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Hepatocellular Injury (hepatocellular + injury)
Selected AbstractsClinical significance of TT virus in chronic hepatitis CJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 2 2001Xiang Wei Meng Abstract Background and Aims: Much is still unknown about the clinical significance of TT virus (TTV), which has been reported as a candidate for non A,G hepatitis virus. The aim of this study was to clarify the clinical significance of TTV in patients coinfected with TTV and hepatitis C virus (HCV). Methods: The 95 subjects studied had chronic hepatitis C (CHC), and underwent interferon (IFN) therapy. TT Virus DNA was detected by using polymerase chain reaction. The nucleotide sequences were determined by using a dideoxy chain termination method. A phylogenetic tree was drawn up by using the neighbor-joining method. Results: TT Virus DNA was detected in 37.9% of patients with the use of an open reading frame 1 (ORF1) primer, and in 88.4% of patients by using a 5, untranslated region (5, UTR) primer. Using both sets of primers, no differences were found between TTV-DNA-positive and -negative subjects with CHC in the clinical findings. Serum TTV DNA was eradicated in 30.6% of patients with the ORF1 primer, and in 19.1% of patients with the 5, UTR primer at 6 months after the cessation of IFN therapy. The levels of TTV DNA before IFN therapy were significantly lower in the viral eradication group than in non-eradication group. The changes in alanine aminotransferase (ALT) concentrations were significantly correlated with changes in HCV-RNA in CHC patients with TTV. Moreover, there was no correlation between the changes in TTV DNA and the course of ALT. Conclusion: Hepatocellular injury in patients with chronic hepatitis who are coinfected with HCV and TTV appears to primarily be caused by HCV and is less attributable to TTV. [source] Remote Liver Injury is Attenuated by Adenovirus-Mediated Gene Transfer of Heme Oxygenase-1 During the Systemic Inflammatory Response SyndromeMICROCIRCULATION, Issue 7 2004SARAH D. MCCARTER ABSTRACT Objectives: Adenovirus-mediated gene therapy is being investigated with increasing success for future treatment of autoimmune diseases. However, the use of adenoviruses is still limited by inflammatory and immune responses in the target organ. Previous work by the authors' laboratory established that the adenovirus encoding inducible heme oxygenase (Ad-HO-1) does not elicit the acute hepatic inflammation normally caused by adenoviruses, inviting further investigation in models of severe inflammation. Concurrently, there is increasing evidence for an endogenous protective role for heme oxygenase (HO) in the liver during the systemic inflammatory response syndrome (SIRS). Building on our previous results, this study investigated the effect of Ad-HO-1 pretreatment on remote liver injury during normotensive SIRS, induced by bilateral hind limb ischemia and reperfusion. Methods: Microvascular perfusion and hepatocyte death were quantified using established intravital videomicroscopy techniques. Hepatocellular injury and liver function were assessed using blood-borne indicators. Results: Microvascular perfusion deficits and increased hepatocyte death occurred following limb ischemia and 3 h of reperfusion in vehicle-pretreated animals; however, Ad-HO-1 pretreatment prevented these deficits. In contrast, the increase in serum alanine transaminase levels was unaffected by Ad-HO-1 pretreatment. Serum bilirubin levels were increased during systemic inflammation, predominantly in the conjugated form; and, this increase was prevented by administration of Ad-HO-1. Conclusions: These data indicate that gene transfer of inducible HO is an effective method to protect the liver during SIRS, providing incentive for further investigation into gene therapy strategies exploiting this anti-inflammatory enzyme. [source] Endothelially Derived Nitric Oxide Affects the Severity of Early Acetaminophen-induced Hepatic Injury in MiceACADEMIC EMERGENCY MEDICINE, Issue 5 2006Steven D. Salhanick MD Abstract Objectives: The precise mechanism of hepatocellular toxicity following acetaminophen (APAP) poisoning remains unclear. Nitric oxide is implicated in APAP toxicity as an inflammatory signaling molecule and as a precursor to the free radical peroxynitrate. The effects of inducible nitric oxide synthase (iNOS)-derived NO in APAP toxicity are known; however, the role of endothelial nitric oxide synthase (eNOS)-derived NO is unknown. The authors sought to evaluate the effect of eNOS-derived NO during APAP toxicity. Methods: C57BL6/J mice deficient in eNOS (eNOS KO) or iNOS (iNOS KO) and wild-type mice (WT) were treated with 300 mg/kg APAP. Alanine aminotransferase levels and plasma nitrate and nitrite levels were measured. Hypoxia inducible factor (HIF)-1, and Glucose Transporter 1 (Glut-1) levels were determined by Western blot. Results: Alanine aminotransferase levels were significantly elevated in all treated animals. Alanine aminotransferase levels were significantly lower in eNOS KO and iNOS KO than in treated WT animals. Plasma nitrate/nitrite levels were significantly higher in WT animals than in iNOS KO and eNOS KO animals. HIF-1, expression was increased in WT mice and decreased in iNOS KO mice. Glut-1 is a downstream, indirect marker of HIF function. Glut-1 expression was increased in WT and eNOS KO mice. Conclusions: Deficiency of either iNOS or eNOS results in decreased NO production and is associated with reduced hepatocellular injury following APAP poisoning. HIF-1, and Glut-1 levels are increased following APAP poisoning, implying that HIF-1, is functional during the pathogenic response to APAP poisoning. [source] Combination therapy using metformin or thiazolidinediones and insulin in the treatment of diabetes mellitusDIABETES OBESITY & METABOLISM, Issue 6 2005Suzanne M. Strowig The biguanide, metformin, sensitizes the liver to the effect of insulin, suppressing hepatic glucose output. Thiazolidinediones such as rosiglitazone and pioglitazone enhance insulin-mediated glucose disposal, leading to reduced plasma insulin concentrations. These classes of drugs may also have varying beneficial effects on features of insulin resistance such as lipid levels, blood pressure and body weight. Metformin in combination with insulin has been shown to significantly improve blood glucose levels while lowering total daily insulin dose and body weight. The thiazolidinediones in combination with insulin have also been effective in lowering blood glucose levels and total daily insulin dose. Triple combination therapy using insulin, metformin and a thiazolidinedione improves glycaemic control to a greater degree than dual therapy using insulin and metformin or insulin and a thiazolidinedione. There is insufficient evidence to recommend the use of metformin or thiazolidinediones in type 1 diabetic patients. Although these agents are largely well tolerated, some subjects experience significant gastrointestinal problems while using metformin. Metformin is associated with a low risk of lactic acidosis, but should not be used in patients with elevated serum creatinine or those being treated for congestive heart failure. The thiazolidinediones are associated with an increase in body weight, although this can be avoided with careful lifestyle management. Thiazolidinediones may also lead to oedema and are associated with a low incidence of hepatocellular injury. Thiazolidinediones are contraindicated in patients with underlying heart disease who are at risk of congestive heart failure and in patients who have abnormal hepatic function. The desired blood glucose-lowering effect and adverse event profiles of these agents should be considered when recommending these agents to diabetic patients. The potential for metformin or the thiazolidinediones to impact long-term cardiovascular outcomes remains under investigation. [source] Dissociation between liver inflammation and hepatocellular damage induced by carbon tetrachloride in myeloid cell,specific signal transducer and activator of transcription 3 gene knockout mice,HEPATOLOGY, Issue 5 2010Norio Horiguchi Liver injury is associated with inflammation, which is generally believed to accelerate the progression of liver diseases; however, clinical data show that inflammation does not always correlate with hepatocelluar damage in some patients. Investigating the cellular mechanisms underlying these events using an experimental animal model, we show that inflammation may attenuate liver necrosis induced by carbon tetrachloride (CCl4) in myeloid-specific signal transducer and activator of transcription 3 (STAT3) knockout mice. As an important anti-inflammatory signal, conditional deletion of STAT3 in myeloid cells results in markedly enhanced liver inflammation after CCl4 injection. However, these effects are also accompanied by reduced liver necrosis, correlating with elevated serum interleukin-6 (IL-6) and hepatic STAT3 activation. An additional deletion of STAT3 in hepatocytes in myeloid-specific STAT3 knockout mice restored hepatic necrosis but decreased liver inflammation. Conclusion: Inflammation-mediated STAT3 activation attenuates hepatocellular injury induced by CCl4 in myeloid-specific STAT3 knockout mice, suggesting that inflammation associated with a predominance of hepatoprotective cytokines that activate hepatic STAT3 may reduce rather than accelerate hepatocellular damage in patients with chronic liver diseases. Hepatology 2010 [source] Ischemic preconditioning of the murine liver protects through the Akt kinase pathway,HEPATOLOGY, Issue 3 2006Kunihiko Izuishi Hepatic ischemia-reperfusion (I/R) injury occurs in the settings of transplantation, trauma, and elective liver resection. Ischemic preconditioning has been used as a strategy to reduce inflammation and organ damage from I/R of the liver. However, the mechanisms involved in this process are poorly understood. We examined the role of the phosphatidylinositol 3 (PI3) kinase/Akt-signaling pathway during hepatic ischemic preconditioning (IPC). Prior to a prolonged warm ischemic insult, BALB/c mice were subjected to a 20-minute IPC period consisting of 10 minutes of ischemia and 10 minutes of reperfusion. Mice undergoing IPC demonstrated a significantly greater level and earlier activation of Akt in the liver compared with control animals. IPC also resulted in markedly less hepatocellular injury and improved survival compared with control animals. Akt activation associated with hepatic IPC suppressed the activity of several modulators of apoptosis, including Bad, glycogen synthase kinase ,, and caspase-3. In addition, IPC also inhibited the activities of c-Jun N -terminal kinase and nuclear factor ,B after I/R. Pretreatment of mice with PI3 kinase inhibitors completely abolished Akt phosphorylation and the protective effects seen with IPC. In conclusion, these results indicate that the PI3 kinase/Akt pathway plays an essential role in the protective effects of IPC in hepatic I/R injury. Modulation of this pathway may be a potential strategy in clinical settings of ischemic liver injury to decrease organ damage. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). (HEPATOLOGY 2006;44:573,580.) [source] Interleukin 18 causes hepatic ischemia/reperfusion injury by suppressing anti-inflammatory cytokine expression in miceHEPATOLOGY, Issue 3 2004Dan Takeuchi Hepatic ischemia/reperfusion injury is a clinically important problem. While the mechanisms of the initial event and subsequent neutrophil-dependent injury are somewhat understood, little is known about the regulation of endogenous hepatoprotective effects on this injury. Interleukin 12 (IL-12) plays a role in the induction of this injury, but involvement of interleukin 18 (IL-18) has not been clarified. Using a murine model of partial hepatic ischemia and subsequent reperfusion, the aim of the current study was to determine whether IL-18 is up-regulated during hepatic ischemia/reperfusion and to determine the role of endogenous IL-18 in the development and regulation of inflammatory hepatic ischemia/reperfusion injury. Hepatic IL-18 expression was up-regulated from 1 to 8 hours after reperfusion. Hepatic ischemia/reperfusion induced nuclear factor-,B (NF-,B) and activator protein 1 (AP-1) activation, as defined by electrophoretic mobility shift assay, and caused significant increases in liver neutrophil recruitment, apoptosis, hepatocellular injury, and liver edema as defined by liver myeloperoxidase content, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end-labeling (TUNEL) staining, serum aminotransferase levels, and liver wet-to-dry weight ratios. In mice treated with neutralizing antibody to IL-18, ischemia/reperfusion-induced increases in CXC chemokine expression, activation of NF-,B and AP-1, and apoptosis were greatly reduced. Furthermore, under blockade of IL-18, anti-inflammatory cytokines such as IL-4 and IL-10 were greatly up-regulated. Signal transducer and activator of transcription 6 (STAT6) was significantly activated under blockade of IL-18. These conditions also caused significant reduction in liver neutrophil sequestration and liver injury. In conclusion, the data suggest that IL-18 is required for facilitating neutrophil-dependent hepatic ischemia/reperfusion injury through suppressing anti-inflammatory cytokine expression. (HEPATOLOGY 2004;39:699,710.) [source] Severe toxic hepatitis associated with amoxycillin and clavulanic acidJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2001G. Ersoz MD Toxic hepatitis secondary to amoxycillin,clavulanic acid is an infrequent clinical picture. Most of the cases are reported to have a benign course. We report two cases of severe hepatic failure following amoxycillin,clavulanic acid use. One of the cases had cholestatic features primarily, and the other had hepatocellular injury prominently. The first case had also findings of trombotic trombositic purpura and had a fatal course. [source] Inhibition of TXA2 synthesis with OKY-046 improves liver preservation by prolonged hypothermic machine perfusion in ratsJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 7pt2 2008Hongzhi Xu Abstract Background and Aim:, We previously reported that hypothermic machine perfusion (HMP) for liver preservation is feasible, but hepatic microcirculatory dysfunction and significant liver damage remain major obstacles in its application when the preservation is extended to 24 h. The underlying injury mechanism is not well understood. The present study sought to investigate the role of thromboxane A2 (TXA2) in the pathogenesis of liver injury after prolonged HMP. Methods:, Livers isolated from Sprague,Dawley rats were subjected to continuous machine perfusion with University of Wisconsin (UW) solution at a flow rate of 0.4 mL/min/g liver at 4°C for 24 h. A specific TXA2 synthase inhibitor, OKY-046 (OKY), was added to UW solution during the preservation period and to the Krebs,Henseleit buffer during reperfusion. The performance of the livers after preservation was evaluated using an isolated liver perfusion system with Krebs,Henseleit buffer at a flow rate of 15 mL/min at 37°C for 30 min. Results:, Prolonged HMP induced a significant release of TXA2 into the portal circulation as indicated by markedly increased levels of TXB2 in the perfusate during reperfusion (at 30 min, 1447.4 ± 163.6 pg/mL vs 50.91 ± 6.7 pg/mL for control). Inhibition of TXA2 synthesis with OKY significantly decreased releases of TXA2 (69.8 ± 13.4 pg/mL) concomitant with reduced lactate dehydrogenase (LDH) releases (at 30 min, HMP + OKY: 144.9 ± 27.9 U/L; HMP: 369.3 ± 68.5 U/L; simple cold storage or SCS: 884.4 ± 80.3 U/L), decreased liver wet/dry weight ratio (HMP + OKY vs SCS and HMP: 3.6 ± 0.3 vs 4.4 ± 0.1 and 3.9 ± 0.2, respectively) and increased hyaluronic acid uptake (at 30 min, HMP + OKY vs SCS, HMP: 33.1 ± 2.9% vs 13.9 ± 3.6%, 18.6 ± 2.4%, respectively). Liver histology also showed significant improvement in tissue edema and hepatocellular necrosis with OKY compared with HMP without OKY. Conclusion:, The results demonstrate that TXA2 is involved in the development of hepatocellular injury induced by HMP, and inhibition of TXA2 synthesis during preservation and reperfusion protects liver hepatocytes and sinusoidal endothelial cells from injuries caused by prolonged HMP. [source] Alcohol and Hepatitis C Virus,Interactions in Immune Dysfunctions and Liver DamageALCOHOLISM, Issue 10 2010Gyongyi Szabo Hepatitis C virus infection affects 170 million people worldwide, and the majority of individuals exposed to HCV develop chronic hepatitis leading to progressive liver damage, cirrhosis, and hepatocellular cancer. The natural history of HCV infection is influenced by genetic and environmental factors of which chronic alcohol use is an independent risk factor for cirrhosis in HCV-infected individuals. Both the hepatitis C virus and alcohol damage the liver and result in immune alterations contributing to both decreased viral clearance and liver injury. This review will capture the major components of the interactions between alcohol and HCV infection to provide better understanding for the molecular basis of the dangerous combination of alcohol use and HCV infection. Common targets of HCV and alcohol involve innate immune recognition and dendritic cells, the critical cell type in antigen presentation and antiviral immunity. In addition, both alcohol and HCV affect intracellular processes critical for hepatocyte and immune cell functions including mitochondrial and proteasomal activation. Finally, both chronic alcohol use and hepatitis C virus infection increase the risk of hepatocellular cancer. The common molecular mechanisms underlying the pathological interactions between alcohol and HCV include the modulation of cytokine production, lipopolysaccharide (LPS)-TLR4 signaling, and reactive oxygen species (ROS) production. LPS-induced chronic inflammation is not only a major cause of progressive liver injury and fibrosis, but it can also contribute to modification of the tissue environment and stem cells to promote hepatocellular cancer development. Alteration of these processes by alcohol and HCV produces an environment of impaired antiviral immune response, greater hepatocellular injury, and activation of cell proliferation and dedifferentiation. [source] Clinical trial: the efficacy and safety of oral PF-03491390, a pancaspase inhibitor , a randomized placebo-controlled study in patients with chronic hepatitis CALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 9 2010M. L. SHIFFMAN Aliment Pharmacol Ther,31, 969,978 Summary Background, Elevated serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) reflect hepatocellular injury in patients with chronic hepatitis C virus (HCV). Increased apoptosis and activated caspases are present in these patients. PF-03491390 inhibits multiple caspases and lowers serum AST and ALT levels in patients with chronic liver diseases. Aim, To determine if treatment with an oral pancaspase inhibitor could reduce serum AST and ALT in patients with HCV. Methods, Double-blind, randomized, placebo-controlled, parallel-dose study in 204 patients treated with placebo or PF-03491390 (5, 25 or 50 mg) orally twice daily (b.d.) for up to 12 weeks. Serum AST and ALT were monitored weekly. Results, Significant reductions in serum AST and ALT were observed within 1 week of initiating PF-03491390 in all treatment groups (P < 0.0001). These reductions in AST and ALT were maintained throughout the 12 week treatment period and returned to baseline levels when PF-03491390 was discontinued. Increasing the dose did not further lower AST or ALT. The most frequently reported adverse events were headache and fatigue. Conclusion, PF-03491390 significantly reduced serum AST and ALT levels in patients with chronic HCV, and was well tolerated over 12 weeks. [source] Effect of tumour necrosis factor-, and irradiation alone or in combination on the viability of hepatocellular and biliary adenocarcinoma cell lines in vitroLIVER INTERNATIONAL, Issue 6 2009Blendi Qesaraku Abstract Background: Tumour necrosis factor , (TNF-,) may exhibit antitumoral activity and can influence the reaction of both tumour and normal tissue to radiation. Aims: To test the effect of TNF-, and/or irradiation on hepatocellular (HepG2, Hep3B, Sk-Hep1, HuH7) and cholangiocellular (Sk-chA1, Mz-chA1) tumour cell lines. Methods: Colony formation, apoptosis analysis and trypan blue exclusion were used to assess cell viability. Doses of radiation (2,25 Gy) and TNF-, (100,50 000 U) as well as their respective sequencing were varied (24 and 12 h before and 6 h after). The expression of TNF-, and TNF receptors 1/2 was determined using real-time polymerase chain reaction and I,B, protein expression was detected by Western blot. Results: Sole irradiation induced a reduction in colony formation in all cell lines and sole TNF-, in HepG2 and Sk-chA1 cells only. No difference in apoptosis induction after TNF-, or irradiation was observed. Cellular death induced by the combination of TNF-, and radiation was not superior to the use of any of the two agents alone. All cell lines revealed that radiation induced upregulation of TNF-, whereas the extent of TNF receptor-specific transcription did not change. Furthermore, radiation-induced changes in I,B, expression were not detectable. Conclusions: Our data suggest that both TNF-, and radiation may be treatment options for hepatocellular and cholangiocellular carcinomas. Because TNF-, and radiation do not interact in terms of radiosensitization, anti-TNF-, treatment may have the potential to protect against hepatocellular injury after abdominal irradiation. However, further in vivo studies are needed to confirm that anti-TNF-, treatment does not compromise tumour control and actually attenuates radiation-induced liver injury. [source] Liver-infiltrating CD56 positive T lymphocytes in hepatitis C virus infectionLIVER INTERNATIONAL, Issue 5 2000Kenji Yonekura Abstract:Aim: Hepatitis C virus (HCV) is a major cause of post-transfusional and sporadic hepatitis, and leads to chronic liver disease. It has been suggested that virus-specific cytotoxic T lymphocytes are responsible for liver injuries that occur in HCV-infected patients. However, the detailed characteristics of these lymphocytes have not yet been defined. We have previously reported that CD56+ T lymphocytes, as intermediates between natural killer cell and T lymphocytes, predominantly infiltrated the liver and were increased in patients with chronic hepatitis related to HCV (CH-C). Material and Methods: We obtained peripheral blood and liver tissues from 32 patients diagnosed as having CH-C, and 10 other liver disease patients (5 chronic hepatitis related to HBV, 5 alcoholics), and analyzed peripheral blood and liver-infiltrating lymphocytes using flow cytometric and immunohistochemical techniques. Results: The CD56+ T lymphocyte ratio in the liver of patients with a high histology activity index (HAI) score for chronic hepatitis was higher than that of patients with a low HAI score and patients with other liver diseases. In addition, T lymphocytes from patients with chronic hepatitis with a high HAI score carried mostly ,,-TCR. There was a correlation between the ratio of CH-C and serum alanine aminotransferase, category I (periportal inflammation and necrosis), and IV (fibrosis) of the HAI scoring system. The ratio was highest in zone 1 of the hepatic lobules. Conclusion: The correlation between CD56+ T lymphocyte ratios and hepatocellular damage was examined. These findings suggest strongly that liver-infiltrating CD56+ T lymphocytes play an important pathologic role in hepatocellular injury in CH-C. [source] High mobility group box 1 protein as a marker of hepatocellular injury in human liver transplantationLIVER TRANSPLANTATION, Issue 10 2008Minna Ilmakunnas High mobility group box 1 protein (HMGB1), a cytokine actively secreted by phagocytes and passively released from necrotic cells, is an inflammatory mediator in experimental hepatic ischemia/reperfusion injury. We characterized its expression in human liver transplantation. In 20 patients, in addition to systemic samples, blood was drawn from portal and hepatic veins during and after reperfusion to assess changes within the graft. Plasma HMGB1, tumor necrosis factor , (TNF-,), and interleukin-6 (IL-6) levels were measured, and HMGB1 immunohistochemistry was performed on biopsies taken before and after reperfusion. Plasma HMGB1 was undetectable before reperfusion, and levels in systemic circulation peaked after graft reperfusion. At portal declamping, HMGB1 levels were substantially higher in the caval effluent [188 (80-371) ng/mL] than in portal venous blood [0 (0-3) ng/mL, P < 0.001]. HMGB1 release from the graft continued thereafter. HMGB1 levels were not related to TNF-, or IL-6 levels. HMGB1 expression was up-regulated in biopsies taken after reperfusion (P = 0.020), with intense hepatocyte and weak neutrophil staining. HMGB1 levels in hepatic venous blood correlated with graft steatosis (r = 0.497, P = 0.03) and peak postoperative alanine aminotransferase levels (r = 0.588, P = 0.008). Our results indicate that HMGB1 originates from the graft and is a marker of hepatocellular injury in human liver transplantation. Liver Transpl 14:1517,1525, 2008. © 2008 AASLD. [source] Carbon Monoxide has Antioxidative Properties in the Liver Involving p38 MAP Kinase Pathway in a Murine Model of Systemic InflammationMICROCIRCULATION, Issue 7 2010JÜRGEN BRUGGER Please cite this paper as: Brugger, Schick, Brock, Baumann, Muellenbach, Roewer and Wunder (2010). Carbon Monoxide has Antioxidative Properties in the Liver Involving p38 MAP Kinase Pathway in a Murine Model of Systemic Inflammation. Microcirculation17(7), 504,513. Abstract Objective:, Reactive oxygen species (ROS) are important in the hepatocellular injury process during a systemic inflammation. We examined the role of carbon monoxide (CO) on the hepatic generation of ROS with in-vivo and in-vitro models of systemic inflammation. Methods:, Using a murine model of bilateral hindlimb ischemia-reperfusion (I/R) we examined the effect of CO treatment on hepatic ROS formation, oxidative status, and cell injury. Cultured HUVEC were used to investigate intracellular pathways. Results:, CO treatment reduced hepatic lipid peroxidation, re-established total hepatic glutathione and glutathione disulfide (GSH/GSSG) levels and reduced hepatocellular injury. Inhibition of heme oxygenase (HO) during treatment with CO during hindlimb I/R failed to alter the antioxidant qualities provided by CO. The production of ROS after tumor necrosis factor-, (TNF-,) stimulation in HUVEC was diminished after exposure to CO. Treatment with CO during HO inhibition reduced both ROS formation and cell injury. Inhibiting the p38 MAPK (mitogen-activated protein kinase) pathway with pyridinyl imidazol (SB203580) revealed that the antioxidant potential of CO involved the activation of p38 MAPK. Conclusions:, CO has direct antioxidant potential independently of any HO activity during systemic inflammation. The antioxidant effects afforded by CO involve the activation of the p38 MAPK pathway. [source] Early Hepatic Microvascular Injury in Response to Acetaminophen ToxicityMICROCIRCULATION, Issue 5 2003YOSHIYA ITO ABSTRACT Objective: The hepatic toxic response to acetaminophen (APAP) is characterized by centrilobular (CL) necrosis preceded by hepatic microvascular injury and congestion. The present study was conducted to examine changes in liver microcirculation after APAP dosing. Methods: Male C57Bl/6 mice were treated with APAP (600 mg/kg body weight) by oral gavage. The livers of anesthetized mice were examined using established in vivo microscopic methods at 0, 0.5, 1, 2, 4, 6, 12 hours after APAP. Results: The levels of hepatic transaminases (i.e., alanine aminotransferase [ALT] and aspartate transaminase) increased minimally for up to 2 hours. Thereafter, their levels were significantly and progressively increased. The numbers of swollen sinusoidal endothelial cells (SECs) in periportal regions were increased (3.5-fold) from 0.5 to 6 hours, and those in CL regions were increased (4.0-fold) at 0.5 and 1 hour. The intensity of in vivo staining for formaldehyde-treated serum albumin, which is a specific ligand for SECs, was reduced from 2 to 12 hours. Erythrocytes infiltrated into the space of Disse as early as 2 hours, and the area occupied by these cells was markedly increased at 6 hours. Sinusoidal perfusion was reduced from 1 through 12 hours, with a nadir (35% decrease) at 4 and 6 hours. Phagocytic Kupffer cell activity was significantly elevated from 0.5 through 12 hours. Although gadolinium chloride minimized the changes in sinusoidal blood flow and reduced ALT levels 6 hours after APAP, it failed to inhibit endothelial swelling, extravasation of erythrocytes, and CL parenchymal necrosis. Conclusions: These results confirm that APAP-induced SEC injury precedes hepatocellular injury, supporting the hypothesis that SECs are an early and direct target for APAP toxicity. These findings also suggest that reduced sinusoidal perfusion and increased Kupffer cell activity contribute to the development of APAP-induced liver injury. [source] Lymphocyte function antigen-1 mediates leukocyte adhesion and subsequent liver damage in endotoxemic miceBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2004Xiang Li Sepsis is associated with leukocyte activation and recruitment in the liver. We investigated the role of lymphocyte function antigen-1 (LFA-1) in endotoxin-induced leukocyte,endothelium interactions, microvascular perfusion failure, hepatocellular injury and apoptosis in the liver by use of gene-targeted mice, blocking antibodies and a synthetic inhibitor of LFA-1 (LFA703). For this purpose, mice were challenged with lipopolysaccharide (LPS)+D -galactosamine (Gal), and intravital microscopy of the liver microcirculation was conducted 6 h later. The number of firmly adherent leukocytes in response to LPS/Gal was reduced by 48% in LFA-1-deficient mice. Moreover, endotoxin-induced increases of apoptosis and enzyme markers of hepatocellular injury were decreased by 64 and 69,90%, respectively, in LFA-1-deficient mice. Furthermore, sinusoidal perfusion was improved in endotoxemic mice lacking LFA-1. A similar protective pattern was observed in endotoxemic mice pretreated with an antibody against LFA-1. Thus, immunoneutralization of LFA-1 reduced endotoxin-induced leukocyte adhesion by 55%, liver enzymes by 64,66% and apoptosis by 42%, in addition to the preservation of microvascular perfusion. Administration of a novel statin-derived inhibitor of LFA-1, LFA703, significantly decreased leukocyte adhesion (more than 56%) and the subsequent liver injury in endotoxemic mice. Thus, this study demonstrates a pivotal role of LFA-1 in supporting leukocyte adhesion in the liver. Moreover, interference with LFA-1-mediated leukocyte adhesion protects against endotoxemic liver damage, and may constitute a potential therapeutic strategy in sepsis. British Journal of Pharmacology (2004) 141, 709,716. doi:10.1038/sj.bjp.0705634 [source] | |||||||||||||||||||||||||