemical markers and histopathological findings, both at 24 hours evolution time, were compared with control (C) and normothermic ischemia (NI) groups. All groups were homogeneous with respect to intraoperative physiological parameters. There were no losses once the model was stablished. Animals subjected to NI and IPC had worse biochemical (gamma-glutamyl transpeptidase, alkaline phosphatase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, direct bilirubin, and total bilirubin) and histopathological scores (modified Suzuki score) compared to those of control groups and groups with isolated or associated TH (p < 0.05). The new extended model demonstrates liver ischemia and reperfusion at 24 hour of evolution and, in this extreme scenario, only the groups subjected to topical hypothermia, combined with ischemic preconditioning or alone, had better outcomes than those subjected to only ischemic preconditioning and normothermic ischemia, reaching similar biochemical and histopathological scores to those of the control group.

Sexual Dimorphism in Liver Ischemia and Reperfusion Injury in Mice: Role of Male-Specific Gene SRY

Sexual Dimorphism in Liver Ischemia and Reperfusion Injury in Mice: Role of Male-Specific Gene SRY

Rivastigmine prevents injury induced by ischemia and reperfusion in rat liver.

To evaluate whether pre-treatment with rivastigmine is able to attenuate the I/R induced lesions in rat liver. SHAM animals or those submitted to I/R, non-treated or pre-treated with rivastigminine (2mg/kg) either 50 or 15 minutes before ischemia, were used. After I/R protocol, these animals were killed and their livers were harvested to measurement of the mitochondrial swelling as well as the malondialdehyde (MDA), nitrite and nitrate tissue concentration. Blood was also harvested for serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) determinations. I/R promoted a significant increase of mitochondrial swelling in the studied animals. This increase of mitochondrial swelling was partially prevented by rivastigmine, but only if administered 50 minutes before ischemia. No significant modification of MDA, nitrite or nitrate tissue concentrations was observed in consequence of I/R, followed or not by rivastigmine treatments. In addition, I/R elevated both AST and ALT. These elevations of serum enzymes were not reversed by the different rivastigmine treatments. Rivastigmine administered 50 minutes before ischemia attenuates I/R-induced mitochondrial swelling, that indicates liver injury. This protective effect may be related to a greater stimulation of α7nAChR present in the Kupffer cells by the non-methabolized ACh, leading to an attenuation of I/R-induced inflammation.