Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Replication-deficient adenoviruses are known to induce acute injury and inflammation of infected tissues, thus limiting their use for human gene therapy. However, molecular mechanisms triggering this response have not been fully defined. To characterize this response, chemokine expression was evaluated in DBA/2 mice following the intravenous administration of various adenoviral vectors. Administration of adCMVbeta gal, adCMV-GFP, or FG140 intravenously rapidly induced a consistent pattern of C-X-C and C-C chemokine expression in mouse liver in a dose-dependent fashion. One hour following infection with 10(10) PFU of adCMVbeta gal, hepatic levels of MIP-2 mRNA were increased >60-fold over baseline. MCP-1 and IP-10 mRNA levels were also increased immediately following infection with various adenoviral vectors, peaking at 6 hr with >25- and >100-fold expression, respectively. Early induction of RANTES and MIP-1beta mRNA by adenoviral vectors also occurred, but to a lesser degree. The induction of chemokines occurred independently of viral gene expression since psoralen-inactivated adenoviral particles produced an identical pattern of chemokine gene transcription within the first 16 hr of administration. The expression of chemokines correlated as expected with the influx of neutrophils and CD11b+ cells into the livers of infected animals. At high titers, all adenoviral vectors caused significant hepatic necrosis and apoptosis following systemic administration to DBA/2 mice. To investigate the role of neutrophils in this adenovirus-induced hepatic injury, animals were pretreated with neutralizing anti-MIP-2 antibodies or depleted of neutrophils. MIP-2 antagonism and neutrophil depletion both resulted in reduced serum ALT/AST levels and attenuation of the adenovirus-induced hepatic injury histologically, confirming that this early injury is largely due to chemokine production and neutrophil recruitment. Our findings further clarify the early immune response against replication-deficient adenoviral vectors and suggest a strategy to prevent adenovirus-mediated inflammation and tissue injury by interfering with chemokine or neutrophil function.
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PMID:Adenoviral gene therapy leads to rapid induction of multiple chemokines and acute neutrophil-dependent hepatic injury in vivo. 1022 30

Inflammation of the portal and periportal areas is a common feature of chronic hepatitis C. Antigen-presenting dendritic cells are located in the portal area, and infiltrating T cells are initially exposed to infected hepatocytes in the periportal area. Thus, these areas could be sites of the initial processes of the immune response in chronic hepatitis C. C-C chemokines (dendritic-cell-derived C-C chemokine [DC-CK1] and regulated upon activation, normal T-cell expressed and secreted [RANTES])-attracting T cells may play a role in the portal inflammatory changes. The relationship between the expression of these C-C chemokines, which attract T cells and the infiltration of T cells into the liver of patients with chronic hepatitis C, was examined by in situ hybridization and reverse transcription-polymerase chain reaction. T-cell activation was examined by immunostaining T-cell subsets. Specific signals were detected for DC-CK1 mRNA in mononuclear cells mainly in the portal area and for RANTES mRNA in the portal area and at sites of piecemeal necrosis in the liver of patients with chronic hepatitis C. Naive T cells were located mainly in the portal area, whereas active T cells were found mainly at sites of piecemeal necrosis in the periportal area. In addition, hepatic DC-CK1- and RANTES-mRNA levels were significantly correlated with serum alanine aminotransferase levels (p < 0.001). These results suggest that the local production of DC-CK1 and RANTES participates in immune responses by attracting naive and active T cells to the portal and periportal areas, respectively.
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PMID:Expression of C-C chemokines is associated with portal and periportal inflammation in the liver of patients with chronic hepatitis C. 1074 77

Chemokines are involved in the pathogenesis of alcoholic hepatitis and are considered to contribute to the migration of leukocytes into the liver during chronic ethanol intoxication. This work tests the hypothesis that chronic ethanol consumption selectively enhances chemokine release by Kupffer cells and hepatic sinusoidal endothelial cells and migration of inflammatory cells into the liver. Furthermore, enhanced hepatic chemokine secretion may induce an autocrine effect on the ability of Kupffer cells and endothelial cells to chemotax and ingest microbial particles. Male Wistar rats were fed with ethanol in agar block and water for 32 weeks, and were allowed free access to solid food. Results show that after 32 weeks of feeding, leukocyte infiltration and steatosis were observed in the livers of ethanol-fed rats. The majority of the infiltrated cells were CD8+ cells. Serum ALT, endotoxin, MIP-1alpha, MCP-1 and RANTES, (but not CINC and MIP-2) were also increased in the ethanol-fed rats than in the pair-fed group. Isolated Kupffer cells from ethanol-fed rats were primed for enhanced MIP-1alpha, MCP-1, and RANTES production in vitro, while the endothelial cells were primed for enhanced MIP-1alpha release only. Chronic alcohol intoxication was also associated with increased basal H2O2 formation, enhanced nuclear translocation and binding of NF-kappaB, AP-1 and MNP-1 in Kupffer Cells. Chronic ethanol feeding significantly enhanced MNP-1 binding, but not those of NF-kappaB and AP-1 in endothelial cells. Concomitantly, chemokine-induced chemotaxis, E.coli phagocytosis and f-met-leu-phe-induced superoxide anion production by Kupffer cells were downregulated in the ethanol-fed group. Taken together these data demonstrate that prolonged alcohol consumption may compromise the host to hepatitis as a result of increased chemokine production and at the same time may suppress the innate immune function of hepatic non-parenchymal cells.
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PMID:Chronic alcohol intoxication primes Kupffer cells and endothelial cells for enhanced CC-chemokine production and concomitantly suppresses phagocytosis and chemotaxis. 1204 6

The pathogenesis of liver cell injury during chronic hepatitis C (CHC) is poorly understood. The cellular immune response is thought to play a key role in both inhibition of viral replication and liver pathology. However, little is currently known about which lymphocyte populations and which immune effectors contribute to or control liver damage. We investigated a panel of 15 phenotypic and functional markers of intrahepatic T-lymphocyte subsets irrespective of their antigen specificity in 48 hepatitis C virus (HCV)-infected patients and 8 healthy control subjects. Lymphocyte characteristics were evaluated from liver biopsy specimens both at gene expression level by real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) and by immunochemistry, in relation with the degree of liver injury and with intrahepatic HCV-RNA levels. As compared with controls, we found major changes in T-lymphocyte subsets in HCV-infected patients, with a significant decrease of T-cell antigen receptor (TCR) delta and CD56 gene expression, associated with a concomitant increase of TCRalpha and CD8beta that were correlated with cytotoxic factors, proinflammatory chemokines, and chemokine receptors including peforin, interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), RANTES, and CXCR3. The gene expression of CD8beta, a specific marker for conventional TCRalpha+CD8+ lymphocytes, was correlated by multivariate analysis with both alanine aminotransferase (ALT) serum levels and histologic activity index. Furthermore, CD8 staining was observed by immunochemistry in the areas of lobular and piecemeal necrosis. In contrast, no lymphocyte marker was correlated with viral load, measured both in serum and in liver. In conclusion, these results strongly suggest key roles for CD8+ T cells as effectors of liver damage during chronic HCV infection and for their inability to control viral replication.
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PMID:Phenotypic and functional characterization of intrahepatic T lymphocytes during chronic hepatitis C. 1451 70

Activation of the A2A adenosine receptor (A(2A)R) during reperfusion of various tissues has been found to markedly reduce ischemia-reperfusion injury. In this study, we used bone marrow transplantation (BMT) to create chimeric mice that either selectively lack or selectively express the A(2A)R on bone marrow-derived cells. Bolus i.p. injection of the selective A2A agonist, 4-[3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-piperidine-1-carboxylic acid methyl ester (ATL313; 3 microg/kg), at the time of reperfusion protects wild-type (wt) mice from liver ischemia-reperfusion injury. ATL313 also protects wt/wt (donor/recipient BMT mouse chimera) and wt/knockout chimera but produces modest protection of knockout/wt chimera as assessed by alanine aminotransferase activity, induction of cytokine transcripts (RANTES, IFN-gamma-inducible protein-10, IL-1alpha, IL-1-beta, IL-1Ralpha, IL-18, IL-6, and IFN-gamma), or histological criteria. ATL313, which is highly selective for the A(2A)R, produces more liver protection of chimeric BMT mice than 4-[3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-cyclohexanecarboxylic acid methyl ester, which is rapidly metabolized in mice to produce 4-[3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-cyclohexanecarboxylic acid, which has similar affinity for the A(2A)R and the proinflammatory A3 adenosine receptor. GFP chimera mice were created to show that vascular endothelial cells in the injured liver do not account for liver protection because they are not derived by transdifferentiation of bone marrow precursors. The data suggest that activation of the A(2A)R on bone marrow-derived cells is primarily responsible for protecting the liver from reperfusion injury.
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PMID:A2A adenosine receptors on bone marrow-derived cells protect liver from ischemia-reperfusion injury. 1581 35

Vasoactive intestinal peptide (VIP) was administered in a model of zymosan-induced generalized inflammation (ZIGI). Its beneficial action was associated with reduced TNF-alpha and increased IL-10 production, lowered levels of creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin in circulation. VIP diminished the level of RANTES and MIP-1alpha in peritoneal exudate and circulation. The neuropeptide inhibited NO release from stimulated peritoneal macrophages. Decreased spleen, liver and kidney enlargement and less pathological changes in liver were observed. The effect of VIP was attenuated by pretreatment with VIP antagonist (anti-VIP) before the induction of shock.
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PMID:Exogenous VIP limits zymosan-induced generalized inflammation (ZIGI) in mice. 1753 56

IL-19, a proinflammatory cytokine, belongs to the IL-10 family. IL-19 is induced in systemic inflammatory response syndrome, but its pathophysiological function in sepsis is unclear. Our aim was to determine the roles of IL-19 in endotoxin-induced tissue damage in vivo and in vitro. We examined serum levels of IL-19 in sepsis patients and healthy volunteers, determined the in vitro effects of IL-19 on lung epithelial cells, liver cells, and neutrophils, and analyzed the tissue expression of IL-19 and its receptors in murine endotoxic shock. Electroporation-mediated gene transfer of mouse IL-19-soluble receptor plasmid DNA was used to determine the effects of IL-19 depletion in preventing endotoxic shock-induced tissue damage in mice. We found that serum levels of IL-19 were higher in patients than in healthy volunteers (n = 28, P = 0.001). IL-19 induced apoptosis in lung epithelial cells and reactive oxygen species production in liver cells in vitro. IL-19 also promoted neutrophil chemotaxis, reduced neutrophil apoptosis, and induced the production of proinflammatory cytokines and chemokines (IL-1[beta], IL-6, IL-8, CCL5, and CXCL9) in lung epithelial cells. In LPS-challenged mice, transcripts of IL-19 and its receptors were up-regulated in heart, lung, liver, and kidney tissue. Neutrophil infiltration in lung and liver tissue, and serum levels of alanine transaminase and aspartate transaminase, were lower in mice electroporated with IL-19-soluble receptor plasmid DNA before LPS treatment compared with control mice. These results suggest that up-regulated IL-19 may be involved in lung and liver tissue injury in murine endotoxic shock.
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PMID:IL-19 is involved in the pathogenesis of endotoxic shock. 1824 2

Most invasive fungal infections such as candidemia are frequent in patients with hematologic malignancies. We measured cytokines/chemokines (IL-6, IL-8, monocytic chemoattractant protein 1, RANTES and epithelial neutrophil-activating peptide 78), soluble molecules (sFas, sE-selectin and soluble vascular cell adhesion molecule 1) and platelet activation markers (soluble CD40 ligand, sP-selectin and platelet-derived microparticles) in patients with hematologic malignancies under prophylactic treatment with an antifungal drug (fosfluconazole). We classified patients into 2 groups by the level of beta-D-glucan. The level of C-reactive protein was higher in the high beta-D-glucan group (>5 pg/ml) than in the low beta-D-glucan group. However, there were no differences in the levels of other parameters (peripheral blood cells, glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, lactate dehydrogenase, blood urea nitrogen and creatinine). Patients in the high beta-D-glucan group exhibited a significant elevation of several chemokines, soluble molecules and platelet activation markers compared with those in the low beta-D-glucan group, but the levels of IL-8, monocytic chemoattractant protein 1 and sFas did not differ significantly. The levels of C-reactive protein and IL-6 increased significantly after 1 or 2 weeks on fosfluconazole in both groups. In contrast, the high beta-D-glucan group exhibited a significant decrease in chemokines, soluble markers and platelet-derived microparticles compared with the low beta-D-glucan group after treatment with fosfluconazole, although the patients in the low beta-D-glucan group exhibited no significant changes. Furthermore, the levels of RANTES, epithelial neutrophil-activating peptide 78, soluble vascular cell adhesion molecule 1 and sE-selectin correlated positively with platelet-derived microparticles in the high beta-D-glucan group. These findings suggest that fungal infection may modulate the vascular events in which some platelet-related chemokines are involved.
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PMID:Elevation of activated platelet-dependent chemokines and soluble cell adhesion molecules in patients with hematologic malignancies and high levels of beta-D-glucan. 1833 12

Diets high in cholesterol and cholate such as the Paigen diet have been used to study atherogenesis, lithogenesis, and proinflammatory microvascular changes induced by nutritional hypercholesterolemia. Although these diets lead to chronic hepatic inflammation and fibrosis, the early inflammatory changes have been poorly characterized. TLR4, a known receptor for LPS, is also a receptor for a variety of endogenous ligands and has been implicated in atheroma formation. Here, we specifically examined the early inflammatory response of the liver to the atherogenic (ATH) diet and the possible contribution of TLR4. Animals fed the high-cholesterol/cholate diet for 3 weeks developed a significant, predominantly mononuclear leukocyte infiltration in the liver, hepatic steatosis, elevated hepatic expression of MCP-1, RANTES, and MIP-2, and increased serum levels of liver enzymes. In TLR4-deleted animals, there was a 30% attenuation in the serum alanine transaminase levels and a 50% reduction in the leukocyte infiltration with a fourfold reduction in chemokine expression. In contrast, hepatic steatosis did not differ from wild-type controls. TLR2 deletion had no effect on diet-induced hepatitis but increased the amount of steatosis. We conclude that the early inflammatory liver injury but not hepatic lipid loading induced by the ATH diet in mice is mediated in part by TLR4.
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PMID:Atherogenic diet-induced hepatitis is partially dependent on murine TLR4. 1833 42

Overdose of acetaminophen (APAP) causes necrosis of centrilobular cells of the liver. Accumulating evidence suggests that innate immune system may contribute to APAP-induced hepatotoxicity. Interaction between RANTES and its receptor C-C chemokine receptor (CCR) 5 is related to recruitment of macrophages to sites of inflammation. In this study, we examined effects of CCR5 deficiency on APAP-mediated liver injury by employing CCR5 knockout (KO) mice. CCR5 wild-type (WT) and KO mice received intraperitoneal injection of APAP (300 mg/kg) and were killed 24 h after the injection. Hepatic injury was determined by using histological and biochemical analyses. Intraperitoneal APAP caused the hepatocytic necrosis, as evidenced by hematoxylin and eosin staining and an increase in alanine transaminase and aspartate transaminase levels in serum. Hepatic damage appeared to be larger in CCR5 WT animals compared with KO animals. There were no differences in cytochrome P450 2E1 between CCR5 WT and KO animals suggesting that the resistance of CCR5 KO mice did not come from alterations in APAP metabolism. Infiltration of macrophages into the liver was reduced in CCR5 KO mice, and this was accompanied decreased inflammatory responses. Inhibition of macrophage activity by pretreatment of gadolinium chloride significantly blocked APAP-caused hepatotoxicity. These results indicate that recruitment of macrophage into the inflammatory sites significantly contributes to APAP-mediated hepatocytic death and CCR5 gene deletion protects from APAP-induced liver injury by alleviating macrophage recruitment and inflammatory responses. This study represents a critical role of CCR5 in macrophage infiltration into the liver and subsequent hepatotoxicity upon challenge of APAP.
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PMID:CCR5 knockout mice with C57BL6 background are resistant to acetaminophen-mediated hepatotoxicity due to decreased macrophages migration into the liver. 2578 49


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