Induced Liver Injury (induced + liver_injury)

Distribution by Scientific Domains

Selected Abstracts

Binge drinking,induced liver injury,

HEPATOLOGY, Issue 5 2009
Napoleon Waszkiewicz
No abstract is available for this article. [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 naďve 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]

Neutrophil depletion protects against murine acetaminophen hepatotoxicity,,

HEPATOLOGY, Issue 6 2006
Zhang-Xu Liu
We previously reported that liver natural killer (NK) and NKT cells play a critical role in mouse model of acetaminophen (APAP)-induced liver injury by producing interferon gamma (IFN-,) and modulating chemokine production and subsequent recruitment of neutrophils into the liver. In this report, we examined the role of neutrophils in the progression of APAP hepatotoxicity. C57BL/6 mice were given an intraperitoneal toxic dose of APAP (500 mg/kg), which caused severe acute liver injury characterized by significant elevation of serum ALT, centrilobular hepatic necrosis, and increased hepatic inflammatory cell accumulation. Flow cytometric analysis of isolated hepatic leukocytes demonstrated that the major fraction of increased hepatic leukocytes at 6 and 24 hours after APAP was neutrophils (Mac-1+Gr-1+). Depletion of neutrophils by in vivo treatment with anti-Gr-1 antibody (RB6-8C5) significantly protected mice against APAP-induced liver injury, as evidenced by markedly reduced serum ALT levels, centrilobular hepatic necrosis, and improved mouse survival. The protection was associated with decreased FasL-expressing cells, cytotoxicity against hepatocytes, and respiratory burst in hepatic leukocytes. In intracellular adhesion molecule (ICAM)-1,deficient mice, APAP caused markedly reduced liver injury when compared with wild-type mice. The marked protection in ICAM-1,deficient mice was associated with decreased accumulation of neutrophils in the liver. Hepatic GSH depletion and APAP-adducts showed no differences among the antibody-treated, ICAM-1,deficient, and normal mice. In conclusion, accumulated neutrophils in the liver contribute to the progression and severity of APAP-induced liver injury. (HEPATOLOGY 2006;43:1220,1230.) [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]

Systemic infusion of angiotensin II exacerbates liver fibrosis in bile duct,ligated rats,

HEPATOLOGY, Issue 5 2005
Ramón Bataller
Recent evidence indicates that the renin,angiotensin system (RAS) plays a major role in liver fibrosis. Here, we investigate whether the circulatory RAS, which is frequently activated in patients with chronic liver disease, contributes to fibrosis progression. To test this hypothesis, we increased circulatory angiotensin II (Ang II) levels in rats undergoing biliary fibrosis. Saline or Ang II (25 ng/kg/h) were infused into bile duct,ligated rats for 2 weeks through a subcutaneous pump. Ang II infusion increased serum levels of Ang II and augmented bile duct ligation,induced liver injury, as assessed by elevated liver serum enzymes. Moreover, it increased the hepatic concentration of inflammatory proteins (tumor necrosis factor , and interleukin 1,) and the infiltration of CD43-positive inflammatory cells. Ang II infusion also favored the development of vascular thrombosis and increased the procoagulant activity of tissue factor in the liver. Livers from bile duct,ligated rats infused with Ang II showed increased transforming growth factor ,1 content, collagen deposition, accumulation of smooth muscle ,-actin,positive cells, and lipid peroxidation products. Moreover, Ang II infusion stimulated phosphorylation of c-Jun and p42/44 mitogen-activated protein kinase and increased proliferation of bile duct cells. In cultured rat hepatic stellate cells (HSCs), Ang II (10,8 mol/L) increased intracellular calcium and stimulated reactive oxygen species formation, cellular proliferation and secretion of proinflammatory cytokines. Moreover, Ang II stimulated the procoagulant activity of HSCs, a newly described biological function for these cells. In conclusion, increased systemic Ang II augments hepatic fibrosis and promotes inflammation, oxidative stress, and thrombogenic events. (HEPATOLOGY 2005;41:1046,1055.) [source]

Adiponectin protects LPS-induced liver injury through modulation of TNF-, in KK-Ay obese mice

HEPATOLOGY, Issue 1 2004
Takayuki Masaki
Adiponectin, an adipocytokine, has been identified in adipose tissue, and its receptors are widely distributed in many tissues, including the liver. The present study was performed to clarify the role of adiponectin in lipopolysaccharide (LPS)-induced liver injury using KK-Ay obese mice. We analyzed the effects of adiponectin pretreatment on liver injury induced by D -galactosamine/LPS (GalN/LPS) in KK-Ay obese mice. GalN/LPS treatment induced significant increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in the blood, apoptotic and necrotic changes in hepatocytes, and/or showed a high degree of lethality. The GalN/LPS-induced liver injury was more pronounced in KK-Ay obese mice than in lean controls. Pretreatment with adiponectin ameliorated the GalN/LPS-induced elevation of serum AST and ALT levels and the apoptotic and necrotic changes in hepatocytes, resulting in a reduction in lethality. In addition, pretreatment with adiponectin attenuated the GalN/LPS-induced increases in serum and hepatic tumor necrosis factor , (TNF-,) levels and increased peroxisome proliferator-activated receptor (PPAR) , messenger RNA expression in the liver. Furthermore, abdominal macrophages from KK-Ay obese mice pretreated with adiponectin in vitro exhibited decreased LPS-induced TNF-, production compared with controls. Finally, adiponectin pretreatment also ameliorated TNF-,-induced liver injury. In conclusion, these findings suggest that adiponectin prevents LPS-induced hepatic injury by inhibiting the synthesis and/or release of TNF-, of KK-Ay obese mice. (HEPATOLOGY 2004;40:177,184.) [source]

,-Glucuronidase inhibitor tectorigenin isolated from the flower of Pueraria thunbergiana protects carbon tetrachloride-induced liver injury

Hae-Woong Lee
Abstract Background/Aim: To understand the relationship between the fluctuation in serum ,-glucuronidase and hepatotoxicity, an inhibitor of ,-glucuronidase was isolated from the flowers of Pueraria thunbergiana and its hepatoprotective activity was measured. Method: Tectorigenin was isolated from the flowers of pueria thunbergiana as an inhibitor of ,-glucuronidase, and serum ALT, AST and biological parameters as markers for its hepatoprotective activity were measured on CCl4 -induced liver injury in mice. The relationship between serum ,-glucuronidase and hepatoprotective activities in mice was measured. Results: When tectorigenin at a dose of 100 mg/kg was intraperitoneally administered on CCl4 -induced liver injury in mice, it significantly inhibited the increase of plasma ALT, AST and LDH activities. The inhibitory effect of tectorigenin is much more potent than that of dimethyl diphenyl bicarboxylate (DDB), which has been used as a commercial hepatoprotective agent. When tectoridin transformed to tectorigenin by intestinal bacteria was orally administered to mice, it showed hepatoprotective activity. However, when tectoridin was intraperitoneally administrated to mice, it did not exhibit hepatoprotective activity. Moreover, orally administered tectoridin not only inhibited ,-glucuronidase but also increased GSH content and GST activity on CCl4 -induced hepatotoxicity of mice. Conclusion: We insist that an inhibitor of ,-glucuronidase tectorigenin may be hepatoprotective and tectoridin should be a prodrug transformed to tectorigenin. [source]

Effect of pumpkin seed (Cucurbita pepo) protein isolate on the activity levels of certain plasma enzymes in CCl4 -induced liver injury in low-protein fed rats

C. Z. Nkosi
Abstract The effects of pumpkin seed (Cucurbita pepo) protein isolate on the activity levels of lactate dehydrogenase (LD), alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) against carbon tetrachloride (CCl4)-induced acute liver injury in low-protein fed rats were investigated. A group of male Sprague-Dawley rats maintained on a low-protein diet for 5 days were divided into three subgroups. Two subgroups were injected with carbon tetrachloride and the other group with an equivalent amount of olive oil. Two hours after CCl4 intoxication one of the two subgroups was administered with pumpkin seed protein isolate. All three subgroups of rats were maintained on the low-protein diet for the duration of the investigation. Groups of rats from the different subgroups were killed at 24, 48 and 72 h after their respective treatments. After 5 days on the low-protein diet the activity levels of all four enzymes were significantly higher than their counterparts on a normal balanced diet. CCl4 intoxication resulted in significant increases in the activity levels of all four enzymes investigated. The administration of pumpkin seed protein isolate after CCl4 intoxication resulted in significantly reduced activity levels of all four enzymes. It is concluded that pumpkin seed protein isolate administration was effective in alleviating the detrimental effects associated with protein malnutrition. Copyright © 2005 John Wiley & Sons, Ltd. [source]