CCl4

Distribution by Scientific Domains
Distribution within Medical Sciences

Terms modified by CCl4

  • ccl4 administration
  • ccl4 alone
  • ccl4 intoxication
  • ccl4 treatment

  • Selected Abstracts


    Acquisition of regulatory function by human CD8+ T cells treated with anti-CD3 antibody requires TNF

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2010
    Vitaly Ablamunits
    Abstract Anti-CD3 mAb can modulate graft rejection and attenuate autoimmune diseases but their mechanism(s) of action remain unclear. CD8+ T cells with regulatory function are induced in vitro by Teplizumab, a humanized anti-CD3 antibody and inhibit responses of autologous and allogeneic T cells. They inhibit CD4+ T-cell proliferation by mechanisms involving TNF and CCL4, and by blocking target cell entry into G2/M phase of cell cycle but neither kill them, nor compete for IL-2. CD8+ Treg can be isolated from peripheral blood following treatment of patients with Type 1 diabetes with Teplizumab, but not from untreated patients. The induction of CD8+ Treg by anti-CD3 mAb requires TNF and signaling through the NF-,B cascade. The CD8+ Treg express CD25, glucocorticoid-induced TNF receptor family, CTLA-4, Foxp3, and TNFR2, and the combined expression of TNFR2 and CD25 identifies a potent subpopulation of CD8+ Treg. These studies have identified a novel mechanism of immune regulation by anti-CD3 mAb and markers that may be used to track inducible CD8+ Treg in settings such as chronic inflammation or immune therapy. [source]


    The interferon-inducible gene IFI16 secretome of endothelial cells drives the early steps of the inflammatory response

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2010
    Rossella Baggetta
    Abstract The IFN-inducible human IFI16 gene is highly expressed in endothelial cells as well as epithelial and hematopoietic tissues. Previous gene array analysis of human umbilical vein endothelial cells overexpressing IFI16 has revealed an increased expression of genes involved in inflammation and apoptosis. In this study, protein array analysis of the IFI16 secretome showed an increased production of chemokines, cytokines and adhesion molecules responsible for leukocyte chemotaxis. Functional analysis of the promoter for CCL20, the chemokine responsible for leukocyte recruitment in the early steps of inflammation, by site-specific mutation demonstrated that NF-,B is the main mediator of CCL20 induction at the transcriptional level. Finally, both Langerhans DC and B-lymphocyte migration triggered by supernatants from IFI16-overexpressing endothelial cells was partially inhibited by Ab inactivating CCL4, CCL5 and CCL20 chemokines. Altogether, these results demonstrate that the IFI16 gene, through its secretome, regulates proinflammatory activity of endothelial cells, thus corroborating its role in the early steps of inflammation. [source]


    Hematopoietic mobilization in mice increases the presence of bone marrow,derived hepatocytes via in vivo cell fusion,

    HEPATOLOGY, Issue 1 2006
    Oscar Quintana-Bustamante
    The mechanisms for in vivo production of bone marrow,derived hepatocytes (BMDHs) remain largely unclear. We investigated whether granulocyte colony,stimulating factor (G-CSF),mediated mobilization of hematopoietic cells increases the phenomenon. Recurrent liver injury in mice expressing green fluorescent protein (EGFP) in all hematopoietic-derived cells was produced by 3 months of carbon tetrachloride (CCL4) injections. Histologically, there were necrotic foci with histiocyte-rich infiltrates, but little oval cell proliferation. Subsequently, some animals were mobilized with G-CSF for 1, 2, or 3 weeks. Animals were sacrificed 1 month after growth factor treatment. BMDH percentages were lower than previously reported, though G-CSF mobilization significantly augmented BMDH production in injured livers. BMDHs originating from in vivo fusion were evaluated by transplanting female EGFP+ cells into male mice. Binucleated, EGFP+ hepatocytes with one Y chromosome, indicating fusion, were identified. In conclusion, (1) mobilization of hematopoietic cells increases BMDH production and (2) as with the FAH-null model, the first model demonstrating hematopoietic/hepatocyte fusion, recurring CCl4 -induced injury has macrophage-rich infiltrates, a blunted oval cell response, and a predominantly in vivo fusion process for circulating cell engraftment into the liver. These findings open the possibility of using hematopoietic growth factors to treat nonhematopoietic degenerative diseases. (HEPATOLOGY 2006;43:108,116.) [source]


    CCR5 deficiency exacerbates T-cell,mediated hepatitis in mice,

    HEPATOLOGY, Issue 4 2005
    Christophe Moreno
    Experimental T-cell,mediated hepatitis induced by concanavalin A (Con A) involves the production of different cytokines and chemokines and is characterized by leukocyte infiltration. Because the chemokine receptor CCR5 and its ligands (CCL3, CCL4, and CCL5) regulate leukocyte chemotaxis and activation, we investigated the role of CCR5 during Con A,induced liver injury. Serum levels of CCR5 ligands and their hepatic transcript levels were significantly increased after Con A injection, whereas CCR5+ liver mononuclear cells were recruited to the liver. CCR5-deficient (CCR5,/,) mice disclosed increased mortality and liver injury following Con A administration compared with wild-type mice. CCR5,/, mice also exhibited increased production of interleukin 4, tumor necrosis factor ,, CCL3, CCL4, and CCL5, and a prominent liver mononuclear cell infiltrate, among which many cells were CCR1+. In vivo neutralization of CCR5 ligands in CCR5,/, mice afforded a protection against hepatitis only when CCL5 was neutralized. In conclusion, CCR5 deficiency exacerbates T-cell,mediated hepatitis, and leads to increased levels of CCR5 ligands and a more pronounced liver mononuclear infiltrate, suggesting that CCR5 expression can modulate severity of immunomediated liver injury. (HEPATOLOGY 2005;42:854,862.) [source]


    Alcohol Suppresses IL-2,Induced CC Chemokine Production by Natural Killer Cells

    ALCOHOLISM, Issue 9 2005
    Ting Zhang
    Background: Natural killer (NK) cells are a critical component of the host innate immune system. We investigated whether alcohol impairs NK cell function, particularly production of CC chemokines induced by interleukin (IL)-2, the natural ligands for CCR5 receptor. Methods: Primary NK cells and NK cell line (YTS) were cultured with or without alcohol (10 to 80 mM) for three hours. The culture supernatants were then harvested and used to treat human peripheral blood monocyte-derived macrophages and a HeLa cell line, which expresses CD4, CCR5, and CXCR4 receptors (MAGI cells). CC chemokine expression by YTS and primary NK cells treated with or without alcohol was analyzed with the real-time RT-PCR and ELISA. Ca2+i and Western blot assays were used to determine calcium-mediated intracellular signaling pathway and NF-,B p65 expression. HIV strains (Bal and UG024) were used to infect macrophages and MAGI cells. In addition, ADA (macrophage-tropic strain) and murine leukemia virus (MLV) envelope-pseudotyped HIV infection was carried out in macrophages. HIV infectivity was determined by HIV reverse transcriptase (RT) and ,-galactosidase activity assays. Results: Alcohol inhibited IL-2,induced CC chemokine (CCL3 and CCL4) expression by NK cells. Functional tests demonstrated that this reduced expression of CC chemokines was associated with diminished anti-HIV ability of NK cells. Alcohol also reduced the ability of NK cells to response to CCL3-mediated chemotaxis. Alcohol inhibited IL-2,induced NF-,B p65 protein expression and calcium mobilization by NK cells. Conclusions: Alcohol, through the inhibition of IL-2,induced NF-,B p65 protein expression and intracellular calcium mobilization, suppressed NK cell production of CC chemokines. This suppression of CC chemokine production was associated with diminished anti-HIV activity of NK cells. Thus, by inhibiting NK cell,mediated innate immunity against HIV, alcohol consumption may have a cofactor role in the immunopathogenesis of HIV disease. [source]


    Tumor necrosis factor neutralization results in disseminated disease in acute and latent Mycobacterium tuberculosis infection with normal granuloma structure in a cynomolgus macaque model

    ARTHRITIS & RHEUMATISM, Issue 2 2010
    Philana Ling Lin
    Objective An increased risk of tuberculosis has been documented in humans treated with tumor necrosis factor , (TNF,),neutralizing agents. In murine models, impaired signaling by TNF causes exacerbation of both acute and chronic infection associated with aberrant granuloma formation and maintenance. This study was undertaken to investigate immune modulation in the setting of TNF neutralization in primary and latent tuberculosis in a non-human primate model. Methods Cynomolgus macaques 4 years of age or older were infected with Mycobacterium tuberculosis and subjected to clinical, microbiologic, immunologic, and radiographic examinations. Monkeys were classified as having active or latent disease 6,8 months after infection, based on clinical criteria. Monkeys used in acute infection studies were randomized to receive either adalimumab (prior to and during infection) or no treatment. Monkeys with latent infection that were randomized to receive TNF-neutralizing agent were given either an inhibitor of soluble TNF, recombinant methionyl human soluble TNF receptor I (p55-TNFRI), or adalimumab. Control monkeys with latent infection were given no treatment or saline. Data from previously studied monkeys with active or latent disease were also used for comparison. Results Administration of TNF-neutralizing agents prior to M tuberculosis infection resulted in fulminant and disseminated disease by 8 weeks after infection. Neutralization of TNF in latently infected cynomolgus macaques caused reactivation in a majority of animals as determined by gross pathologic examination and bacterial burden. A spectrum of dissemination was noted, including extrapulmonary disease. Surprisingly, monkeys that developed primary and reactivation tuberculosis after TNF neutralization had similar granuloma structure and composition to that of control monkeys with active disease. TNF neutralization was associated with increased levels of interleukin-12, decreased levels of CCL4, increased chemokine receptor expression, and reduced mycobacteria-induced interferon-, production in blood but not in the affected mediastinal lymph nodes. Finally, the first signs of reactivation often occurred in thoracic lymph nodes. Conclusion These findings have important clinical implications for determining the mechanism of TNF neutralization,related tuberculosis. [source]


    CCR5 is involved in resolution of inflammation in proteoglycan-induced arthritis

    ARTHRITIS & RHEUMATISM, Issue 10 2009
    Paul D. Doodes
    Objective CCR5 and its ligands (CCL3, CCL4, and CCL5) may play a role in inflammatory cell recruitment into the joint. However, it was recently reported that CCR5 on T cells and neutrophils acts as a decoy receptor for CCL3 and CCL5 to assist in the resolution of inflammation. The aim of this study was to determine whether CCR5 functions as a proinflammatory or antiinflammatory mediator in arthritis, by examining the role of CCR5 in proteoglycan (PG),induced arthritis (PGIA). Methods Arthritis was induced by immunizing wild-type (WT) and CCR5-deficient (CCR5,/,) BALB/c mice with human PG in adjuvant. The onset and severity of PGIA were monitored over time. Met-RANTES was used to block CCR5 in vivo. Arthritis was transferred to SCID mice, using spleen cells from arthritic WT and CCR5,/, mice. The expression of cytokines and chemokines was measured by enzyme-linked immunosorbent assay. Results In CCR5,/, mice and WT mice treated with the CCR5 inhibitor Met-RANTES, exacerbated arthritis developed late in the disease course. The increase in arthritis severity in CCR5,/, mice correlated with elevated serum levels of CCL5. However, exacerbated arthritis was not intrinsic to the CCR5,/, lymphoid cells, because the arthritis that developed in SCID mouse recipients was similar to that in WT and CCR5,/, mice. CCR5 expression in the SCID mouse was sufficient to clear CCL5, because serum levels of CCL5 were the same in SCID mouse recipients receiving cells from either WT or CCR5,/, mice. Conclusion These data demonstrate that CCR5 is a key player in controlling the resolution of inflammation in experimental arthritis. [source]


    Pharmacokinetics of diclofenac in rats intoxicated with CCL4, and in the regenerating liver

    BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2007
    Karina Reyes-Gordillo
    Abstract The pharmacokinetics of an intravenous and oral diclofenac dose of 3.2 mg/kg was studied in male Wistar rats under control conditions, 1 and 3 days after liver damage and regeneration induced by an oral injection of CCl4. One day after CCl4 administration, indicators of necrosis (alanine aminotransferase), cholestasis (,-glutamyl transpeptidase) and regeneration (,-fetoprotein) were significantly increased; these effects were reversed after 3 days. In nonintoxicated rats, t1/2 was 43.83 ± 4.95 min, Vd was 0.37 ± 0.04 l/kg, Cl was 129.21 ± 9.20 ml/min kg, AUCi.v. was 25.62 ± 1.45 µg/min ml, and AUCp.o. was 20.21 ± 1.03. One day after intoxication, when the liver was damaged and regenerating, the metabolism was decreased: diclofenac t1/2 was increased to 258.21 ± 30.80 min but Vd did not change significantly, therefore Cl was reduced to 32.81 ± 3.38 ml/min kg. By day 3 after intoxication, liver function, regeneration and pharmacokinetics returned to normal. The results show that liver damage and regeneration increases the bioavailability by decreasing elimination. The present observations suggest that reduction of the pharmacokinetic parameters may lead to drug accumulation in the regenerating-damaged liver with an attendant possible increase in toxic effects. The results in rats, also suggest that once hepatic injury is finished and regeneration is complete, diclofenac can be administered normally. Copyright © 2007 John Wiley & Sons, Ltd. [source]


    Azide,Tetrazole Ring-Chain Isomerism in Polyazido-1,3,5-triazines, Triazido- s -heptazine, and Diazidotetrazines

    EUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 11 2006
    Anton Hammerl
    Abstract The azide,tetrazole isomerism in several polyazido-1,3,5-triazines, triazido- sym -heptazine, and some diazido-1,2,4,5-tetrazines was investigated by ab initio quantum chemical methods in order to determine whether the polyazides are suitable starting materials for the synthesis of the isomeric tetrazoles. The effects of solvation in CCl4, DMSO and water on this isomerism were included using the self consistent reaction field (SCRF) method. The effect of amino- and nitrosubstituents on the azide,tetrazole isomerism was also examined. In the gas phase all investigated polyazidoheterocycles do not cyclize to form tetrazoles. An electron-donating amino group favors the ring closure to tetrazoles, whereas an electron-withdrawing nitro group favors the azides. Solvation in polar solvents favors the formation of a tetrazole ring system due to higher charge separation in the tetrazole ring system, but for all polyazido-1,3,5-triazines, including triazido- s -heptazine, the effects of solvation are not strong enough to shift the equilibrium to the tetrazole side, which explains why several attempts to detect these compounds have failed. The monotetetrazoles of diazidotetrazine and bis(azido)azo-1,2,4,5-tetrazine and the ditetrazole of bis(azido)hydrazo-1,2,4,5-tetrazine are the minimum energy species in DMSO and water. Thus we predict that the diazidoazo- and hydrazotetrazines will readily cyclize to the tetrazoles in polar solvents. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006) [source]


    Conformational changes of ,-lactoglobulin in sodium bis(2-ethylhexyl) sulfosuccinate reverse micelles

    FEBS JOURNAL, Issue 4 2004
    A fluorescence, CD study
    The effect of ,-lactoglobulin encapsulation in sodium bis(2-ethylhexyl) sulfosuccinate reverse micelles on the environment of protein and on Trp was analysed at different water contents (,0). CD data underlined the distortion of the ,-sheet and a less constrained tertiary structure as the ,0 increased, in agreement with a concomitant red shift and a decrease in the signal intensity obtained in steady-state fluorescence measurements. Fluorescence lifetimes, evaluated by biexponential analysis, were ,1 = 1.28 ns and ,2 = 3.36 ns in neutral water. In reverse micelles, decay-associated spectra indicated the occurrence of important environmental changes associated with ,0. Bimolecular fluorescence quenching by CCl4 and acrylamide was employed to analyse alterations in the accessibility of the two Trp residues in ,-lactoglobulin, induced by changes in ,0. The average bimolecular quenching constant <> was found not to depend on ,0, confirming the insolubility of this quencher in the aqueous interface, while <> increases with ,0. The drastic decrease with ,0 of kq, associated with the longest lifetime, , comparatively to the increase of , emphasizes the location of ,-lactoglobulin in the aqueous interfacial region especially at ,0,,10. The fact that (,0 = 30) , (water) also confirms the important conformational changes of encapsulated ,-lactoglobulin. [source]


    Ferulic acid, a natural protector against carbon tetrachloride-induced toxicity

    FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2005
    M. Srinivasan
    Abstract The present work is aimed at evaluating the protective effect of ferulic acid (FA), a naturally occurring phenolic compound on CCl4 induced toxicity. The activities of liver markers (alanine transaminase, aspartate transaminase, alkaline phosphatase, , -glutamyl transferase), lipid peroxidative index (thiobarbituric acid-reactive substances, hydroperoxides, nitric oxide, protein carbonyl content), the antioxidant status (superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione) were used as biomarkers to monitor the protective role of FA. The liver marker enzymes in plasma and lipid peroxidative index in liver and kidney were increased in CCl4 -treated groups, which were decreased significantly on treatment with FA. The antioxidants, which were depleted in CCl4 -treated groups, were improved significantly by FA treatment. Administration of FA to normal rats did not produce any harmful effects. Thus our results show that FA is an effective antioxidant without any side-effects and may be a great gain in the current search for natural therapy. [source]


    Monitoring Subsurface Contamination Using Tree Branches

    GROUND WATER MONITORING & REMEDIATION, Issue 1 2007
    Gayathri Gopalakrishnan
    This paper proposes a method of assessing the distribution of chlorinated solvents in soil and ground water using tree branches. Sampling branches is a potentially more cost-effective and easier method than sampling tree cores, with less risk of damage to the tree. This approach was tested at Argonne National Laboratory, where phytoremediation is being used to remove tetrachloroethene (PCE), trichloroethene (TCE), and carbon tetrachloride (CCl4) from soil and ground water. The phytoremediation system consists of shallow-rooted willows planted in an area with contaminated soil and deep-rooted poplars planted in an area with clean soil and contaminated ground water. Branch samples were collected from 126 willows and 120 poplars. Contaminant concentrations from 31 soil borings and six monitoring wells were compared to those from branches of adjacent trees. Regression equations with correlation coefficients of at least 0.89 were obtained, which were found to be chemical specific. Kriged profiles of TCE concentration based on soil and willow branch data were developed and showed good agreement. Profiles based on ground water data could not be developed due to lack of sufficient monitoring wells for a meaningful statistical analysis. An analytical model was used to simulate TCE concentrations in tree branches from soil concentrations; the diffusion coefficient for TCE in the tree was used as the fitting parameter and the best-fit value was two orders of magnitude greater than literature values. This work indicates that tree branch sampling is a useful approach to assess contaminant distribution and potentially to determine where to locate monitoring wells or perform detailed soil analysis. Further research is necessary prior to using this method as a quantitative monitoring tool for soil and ground water. [source]


    CX3CL1-CX3CR1 interaction prevents carbon tetrachloride-induced liver inflammation and fibrosis in mice,

    HEPATOLOGY, Issue 4 2010
    Tomonori Aoyama
    Chronic liver disease is associated with hepatocyte injury, inflammation, and fibrosis. Chemokines and chemokine receptors are key factors for the migration of inflammatory cells such as macrophages and noninflammatory cells such as hepatic stellate cells (HSCs). The expression of CX3CR1 and its ligand, CX3CL1, is up-regulated in chronic liver diseases such as chronic hepatitis C. However, the precise role of CX3CR1 in the liver is still unclear. Here we investigated the role of the CX3CL1-CX3CR1 interaction in a carbon tetrachloride (CCl4),induced liver inflammation and fibrosis model. CX3CR1 was dominantly expressed in Kupffer cells in the liver. In contrast, the main source of CX3CL1 was HSCs. Mice deficient in CX3CR1 showed significant increases in inflammatory cell recruitment and cytokine production [including tumor necrosis factor , (TNF-,); monocyte chemoattractant protein 1; macrophage inflammatory protein 1,; and regulated upon activation, normal T cell expressed, and secreted (RANTES)] after CCl4 treatment versus wild-type (WT) mice. This suggested that CX3CR1 signaling prevented liver inflammation. Kupffer cells in CX3CR1-deficient mice after CCl4 treatment showed increased expression of TNF-, and transforming growth factor , and reduced expression of the anti-inflammatory markers interleukin-10 (IL-10) and arginase-1. Coculture experiments showed that HSCs experienced significantly greater activation by Kupffer cells from CCl4 -treated CX3CR1-deficient mice versus WT mice. Indeed, augmented fibrosis was observed in CX3CR1-deficient mice versus WT mice after CCl4 treatment. Finally, CX3CL1 treatment induced the expression of IL-10 and arginase-1 in WT cultured Kupffer cells through CX3CR1, which in turn suppressed HSC activation. Conclusion: The CX3CL1-CX3CR1 interaction inhibits inflammatory properties in Kupffer cells/macrophages and results in decreased liver inflammation and fibrosis. (Hepatology 2010) [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 2010
    Norio 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]


    CXC chemokine ligand 4 (Cxcl4) is a platelet-derived mediator of experimental liver fibrosis,

    HEPATOLOGY, Issue 4 2010
    Mirko Moreno Zaldivar
    Liver fibrosis is a major cause of morbidity and mortality worldwide. Platelets are involved in liver damage, but the underlying molecular mechanisms remain elusive. Here, we investigate the platelet-derived chemokine (C-X-C motif) ligand 4 (CXCL4) as a molecular mediator of fibrotic liver damage. Serum concentrations and intrahepatic messenger RNA of CXCL4 were measured in patients with chronic liver diseases and mice after toxic liver injury. Platelet aggregation in early fibrosis was determined by electron microscopy in patients and by immunohistochemistry in mice. Cxcl4,/, and wild-type mice were subjected to two models of chronic liver injury (CCl4 and thioacetamide). The fibrotic phenotype was analyzed by histological, biochemical, and molecular analyses. Intrahepatic infiltration of immune cells was investigated by fluorescence-activated cell sorting, and stellate cells were stimulated with recombinant Cxcl4 in vitro. The results showed that patients with advanced hepatitis C virus,induced fibrosis or nonalcoholic steatohepatitis had increased serum levels and intrahepatic CXCL4 messenger RNA concentrations. Platelets were found directly adjacent to collagen fibrils. The CCl4 and thioacetamide treatment led to an increase of hepatic Cxcl4 levels, platelet activation, and aggregation in early fibrosis in mice. Accordingly, genetic deletion of Cxcl4 in mice significantly reduced histological and biochemical liver damage in vivo, which was accompanied by changes in the expression of fibrosis-related genes (Timp-1 [tissue inhibitor of matrix metalloproteinase 1], Mmp9 [matrix metalloproteinase 9], Tgf -, [transforming growth factor beta], IL10 [interleukin 10]). Functionally, Cxcl4,/, mice showed a strongly decreased infiltration of neutrophils (Ly6G) and CD8+ T cells into the liver. In vitro, recombinant murine Cxcl4 stimulated the proliferation, chemotaxis, and chemokine expression of hepatic stellate cells. Conclusion: The results underscore an important role of platelets in chronic liver damage and imply a new target for antifibrotic therapies. (HEPATOLOGY 2010.) [source]


    CCR2 promotes hepatic fibrosis in mice,

    HEPATOLOGY, Issue 1 2009
    Ekihiro Seki
    Chemokines and chemokine receptors contribute to the migration of hepatic stellate cells (HSCs) and Kupffer cells, two key cell types in fibrogenesis. Here, we investigate the role of CCR2, the receptor for monocyte chemoattractant protein (MCP)-1, MCP-2, and MCP-3, in hepatic fibrosis. Hepatic CCR2, MCP-1, MCP-2, and MCP-3 messenger RNA expression was increased after bile duct ligation (BDL). Both Kupffer cells and HSCs, but not hepatocytes, expressed CCR2. BDL- and CCl4 -induced fibrosis was markedly reduced in CCR2,/, mice as assessed through collagen deposition, ,-smooth muscle actin expression, and hepatic hydroxyproline content. We generated CCR2 chimeric mice by the combination of clodronate, irradiation, and bone marrow (BM) transplantation allowing full reconstitution of Kupffer cells, but not HSCs, with BM cells. Chimeric mice containing wild-type BM displayed increased macrophage recruitment, whereas chimeric mice containing CCR2,/, BM showed less macrophage recruitment at 5 days after BDL. Although CCR2 expressed in the BM enhanced macrophage recruitment in early phases of injury, CCR2 expression on resident liver cells including HSCs, but not on the BM, was required for fibrogenic responses in chronic fibrosis models. In vitro experiments demonstrated that HSCs deficient in CCR2,/, or its downstream mediator p47phox,/, did not display extracellular signal-regulated kinase and AKT phosphorylation, chemotaxis, or reactive oxygen species production in response to MCP-1, MCP-2, and MCP-3. Conclusion: Our results indicate that CCR2 promotes HSC chemotaxis and the development of hepatic fibrosis. (HEPATOLOGY 2009.) [source]


    Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis,

    HEPATOLOGY, Issue 1 2009
    Karlin Raja Karlmark
    In addition to liver-resident Kupffer cells, infiltrating immune cells have recently been linked to the development of liver fibrosis. Blood monocytes are circulating precursors of tissue macrophages and can be divided into two functionally distinct subpopulations in mice: Gr1hi (Ly6Chi) and Gr1lo (Ly6Clo) monocytes. The role of these monocyte subsets in hepatic fibrosis and the mechanisms of their differential recruitment into the injured liver are unknown. We therefore characterized subpopulations of infiltrating monocytes in acute and chronic carbon tetrachloride (CCl4)-induced liver injury in mice using flow cytometry and immunohistochemistry. Inflammatory Gr1hi but not Gr1lo monocytes are massively recruited into the liver upon toxic injury constituting an up to 10-fold increase in CD11b+F4/80+ intrahepatic macrophages. Comparing wild-type with C-C chemokine receptor (CCR2)-deficient and CCR2/CCR6,deficient mice revealed that CCR2 critically controls intrahepatic Gr1hi monocyte accumulation by mediating their egress from bone marrow. During chronic liver damage, intrahepatic CD11b+F4/80+Gr1+ monocyte-derived cells differentiate preferentially into inducible nitric oxide synthase,producing macrophages exerting proinflammatory and profibrogenic actions, such as promoting hepatic stellate cell (HSC) activation, T helper 1,T cell differentiation and transforming growth factor , (TGF-,) release. Impaired monocyte subset recruitment in Ccr2,/, and Ccr2,/,Ccr6,/, mice results in reduced HSC activation and diminished liver fibrosis. Moreover, adoptively transferred Gr1hi monocytes traffic into the injured liver and promote fibrosis progression in wild-type and Ccr2,/,Ccr6,/, mice, which are otherwise protected from hepatic fibrosis. Intrahepatic CD11b+F4/80+Gr1+ monocyte-derived macrophages purified from CCl4 -treated animals, but not naïve bone marrow monocytes or control lymphocytes, directly activate HSCs in a TGF-,,dependent manner in vitro. Conclusion: Inflammatory Gr1+ monocytes, recruited into the injured liver via CCR2-dependent bone marrow egress, promote the progression of liver fibrosis. Thus, they may represent an interesting novel target for antifibrotic strategies. (HEPATOLOGY 2009;50:261,274.) [source]


    Multidrug resistance,associated proteins are crucial for the viability of activated rat hepatic stellate cells,,

    HEPATOLOGY, Issue 2 2008
    Rebekka A. Hannivoort
    Hepatic stellate cells (HSCs) survive and proliferate in the chronically injured liver. ATP-binding cassette (ABC) transporters play a crucial role in cell viability by transporting toxic metabolites or xenobiotics out of the cell. ABC transporter expression in HSCs and its relevance to cell viability and/or activation have not been reported so far. The aim of this study was to investigate the expression, regulation, and function of multidrug resistance,associated protein (Mrp)-type and multidrug resistance protein (Mdr),type ABC transporters in activated rat HSCs. Rat HSCs were exposed to cytokines or oxidative stress. ABC transporter expression was determined by quantitative polymerase chain reaction and immunohistochemistry. HSCs were exposed to the Mdr inhibitors verapamil and PSC-833 and the Mrp inhibitor MK571. Mdr and Mrp transporter function was evaluated with flow cytometry. Apoptosis was determined by activated caspase-3 and acridine orange staining, and necrosis was determined by Sytox green nuclear staining. An in vivo model of carbon tetrachloride (CCl4),induced liver fibrosis was used. With respect to hepatocytes, activated HSCs expressed high levels of Mrp1 and comparable levels of Mrp3, Mrp4, Mdr1a, and Mdr1b but not the hepatocyte-specific transporters bile salt export pump, Mrp2, and Mrp6. Mrp1 protein staining correlated with desmin staining in livers from CCl4 -treated rats. Mrp1 expression increased upon activation of HSCs. Cytokines induced Mdr1b expression only. Oxidative stress was not a major regulator of Mdr and Mrp transporter expression. Activated HSCs became necrotic when exposed to the Mrp inhibitors. Conclusion: Activated HSCs contain relatively high levels of Mrp1. Mrp-type transporters are required for the viability of activated HSCs. Mrp-dependent export of endogenous metabolites is important for the survival of activated HSCs in chronic liver diseases. (HEPATOLOGY 2008.) [source]


    Hematopoietic mobilization in mice increases the presence of bone marrow,derived hepatocytes via in vivo cell fusion,

    HEPATOLOGY, Issue 1 2006
    Oscar Quintana-Bustamante
    The mechanisms for in vivo production of bone marrow,derived hepatocytes (BMDHs) remain largely unclear. We investigated whether granulocyte colony,stimulating factor (G-CSF),mediated mobilization of hematopoietic cells increases the phenomenon. Recurrent liver injury in mice expressing green fluorescent protein (EGFP) in all hematopoietic-derived cells was produced by 3 months of carbon tetrachloride (CCL4) injections. Histologically, there were necrotic foci with histiocyte-rich infiltrates, but little oval cell proliferation. Subsequently, some animals were mobilized with G-CSF for 1, 2, or 3 weeks. Animals were sacrificed 1 month after growth factor treatment. BMDH percentages were lower than previously reported, though G-CSF mobilization significantly augmented BMDH production in injured livers. BMDHs originating from in vivo fusion were evaluated by transplanting female EGFP+ cells into male mice. Binucleated, EGFP+ hepatocytes with one Y chromosome, indicating fusion, were identified. In conclusion, (1) mobilization of hematopoietic cells increases BMDH production and (2) as with the FAH-null model, the first model demonstrating hematopoietic/hepatocyte fusion, recurring CCl4 -induced injury has macrophage-rich infiltrates, a blunted oval cell response, and a predominantly in vivo fusion process for circulating cell engraftment into the liver. These findings open the possibility of using hematopoietic growth factors to treat nonhematopoietic degenerative diseases. (HEPATOLOGY 2006;43:108,116.) [source]


    Effects of proinflammatory cytokines on rat organic anion transporters during toxic liver injury and cholestasis

    HEPATOLOGY, Issue 2 2003
    Andreas Geier M.D.
    Hepatobiliary transporters are down-regulated in toxic and cholestatic liver injury. Cytokines such as tumor necrosis factor , (TNF-,) and interleukin 1, (IL-1,) are attributed to mediate this regulation, but their particular contribution in vivo is still unknown. Thus, we studied the molecular mechanisms by which Ntcp, Oatp1, Oatp2, and Mrp2 are regulated by proinflammatory cytokines during liver injury. Rats were injected intraperitoneally with either carbon tetrachloride or endotoxin. Inactivation of TNF-, and IL-1, was achieved by repetitive intraperitoneal injection of etanercept and anakinra, respectively. Messenger RNA (mRNA) levels of transporters and binding activities as well as nuclear protein levels of Ntcp, Oatp2, and Mrp2 transactivators were determined 20 to 24 hours later. In contrast to IL-1,, TNF-, inactivation alone fully prevented down-regulation of Ntcp, Oatp1, and Oatp2 mRNA as well as reduced binding activity of hepatocyte nuclear factor 1 (HNF-1) in CCl4 -induced toxic injury. In endotoxemia, down-regulation of Mrp2, and partially in case of Ntcp, could be prevented by IL-1, but not TNF-, blockade. However, inactivation of either cytokine led to preservation of HNF1 and partially of retinoid X receptor/retinoic acid receptor (RXR/RAR) binding activity. No effect of anticytokines was seen on pregnane X receptor (PXR) and constitutive androstane receptor (CAR) binding activity as well as nuclear protein mass. In conclusion, TNF-, represents the master cytokine responsible for HNF1-dependent down-regulation of Ntcp, Oatp1, and Oatp2 in CCl4 -induced toxic liver injury. IL-1, predominates in a complex signaling network of Ntcp and Mrp2 regulation in cholestatic liver injury. In contrast to in vitro studies, HNF1 and RXR/RAR-independent mechanisms appear to be more important in regulation of Mrp2 and Ntcp gene expression in endotoxemia. [source]


    Tissue inhibitor of metalloproteinases-1 attenuates spontaneous liver fibrosis resolution in the transgenic mouse

    HEPATOLOGY, Issue 4 2002
    Hitoshi Yoshiji
    It has been suggested that the tissue inhibitor of metalloproteinases-1 (TIMP-1) is involved in spontaneous resolution of liver fibrosis. The aim of this study was to investigate whether TIMP-1 altered spontaneous resolution of liver fibrosis in conjunction with matrix metalloproteinases (MMP) inhibition and hepatic stellate cell (HSC) activation. The livers of liver-targeted TIMP-1 transgenic (TIMP-Tg) and control hybrid (Cont) mice were harvested at 0, 3, 7, and 28 days following spontaneous recovery from CCl4 -induced liver fibrosis. The extent of fibrosis resolution, MMP expression, ,-smooth-muscle actin (,-SMA) positive cells, and procollagen-(I) messenger RNA (mRNA) in the liver were assessed at the respective periods in both groups. We also examined the effect of TIMP-1 on HSC apoptosis. The TIMP-Tg mice showed significantly attenuated resolution of spontaneous liver fibrosis compared with the Cont mice. The hydroxyproline content, number of ,-SMA positive cells, and procollagen-(I) mRNA rapidly decreased with time in the Cont mice, whereas these markers were little changed in TIMP-Tg mice. The level of the active form of metalloproteinases-2 (MMP-2) in the TIMP-Tg mice was less than that in the Cont mice. TIMP-1 markedly decreased the nonparenchyma apoptotic cells in the liver fibrosis resolution model, and it also inhibited HSC apoptosis associated with suppression of caspase-3 activity in vitro. In conclusion, TIMP-1 significantly attenuated spontaneous resolution of liver fibrosis by the combination of a net reduction of the MMP activity and suppression of apoptosis in HSC. [source]


    Adenosine reverses a preestablished CCl4 -induced micronodular cirrhosis through enhancing collagenolytic activity and stimulating hepatocyte cell proliferation in rats

    HEPATOLOGY, Issue 4 2001
    Rolando Hernández-Muñoz
    Cirrhosis is one of the most common causes of mortality worldwide, because hepatic dysfunction constitutes a potentially lethal condition. Having demonstrated the hepatoprotective effect of adenosine against CCl4 -induced cirrhosis, the present study was aimed at assessing adenosine's effect on an already-established micronodular cirrhosis. Chronic administration of CCl4 (10 weeks) induced a cirrhotic state, characterized by increased liver fibronectin and collagen types I and III content, enhanced expression of ,-1 (I) collagen mRNA, portal hypertension, and liver dysfunction. After CCl4 discontinuation (5 weeks), increased persitance of ,-1 (I) collagen mRNA expression and deposition, enhanced proline incorporation into collagen and prolyl hydroxylase activity evidenced active fibrogenesis. Several weeks after CCl4 withdrawal, deposited collagen showed an enhanced type I/III ratio, which was associated with deficient collagenolytic activity in cirrhotic livers. Liver expression of some metalloproteinases (MMPs) and of tissue inhibitors of MMPs (TIMPs) also indicated decreased collagen breakdown in cirrhotic livers. Parameters indicative of oxidative stress (mainly protein oxidation) were persistently augmented. These events were coincident with diminished regenerative capacity of the cirrhotic liver. Intraperitoneal adenosine administration to CCl4 -induced cirrhotic rats blocked active fibrogenesis and increased the collagen degradation (most probably by decreasing liver TIMPs levels), normalizing collagen-type ratios. In addition, the nucleoside promoted an effective hepatocyte's proliferation in the cirrhotic liver and accelerated normalization of parameters indicative of liver function and oxidative stress. Thus, adenosine readily reversed an experimental cirrhosis through stimulating liver collagenolytic and proliferative capacities, as well as by accelerating functional recovery. [source]


    Earlier expression of the transcription factor HFH-11B diminishes induction of p21CIP1/WAF1 levels and accelerates mouse hepatocyte entry into S-phase following carbon tetrachloride liver injury

    HEPATOLOGY, Issue 6 2001
    Xinhe Wang
    Partial hepatectomy (PH) or toxic liver injury induces the proliferation of terminally differentiated hepatic cells to regenerate the original size of the adult liver. Previous PH liver regeneration studies showed that premature transgenic expression of the Forkhead Box M1b (FoxM1b, HFH-11B) transcription factor accelerated hepatocyte entry into DNA replication (S-phase). In this study, we used carbon tetrachloride (CCl4) liver injury to induce a different type of mouse liver regeneration and show that premature hepatic HFH-11B levels also accelerate the onset of hepatocyte S-phase in this injury model. Unlike PH liver regeneration, earlier hepatocyte proliferation after CCl4 liver injury is correlated with diminished transgenic hepatic levels of p21CIP1/WAF1 at the G1/S transition of the cell cycle. Differential hybridization of cDNA arrays and RNase protection studies determined that CCl4 regenerating liver of transgenic mice displayed early stimulated expression of the S-phase promoting cyclin D1 and cyclin E and sustained levels of Cdc25a phosphatase genes. Compared with previous PH liver regeneration studies, our data suggest that premature expression of HFH-11B activates distinct S-phase promotion pathways in the CCl4 liver injury model. Although proliferating transgenic hepatocytes induced by either PH or CCl4 liver injury displayed early expression of identical M-phase cyclin genes (cyclin B1, B2, A2, and F), only CCl4 regenerating transgenic liver exhibited earlier expression of the M-phase promoting Cdc25b. These studies suggest that CCl4 injury of transgenic liver not only uses the same mechanisms as PH to mediate accelerated hepatocyte entry into mitosis, but also promotes M-phase entry by stimulating Cdc25b expression. [source]


    Tissue inhibitor of metalloproteinases-1 promotes liver fibrosis development in a transgenic mouse model

    HEPATOLOGY, Issue 6 2000
    Hitoshi Yoshiji
    Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been shown to be increased in liver fibrosis development both in murine experimental models and human samples. However, the direct role of TIMP-1 during liver fibrosis development has not been defined. To address this issue, we developed transgenic mice overexpressing human TIMP-1 (hTIMP-1) in the liver under control of the albumin promoter/enhancer. A model of CCl4 -induced hepatic fibrosis was used to assess the extent of fibrosis development in TIMP-1 transgenic (TIMP-Tg) mice and control hybrid (Cont) mice. Without any treatment, overexpression of TIMP-1 itself did not induce liver fibrosis. There were no significant differences of pro-(,1)-collagen-I, (,2)-collagen-IV, and ,-smooth muscle actin (,-SMA) mRNA expression in the liver between TIMP-Tg and Cont-mice, suggesting that overexpression of TIMP-1 itself did not cause hepatic stellate cell (HSC) activation. After 4-week treatment with CCl4, however, densitometric analysis revealed that TIMP-Tg-mice had a seven-fold increase in liver fibrosis compared with the Cont-mice. The hepatic hydroxyproline content and serum hyaluronic acid were also significantly increased in TIMP-Tg-mice, whereas CCl4 -induced liver dysfunction was not altered. An active form of matrix metalloproteinases-2 (MMP-2) level in the liver of TIMP-Tg-mice was decreased relative to that in Cont-mice because of the transgenic TIMP-1. Immunohistochemical analysis revealed that collagen-I and collagen-IV accumulation was markedly increased in the liver of CCl4 -treated TIMP-Tg-mice with a pattern similar to that of ,-SMA positive cells. These results suggest that TIMP-1 does not by itself result in liver fibrosis, but strongly promotes liver fibrosis development. [source]


    Inhibition of hepatic stellate cell proliferation and activation by the semisynthetic analogue of fumagillin TNP-470 in rats

    HEPATOLOGY, Issue 5 2000
    Yan Qing Wang
    Proliferation and activation of hepatic stellate cells (HSCs) are critical steps for the development of postnecrotic fibrosis in the liver. The present study aimed to reveal the inhibitory effect of the semisynthetic analogue of fumagillin TNP-470 on these events for its possible use as an antifibrogenic agent. Rat models of carbon tetrachloride (CCl4)- and dimethylnitrosamine-induced hepatic fibrosis were used for an in vivo study. In both models, the fibrotic area was considerably decreased by concurrent repetitive subcutaneous injections of 30 mg/kg body weight of TNP-470. In CCl4 -induced fibrosis, factor VIII-related antigen-positive blood vessels, desmin-, or ,-smooth muscle actin (,SMA)-positive mesenchymal cells, bromodeoxyuridine (BrdU)-positive mesenchymal cells also decreased in number by treatment with TNP-470. In in vitro experiments, a supplement of 1,000 ng/mL TNP-470 suppressed BrdU incorporation and cyclins D1, D2, and E expression by cultured HSCs in the absence and/or presence of platelet-derived growth factor (PDGF). Expression of HSC activation markers, i.e., ,SMA and PDGF receptor ,, was also suppressed. The present results indicate that TNP-470 inhibits HSC proliferation by blocking the cell-cycle transition from G1 to S and HSC activation, and, as the consequence, prevents the progression of hepatic fibrosis, probably being coupled with its antiangiogenic effect. [source]


    Effect of propranolol on the factors promoting bacterial translocation in cirrhotic rats with ascites

    HEPATOLOGY, Issue 1 2000
    María Pérez-Paramo
    Bacterial translocation appears to be an important mechanism in the pathogenesis of spontaneous infections in cirrhosis. Cirrhotic patients are commonly treated with ,-adrenoceptor blockers, but the impact of this treatment in the factors promoting bacterial translocation has not been investigated. This study was aimed at investigating in cirrhotic rats with ascites the effect of propranolol on intestinal bacterial load, transit, and permeability of the bowel and on the rate of bacterial translocation. Bacterial translocation to mesenteric lymph nodes and intestinal bacterial overgrowth, permeability (urinary excretion of 99mTc-diethylenetriaminepentaacetic acid [99mTc-DTPA]), and transit (geometric center ratio of 51Cr) were assessed in 29 rats with carbon tetrachloride (CCl4 ) cirrhosis and 20 controls. These variables were then measured in 12 placebo- and in 13 propranolol-treated ascitic cirrhotic rats. Bacterial translocation was present in 48% of the cirrhotic rats and in none of the controls. Cirrhotic rats with intestinal bacterial overgrowth had a significantly higher rate of translocation and slower intestinal transit than those without it. Among the 15 rats with overgrowth and a 99mTc-DTPA excretion greater than 10%, 15 had translocation and 2 had bacterial peritonitis. Only 1 of the 14 rats with either intestinal overgrowth or a 99mTc-DTPA excretion greater than 10% presented translocation. Compared with the placebo group, propranolol-treated animals had significantly lower portal pressure, faster intestinal transit, and lower rates of bacterial overgrowth and translocation. In ascitic cirrhotic rats, bacterial translocation results from intestinal overgrowth and severe damage to gut permeability. In this setting, intestinal overgrowth is associated with intestinal hypomotility. Propranolol accelerates the intestinal transit, decreasing the rates of bacterial overgrowth and translocation. [source]


    Emodin reverses CCl4 induced hepatic cytochrome P450 (CYP) enzymatic and ultrastructural changes: The in vivo evidence

    HEPATOLOGY RESEARCH, Issue 3 2009
    Monika Bhadauria
    Aim:, The curative effect of emodin (1,3,8-trihydroxy-6-methyl anthraquinone), an active compound of the plant species Ventilago maderaspatana Gaertn, was evaluated against carbon tetrachloride (CCl4) induced hepatic cytochrome P450 (CYP) enzymatic and ultrastructural alterations in rats. Methods:, Female rats were administered CCl4 (1.5 mL/kg, ip) followed by varying doses of emodin (20, 30 and 40 mg/kg, oral po) after 24 h of CCl4 administration. Animals were euthanized after 24 h of last administration to determine liver function tests in serum, hepatic light microscopic and ultrastructural changes, activity of CYP enzymes, microsomal lipid peroxidation and protein contents, hexobarbitone induced sleep time and bromosulphalein retention. Results:, The CCl4 induced-toxic effects were observed with sharp elevation in the release of serum transaminases, alkaline phosphatase, lactate dehydrogenase and ,-glutamyl transpeptidase. An initial study for an optimum dose of emodin among different dose levels revealed that a 30 mg/kg dose was effective in restoring all the enzymatic variables and liver histoarchitecture in a dose dependent manner. Exposure to CCl4 diminished the activities of CYP enzymes (i.e. aniline hydroxylase and amidopyrine-N-demethylase and microsomal protein contents with concomitant increase in microsomal lipid peroxidation). Emodin at 30 mg/kg effectively reversed the CCl4 induced hepatotoxic events, which was consistent with ultrastructural observations. Hexobarbitone-induced sleep time and plasma bromosulphalein retention also improved liver functions after emodin therapy. Conclusion:, By reversal CYP activity and ultrastructural changes, emodin shows a strong hepatoprotective abilities. [source]


    Differential expression of the genes involved in amino acids and nitrogen metabolisms during liver regeneration of mice

    HEPATOLOGY RESEARCH, Issue 3 2009
    Yunsheng Yuan
    Aim:, Liver regeneration is a highly coordinated response to hepatic injury or resection that is controlled by the body's overall requirement for liver function. The level of circulating amino acids in blood increases after acute liver injury and administration of amino acid mixtures induces hepatic DNA replication. These findings suggest a close connection between amino acid metabolism and hepatic proliferation. However, the underlying molecular mechanisms have not been completely elucidated. Here, we applied a cDNA micro-array technique to analyze expression profiles of the genes associated with nitrogen and amino acid metabolism during liver regeneration in mice following treatment with CCl4. Methods:, Seventy-nine genes were identified for their significantly altered expression patterns at different stages of liver damage and regeneration. Results:, We observed that the numbers of down-regulated genes were remarkably higher than that of up-regulated genes at 1.5 days following carbon tetrachloride administration when hepatic DNA replication was most active, indicating the existence of a counter balance between cell proliferation and liver metabolism functions. Conclusions:, Our results suggest that suppression of amino acids metabolism after acute liver injury results in the accumulation of amino acids in plasma that serves as a driving force for liver regeneration. [source]


    Protective effect of non-mitogenic human acidic fibroblast growth factor on hepatocyte injury

    HEPATOLOGY RESEARCH, Issue 10 2007
    Hua Xu
    Aim:, To study whether non-mitogenic human acidic fibroblast growth factor (nm-haFGF) has protective effects on H2O2 -induced hepatocyte injury in vitro and CCl4 -induced hepatocyte injury in vivo. Methods:, (i) HL-7702 hepatocytes were incubated with different concentrations of nm-haFGF for 12 h, and then the activity of lactate dehydrogenase (LDH) in culture medium was detected, and genomic DNA electrophoresis analysis was observed after being exposed to H2O2 (8 mmol/L) for 4 h. Proximately, apoptotic rates and protein expressions of Bcl-2 and Bax of HL-7702 cell were detected after being exposed to H2O2 (0.2 mmol/L) for 20 h. (ii) Being injected intraperitoneally with nm-haFGF, mice were treated with CCl4 intraperitoneally to induce hepatic injury. Twenty-four hours later, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured and histopathologic changes were evaluated. Results:, (i) In vitro tests: LDH activities and apoptotic rates decreased, the protein expression of Bcl-2 increased and Baxdecreased in nm-haFGF-treated groups at the concentrations of 100 150 and 200 ng/mL, compared with that in the model control group, which was treated with H2O2 alone. The genomic DNA remained nearly intact at the concentrations of 150 and 200 ng/mL. (ii) In vivo tests: serum ALT and AST in nm-haFGF-treated groups (10 ,g/kg and 20 ,g/kg) were much lower as compared to the model control group, which was treated with CCl4 alone. Histological examination showed that nm-haFGF markedly ameliorated hepatocytes vacuolation, cloudy swelling and inflammatory cells infiltration induced by CCl4. Conclusion:, nm-haFGF had protective effects against H2O2 -induced hepatocyte injury in vitro and CCl4 -induced acute liver injury in vivo. [source]


    State-state transitions for CCl2(X1A1, A1B1, a3B1) radical and collisional quenching of CCl2(A1B1 and a3B1) by O2, N2, NO, N2O, NH3, and various aminated molecules

    INTERNATIONAL JOURNAL OF CHEMICAL KINETICS, Issue 6 2002
    Yide Gao
    CCl2 free radicals were produced by a pulsed dc discharge of CCl4 in Ar. Ground electronic state CCl2(X) radicals were electronically excited to the A1B1 (0,4,0) vibronic state with an Nd:YAG laser pumped dye laser at 541.52 nm. Experimental quenching data of excited CCl2(A1B1 and a3B1) by O2, N2, NO, N2O, NH3, NH(CH3)2, NH(C2H5)2, and N(C2H5)3 molecules were obtained by observing the time-resolved total fluorescence signal of the excited CCl2 radical in a cell, which showed a superposition of two exponential decay components under the presence of quencher. The quenching rate constants kA of CCl2(A) state and ka of CCl2(a) state were derived by analyzing the experimental data according to a proposed three-level model to deal with the CCl2(X1A1, A1B1, a3B1) system. The formation cross sections of complexes of electronically excited CCl2 radicals with O2, N2, NO, N2O, NH3, and aminated molecules were calculated by means of a collision-complex model. © 2002 Wiley Periodicals, Inc. Int J Chem Kinet 34: 351,356, 2002 [source]