Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gut-derived substances can activate Kupffer cells to provoke hepatic necrosis after partial hepatectomy in rats. A similar situation may occur during orthotopic liver transplantation (OLT), as congestion in the intestinal wall, caused by portal vein occlusion, is inevitable during the operation. The contribution of such substances to liver injury following OLT was investigated in rats. Oral administration of polymyxin B sulfate for 7 days significantly altered intestinal bacterial flora in rats; Enterobacteriaceae diminished and anaerobes such as Bifidobacterium , Lactobacillus, Bacteroides, and Eubacterium increased in number, compared with the control rats. Also, this treatment significantly reduced endotoxin concentration in the portal blood 30 minutes after blood reflow following portal vein occlusion. When OLT was performed in rats using the liver preserved in cold University of Wisconsin solution for 18 hours, tissue factor activity in Kupffer cells (KC) isolated from the transplanted liver 1 hour after the operation was significantly higher than in that of normal rats. This increase was significantly reduced by pretreatment of the recipients with polymyxin B sulfate. In these recipients, serum alanine aminotransferase activity, tumor necrosis factor alpha (TNF alpha) concentration, and histological extent of liver necrosis were significantly attenuated at 24 hours after the operation compared with those of control rats. We conclude that the substances derived from bacilli sensitive to polymyxin B sulfate in the gut may be a contributing factor to liver injury following OLT in rats; we feel that this probably occurs by entering of the substances into the portal blood during the ahepatic phase of the operation to activate KC. Selective bowel decontamination of recipients with polymyxin B sulfate would be a candidate for protection against early graft failure following OLT.
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PMID:Selective bowel decontamination of recipients for prevention against liver injury following orthotopic liver transplantation: evaluation with rat models. 942 27

Activated Kupffer cells provoke massive liver necrosis after endotoxin stimulation through microcirculatory disturbance caused by sinusoidal fibrin deposition in rats undergoing 70% hepatectomy. In these rats, serum activities of purine nucleoside phosphorylase (PNP) and alanine transaminase (ALT) were increased at 1 and 5 hours, respectively, following endotoxin administration. When 70% resected liver was perfused with Dulbecco's modified Eagle medium (DMEM) containing heat-inactivated fetal calf serum, the increase in both enzyme activities was not affected by addition of endotoxin during perfusion, suggesting that activated Kupffer cells injured neither sinusoidal endothelial cells nor hepatocytes. The activity of tissue factor, an initiator of blood coagulation cascade, was much higher in Kupffer cells isolated from partially hepatectomized rats than in those from normal rats. In contrast, mRNA expressions of tissue factor pathway inhibitor (TFPI) as well as thrombomodulin were almost undetectable in normal and partially resected livers. When recombinant human TFPI was injected intravenously in 70% hepatectomized rats, TFPI was markedly stained on the surfaces of sinusoidal endothelial cells and microvilli of hepatocytes on immunohistochemistry. In these rats, endotoxin-induced liver injury was significantly attenuated compared with rats given no TFPI. Similar attenuation was also found in rats receiving recombinant human thrombomodulin. These results suggest that fibrin deposition developing in 70% hepatectomized rats after endotoxin administration may be caused by deranged blood coagulation in the hepatic sinusoids through increasing tissue factor activity in Kupffer cells and minimal TFPI and thrombomodulin in endothelial cells. The destruction of sinusoidal endothelial cells as well as hepatocytes may occur as a result of microcirculatory disturbance caused by such sinusoidal fibrin deposition.
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PMID:Deranged blood coagulation equilibrium as a factor of massive liver necrosis following endotoxin administration in partially hepatectomized rats. 1021 39

To obtain "exact" laboratory data which show or reflect the pathophysiological conditions of patients, preanalytical, analytical and postanalytical processes should be checked. However, it is difficult to know the preanalytical situation or out of laboratories. We realize preanalytical issue is one of the weak points in current laboratory medicine. I reported the results of analyses on the issues concerning abnormal laboratory data produced by inadequate handling of samples and sample collection. Five issues are described as follows: 1) The effect of detergents on fecal occult blood test. Immunological methods were affected markedly to moderately by various sanitizers and detergents tested. In collecting feces for immunological fecal occult blood test, contact of feces with toilet flush water dissolving sanitizers should be inhibited. 2) Blood storage and potassium(K) release. Causes of slight elevation of K in serum are sometimes unknown. Addition of injection drugs in vitro showed that various drugs induced K release from erythrocytes. Cold storage of blood is well-known to bring elevation of K level, however, the detailed mechanism is still unknown. We developed a simple method to measure K flux activity of erythrocytes and the decreased activity was shown in patients with chronic renal insufficiency and the aged as well as the aged erythrocytes. 3) Thawed serum and concentration difference. Frozen serum samples were thawed without mixing and various layers contained different concentrations in 60 items tested. Comparing the concentration before freezing, the upper layer contained 1/2 and the bottom 2 times more. T3 and FT4 showed exceptionally smaller difference, significance of which is unknown. 4) Two syringe method in blood collection. Blood samples drawn in the first half and the latter half were comparatively measured for APTT, PT and TT. Blood amount of 1 ml or more showed no differences. TT showed elevation in the first half in 0.5 ml-sample. The effects of local treatment by warming, tapping and congestion were examined. In some cases, tissue factor level elevated by such physical pretreatment. However, in usual blood collection in human, two syringe method is not necessarily employed. 5) Heat-inactivation and cold storage of serum. Preheating sera at 56 degrees C for 30 min reduced markedly the levels of ALT, ALP, CK, ChE, ATIII and alpha 2-PI. In seroimmunology, some complement components are markedly affected and rheumatoid factor of IgM classes was also affected. In about a half of HCV-Ab positive sera, CH50 levels were decreased by the cold storage(cold activation). We reported previously the non-participation of C1q in this phenomenon. In such sera, temperature management is important. Scientific data on the storage and collection of samples should be informed not only to laboratory staffs but to nurses and doctors in order to provide "exact" data.
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PMID:[Analyses of preanalytical issues on samplings and samples]. 1130 17

Patients receiving maintenance hemodialysis (HD) present with hemostatic abnormalities, which may be aggravated by comorbid conditions, especially liver disease. The factors that influence plasma levels of thrombomodulin (TM), an initiator of the anticoagulant protein C pathway, and those of tissue factor (TF), which triggers the extrinsic coagulation pathway, were assessed. In 63 HD patients, TM and TF levels were higher than those in healthy controls. In bivariate analysis, TF positively correlated with TM, and both were directly associated with the presence of viral hepatitis B or C marker, serum liver enzymes, use of erythropoietin therapy, hemoglobin levels, and duration of HD therapy, and inversely correlated with body mass index. TF was also positively associated with plasma von Willebrand factor (vWF) antigen, and inversely associated with activated partial thromboplastin time. In multivariate analysis, increased vWF, alanine aminotransferase, and use of erythropoietin independently predicted both TF and TM levels. HD patients with vWF and ALT levels lower than middle, and not treated with erythropoietin had normal TF but increased TM concentrations compared with levels in healthy controls. Increased plasma levels of TM and TF in patients on maintenance HD are surrogates of vascular endothelial injury. Liver disease and use of erythropoietin treatment are also important determinants of these markers, and should be considered in further studies.
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PMID:Tissue factor and thrombomodulin in hemodialysis patients: associations with endothelial injury, liver disease, and erythropoietin therapy. 1465 47

Islet survival in the early posttransplantation period is likely to be influenced by inflammatory events in and around islets. Twenty-seven human islet preparations were transplanted by 24 infusions into 14 patients with brittle type 1 diabetes under the Edmonton protocol. Patients were monitored for their coagulation [cross-linked fibrin degradation products (XDPs)] and liver function test [aspartate and alanine aminotransferase (AST and ALT)] as markers of early posttransplant complications, and these were correlated with in vitro islet number, purification, volume, monocyte-chemoattractant protein-1 (CCL2/MCP-1) and tissue factor (TF) islet release. Consistent with activation of coagulation pathways and hepatic damage, serum XDP values increased early after 11 infusions and transaminase after 13 of 24 infusions. TF and CCL2/MCP-1 were detected in supernatants of 21 and 22 islet preparations, respectively. Serum XDP peak values were correlated with TF/equivalent islets (EI) (r(2)=0.26, P = 0.001) and CCL2/MCP-1/EI (r(2) = 0.42; P < 0.001); serum transaminase areas under the curve in the first week posttransplantation were correlated with CCL2/MCP-1/EI (r(2) = 0.55; P < 0.001 for ALT and r(2) = 0.51; P = 0.001 for AST) and TF/EI (r(2) = 0.31; P = 0.002 for ALT, and r(2) = 0.36; P = 0.002 for AST). These data suggest that reducing the islet proinflammatory state may be a means to reduce the early posttransplant complications and perhaps improve islet engraftment.
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PMID:Tissue factor and CCL2/monocyte chemoattractant protein-1 released by human islets affect islet engraftment in type 1 diabetic recipients. 1553 35

The liver can be injured and its functions altered by activation of the coagulation and inflammatory processes in sepsis. The objective of the present study was to investigate the pattern of protease- activated receptors (PARs) over time in a model of acute liver injury induced by lipopolysaccharide (LPS); and whether PARs play a role in this process and exert their effects through inflammation and coagulation. Levels of tumor necrosis factor-a (TNF-a) were significantly expressed 1 h after LPS administration followed by: i) an increase in levels of tissue factor, factor VIIa, thrombin and plasminogen activator inhibitor-1; ii) unchanged or steady levels of tissue factor pathway inhibitor; and iii) subsequent deposition of fibrin in the liver tissue, that led to the elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which are associated with liver injury. The expression of all PAR isoforms (1-4) was elevated, and each isoform had a distinct cellular localization (hepatocytes, Kupffer cells, the portal triad area, and central veins) and a time-dependent pattern of expression. The immuno-reactivity of PAR2 and 4 in Kupffer cells was intense. Interestingly, PAR2 blocking peptide improved the healing of liver injuries, an effect that was associated with suppression of TNF-a elevation, and normalization of coagulation and fibrinolysis. This ultimately led to decreased fibrin formation in the injured liver. The present study reveals a distinct chronological expression and cellular localization of PARs in LPS-mediated liver injury and shows that blockade of PAR2 may play a crucial role in treating liver injury, via normalization of inflammation, coagulation and fibrinolytic pathways.
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PMID:Chronological expression of PAR isoforms in acute liver injury and its amelioration by PAR2 blockade in a rat model of sepsis. 1713 80

Tissue factor (TF) is one of the proteins that participate in hemostatic and inflammatory processes. Activated monocytes present in the liver increase expression of TF, and while accumulating in the organ they can intensify inflammation. The aim of the present study was to evaluate the expression of TF on monocytes in advanced liver cirrhosis with regard to other activation markers. The flow cytometric analysis of TF (CD142), CD14, adhesive molecules CD11b and CD11c, costimulatory molecules CD40, CD80 and CD86, and HLA-DR on monocytes was carried out in 45 patients with postalcoholic liver cirrhosis (Child Pugh B, 20 patients; Child Pugh C, 25 patients) and in 25 healthy persons. The positive correlation between monocytic TF expression and monocyte [soluble CD14 (sCD14), CD11b, monocyte aggregates] activation, the expression of costimulatory molecules on monocytes (CD40, CD80), blood platelet (soluble P-selectin, microplatelets) activation, the level of tumor necrosis factor-alpha, biochemical parameters of liver damage (alanine aminotransferase, aspartate aminotransferase, alkaline phosphate, gamma-glutamyltransferase, and bilirubin) as well as coagulation disorders were observed in the study. In conclusion, the study revealed that the activation of monocytes and blood platelets is accompanied by the elevation of monocytic TF expression in advanced liver cirrhosis. The monocytic TF is a significant link connecting clotting processes and inflammatory and immunological phenomena in liver cirrhosis.
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PMID:Increase in expression of monocytic tissue factor (CD142) with monocytes and blood platelet activation in liver cirrhosis. 1798 14

Altered hepatic lipid homeostasis, hepatocellular injury, and inflammation are features of nonalcoholic steatohepatitis, which contributes significantly to liver-related morbidity and mortality in the Western population. A collection of inflammatory mediators have been implicated in the pathogenesis of steatohepatitis in mouse models. However, the pathways essential for coordination and amplification of hepatic inflammation and injury caused by steatosis are not completely understood. We tested the hypothesis that tissue factor (TF)-dependent thrombin generation and the thrombin receptor protease activated receptor-1 (PAR-1) contribute to liver inflammation induced by steatosis in mice. Wild-type C57Bl/6J mice fed a diet deficient in methionine and choline for 2 weeks manifested steatohepatitis characterized by increased serum alanine aminotransferase activity, macrovesicular hepatic steatosis, hepatic inflammatory gene expression, and lobular inflammation. Steatohepatitis progression was associated with thrombin generation and hepatic fibrin deposition. Coagulation cascade activation was significantly reduced in low TF mice, which express 1% of normal TF levels. Hepatic triglyceride accumulation was not affected in low TF mice or PAR-1-deficient mice. In contrast, biomarkers of hepatocellular injury, inflammatory gene induction, and hepatic accumulation of macrophages and neutrophils were greatly reduced by TF-deficiency and PAR-1-deficiency. The results suggest that TF-dependent thrombin generation and activation of PAR-1 amplify hepatic inflammation and injury during the pathogenesis of steatohepatitis.
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PMID:Tissue factor-deficiency and protease activated receptor-1-deficiency reduce inflammation elicited by diet-induced steatohepatitis in mice. 2000 34

Tissue factor (TF) antagonists targeting the factor VII (FVII) binding domain have been shown to interrupt acute vascular thrombus formation without impairing haemostasis in non-human primates. In this study, we evaluate whether a human/mouse chimeric monoclonal antibody (ALT-836, formerly known as Sunol-cH36) blocking the factor X/factor IX (FX/FIX) binding site of tissue factor could achieve similar clinical benefits in an arterial thrombosis model induced by surgical endarterectomy in chimpanzees. In this model, sequential surgical endarterectomies on right and left superficial femoral arteries were performed 30 days apart in five chimpanzees. A bolus (1 mg/kg) of ALT-836 was injected intravenously immediately preceding the restoration of flow in the endarterectomised femoral artery. Pre-surgical labelling of autologous platelets using (111)In-Oxine and post-surgical gamma camera imaging of (111)In-platelet deposition at endarterectomy sites was performed. The manipulated arterial segments were harvested for patency analysis 30 days following surgery. The results indicate that ALT-836 was highly effective at reducing acute vascular thrombosis, with no significant variations in surgical blood loss and template-bleeding time in the treated group compared to the control animals. These data suggest that ALT-836 is an effective and safe antithrombotic agent in preventing TF-initiated vascular thrombogenesis without compromising haemostasis.
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PMID:Inhibition of acute vascular thrombosis in chimpanzees by an anti-human tissue factor antibody targeting the factor X binding site. 2006 41

Alpha-naphthylisothiocyanate (ANIT) causes cholestatic hepatitis characterized by intrahepatic bile duct epithelial cell injury and periportal hepatocellular necrosis. The progression of ANIT-induced hepatocyte injury is reported to involve extrahepatic cells including platelets. We showed recently that the procoagulant protein tissue factor (TF) is essential for ANIT-induced coagulation and contributes to ANIT-induced liver necrosis. Platelets have been shown to express TF and can contribute to coagulation cascade activation. To this end, we tested the hypothesis that platelet-dependent coagulation contributes to ANIT-induced liver injury. In ANIT (60 mg/kg)-treated mice, activation of the coagulation cascade occurred prior to a decrease of platelets in the blood. Immunostaining for glycoprotein IIb (CD41) revealed platelet accumulation along the borders of necrotic foci in livers of ANIT-treated mice. Antibody-mediated platelet depletion did not affect coagulation but markedly affected liver histopathology in ANIT-treated mice. Platelet depletion induced marked pooling of blood within necrotic lesions consistent with parenchymal-type peliosis as early as 24 h after ANIT treatment. In contrast, treatment with the P2Y(12) inhibitor clopidogrel significantly reduced ANIT-induced hepatocyte necrosis and serum alanine aminotransferase activity but did not exaggerate bleeding into necrotic foci. Clopidogrel also reduced hepatic neutrophil accumulation but did not affect induction of Intercellular adhesion molecule-1 or chemokine CxC motif ligand-1 messenger RNA expression in liver. The data indicate that ANIT-induced coagulation is platelet independent and that platelets contribute to ANIT-induced hepatocyte necrosis by promoting neutrophil accumulation. In contrast, severe thrombocytopenia induces parenchymal-type peliosis in the livers of ANIT-treated mice, a rare hepatic lesion associated with pooling of blood in the liver.
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PMID:Protective and damaging effects of platelets in acute cholestatic liver injury revealed by depletion and inhibition strategies. 2013 75


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