Hepatic Necrosis In Rats Research Articles

Kadukkai maathirai (a polyherbal traditional siddha formulation) prevents D-galactosamine induced hepatic necrosis in rats

This study evaluated the prophylactic effect of Kadukkai maathirai in D-galactosamine (D-gal) induced hepatotoxicity in rats. D-galactosamine (D-gal) 400 mg/kg intraperitoneally was used to induce liver damage in rats. To assess the hepatoprotective effect of KM, three different doses of KM (36, 72 and 144 mg/kg body weight) were used. The hepatoprotective effect of KM was compared with standard drug silymarin (50 mg/kg). The biochemical parameters such as AST, ALT, ALP and total bilirubin were estimated. The livers were dissected out to look for histological changes. KM 144 mg/kg and silymarin showed a significant decrease in AST, ALP and total bilirubin. Both KM and silymarin significantly prevented decrease in liver weight. In KM treated groups, the liver did not show necrosis of hepatocytes, and apoptotic bodies with mild to moderate inflammatory infiltrate in the lobules and portal tracts. Hence, the results of this study confirms the hepatoprotective effect KM in rats.

Protective effects of Parinari curatellifolia flavonoids against acetaminophen-induced hepatic necrosis in rats

In the present study, we investigated the hepatoprotective potential of Parinari curatellifolia Planch (Chrysobalanaceae) in experimental rats in order to ascertain the validity of folkloric claims of its effectiveness in the treatment of hepatic-related disorders. Flavonoid extract of P. curatellifolia seed, PCF (10-, 20- or 30mg/kg body weight) or silymarin (25mg/kg), dissolved in corn oil, was administered by gavage to experimental animals once daily for 14 consecutive days before liver damage was chemically induced through the administration of acetaminophen (2g/kg p.o.) on the 14th day. Hepatoprotection was assessed by analyzing liver homogenate and serum for markers of hepatotoxicity – alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl transferase (GGT) and lactate dehydrogenase (LDH) activities as well as prothrombin time (PT). Evaluation of biochemical indices of oxidative stress – level of lipid peroxides (LPO), activities of superoxide dismutase (SOD) and catalase, along with histological assessment of hepatic tissue sections were also carried out. Results revealed that all doses of PCF significantly (P<0.001) and dose dependently prevented acetaminophen-induced increase in serum activities of hepatic enzymes (ALT, AST, GGT, LDH) and PT. Furthermore, PCF (10- and 20mg/kg) significantly (P<0.001) reduced lipid peroxidation in liver tissue and restored the activities of the antioxidant enzymes SOD and catalase toward normal levels. Histopathology of the liver tissue showed that PCF mitigated the toxicant-induced hepatocellular necrosis, reduced inflammatory cell infiltration and enhanced hepatocyte regeneration. The results indicated that P. curatellifolia flavonoids demonstrated remarkable hepatoprotective activity in acute liver injury caused by acetaminophen.

Effects of administering testosterone undecanoate in rats subjected to physical exercise: effects on the estrous cycle, motor behavior and morphology of the liver and kidney

The aim of the work was evaluate the effects of testosterone undecanoate (TU) treatment combined with moderate physical training on: the estrous cycle, body weight (BW), motor behavior (MB), and the morphohistology of the reproductive system, the liver and kidney in rats. Female Wistar rats (180 g - 250 g) were divided as follows: sedentary + TU (S + TU), trained + TU (T + TU), sedentary + vehicle (S + V), trained + vehicle (T + V). The rats swam 50 min/Day, strapped with a 5% BW load, for 4 weeks. During this training, (BW) was monitored daily as well as the estrous cycle (EC) by vaginal smear. The TU (15 mg/kg s.c) was administered 3 times/week for 4 weeks. At the end of the study, data on MB, BW and morphohistopathological changes in viscera were compiled. The (T + TU) group had on average, a higher (BW) in the fourth week compared to the first week, and (BW) higher than (S + V) and (S + TU) groups. We noted an interruption in the EC and a decrease in weight of ovaries in animals treated with TU. In addition, there was an increase in the relative weight of the heart in groups (T + V) and (T+ TU), and kidneys in group (T + TU). Histopathological analysis showed periportal congestion and isolated foci of hepatic necrosis in rats with TU. Thus, TU combined with training abolished the EC, promoted ovarian atrophy, liver necrosis, cardiac hypertrophy and a decrease in motor activity.

PRODUCTION of acute massive hepatic necrosis in rats by dietary means.

PRODUCTION of acute massive hepatic necrosis in rats by dietary means.

Human Immunodeficiency Virus-Related Microbial Translocation and Progression of Hepatitis C

Human immunodeficiency virus (HIV)-1 infection has been associated with enhanced microbial translocation, and microbial translocation is a mechanism through which alcohol and some enteric conditions cause liver disease. We hypothesized that HIV promotes liver disease by enhancing microbial translocation. We studied human cohorts in which hepatitis C virus (HCV) and HIV outcomes were carefully characterized. HIV-related CD4(+) lymphocyte depletion was strongly associated with microbial translocation as indicated by elevated levels of circulating lipopolysaccharide (LPS), LPS-binding protein, soluble CD14, and fucose-binding lectin (AAL) reactive to immunoglobulin G specific for the alpha-galactose epitope and suppressed levels of endotoxin core antibodies (EndoCAb IgM) in HIV-infected subjects compared with the same persons before they had HIV infection and compared with HIV-uninfected subjects. The same measures of microbial translocation were strongly associated with HCV-related liver disease progression (cirrhosis), eg, LPS, odds ratio, 19.0 (P = .002); AAL, odds ratio, 27.8 (P < .0001); in addition, levels of LPS were elevated prior to recognition of cirrhosis. Microbial translocation may be a fundamental mechanism through which HIV accelerates progression of chronic liver disease.

Potentiation of the hepatotoxicity of carbon disulfide by chlordane‐induced cytochrome P450 enzymes

Dithiocarbamate drugs such as disulfiram are extensively metabolized in the body to carbon disulfide (CS2), which can produce a variety of toxic effects. When metabolized by phenobarbital‐induced cytochrome P450s (CYPs), CS2 produces hepatic necrosis in rats. In this study we investigated whether CYPs induced by chlordane (CLD), a paradigm of chlorinated hydrocarbon pesticides, potentiate hepatotoxicity of CS2. Male Sprague‐Dawley rats (n=3) were treated with CLD (25 mg/kg, ip) daily for 4 days and 24 h after the final injection, the rats were injected with CS2 (380 mg/kg, ip) in oil while controls received vehicle alone. The rats were then sacrificed at 3, 6 and 24 h. At 3 h post‐treatment, total hepatic GSH decreased modestly but lipid peroxidation increased markedly while all CLD‐inducible CYPs (1A1, 2B1, 2E1 and 3A2) were inhibited by CS2 significantly and variably. At 24 h there was a significant increase in GSH, lipid peroxidation, and ALT activity. Activity of the CYPs was also increased but still remained significantly depressed, especially that of CYP2B1. Livers taken at 3 and 6 h showed subtle to distinct apoptotic changes and at 24 h a severe lesion of hydropic degeneration of the centrilobular cells with apoptosis was observed. These results indicate that the metabolism of CS2 by CLD‐induced CYPs and the generation of lipid peroxides may have contributed to the enhanced hepatocellular damage.

Effect of OP-2507, a prostacyclin analogue, on endotoxin-induced hepatic necrosis in rats after partial hepatectomy

Objective: We assessed the cytoprotective effect and mechanism of action of a prostacyclin analogue, OP-2507, on the massive hepatocytic injuries induced in rats by the administration of lipopolysaccharide (LPS) after 70% hepatectomy. Methods: OP-2507 was injected subcutaneously at 1 of 2 doses (100 μg/kg and 300 μg/kg) 30 minutes before, immediately before, or 10 minutes after LPS administration. Liver function, prothrombin time, and tumor necrosis factor alpha (TNF-α) in the serum as well as hydroxyl radicals in the hepatic tissue were measured serially after LPS administration. Results: Pretreatment with OP-2507 attenuated the increase in plasma TNF-α and hydroxyl radicals in hepatic tissue and the increase in plasma aminotransferase activity; it also improved the survival rate. However, these effects were not observed when OP-2507 was administered immediately before or 10 minutes after LPS administration. Conclusions: These results indicate that OP-2507 prevents hepatic damage induced by LPS administration after 70% hepatectomy when it is given 30 minutes before LPS administration.

Lipopolysaccharide-Induced Hepatic Injury Is Enhanced by Polychlorinated Biphenyls

After intravenous administration of bacterial lipopolysaccharide (LPS) to rats, polymorphonuclear neutrophils (PMNs) rapidly accumulate in the liver, and midzonal hepatic necrosis is prominent by 6 hr. PMNs are required for the development of hepatic injury in rats. Certain polychlorinated biphenyls (PCBs) can activate PMNs, resulting in production of superoxide anion (O2-.) and release of cytolytic factors from granules. This raises the possibility that PCB exposure might enhance PMN-mediated tissue injury, such as LPS-induced hepatotoxicity. We treated female Sprague-Dawley rats with a minimally toxic dose of LPS in saline (2 mg/kg, intravenous) and 90 min later exposed them to Aroclor 1248 (50 mg/kg, intraperitoneal), a mixture of PCBs. The animals were killed 6 hr after LPS administration, and hepatic injury was assessed. Neither LPS nor Aroclor 1248 alone produced liver injury. Co-treatment with LPS and Aroclor 1248 resulted in pronounced liver injury as demonstrated from increased activities of alanine aminotransferase and isocitrate dehydrogenase in plasma. Histological evaluation indicated increased severity of hepatic necrosis in rats receiving both LPS and Aroclor 1248. Hepatic accumulation of PMNs, normally observed after LPS, was not altered by co-exposure to PCBs. Aroclor 1248 stimulated rat PMNs in vitro to produce O2-. and to degranulate. In addition, PMN-mediated cytotoxicity to isolated rat hepatocytes in culture was increased upon addition of Aroclor 1248. PCBs activate PMNs in vitro and increase PMN-dependent hepatocellular damage in vitro and after LPS treatment in vivo. PCBs may act in vivo as an additional inflammatory stimulus to activate PMNs to become cytotoxic, resulting in increased tissue injury.

Role of adhesion molecules in the development of massive hepatic necrosis in rats

Massive hepatic necrosis develops after endotoxin administration in rats pretreated with heat-killed Propionibacterium acnes as a result of microcirculatory disturbance caused by endothelial cell destruction by activated macrophages in the hepatic sinusoids. Immunohistochemical hepatic expression of intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen 1 α (LFA-1 α) and the effect of monoclonal antibodies against both adhesion molecules on liver necrosis provoked after endotoxin administration was studied in these rats. There were increased stains of ICAM-1 in endothelial cells and LFA-1 α in macrophages in the hepatic sinusoids in Propionibacterium acnes-pretreated rats compared with normal rats. Such stains were further increased soon after endotoxin administration, followed by development of hepatic necrosis. Monoclonal antibodies against both adhesion molecules significantly attenuated the extent of liver injury compared with controls, without affecting the infiltration and activation of hepatic macrophages. Polyclonal antibodies against polymorphonuclear leukocytes eradicated circulating neutrophils, but did not change such liver injury, although gum arabic, which suppressed macrophage activation, attenuated the extent of liver injury. Thus, adhesion between endothelial cells and activated macrophages in the hepatic sinusoids via ICAM-1 and LFA-1 α is essential for the initiation of massive hepatic necrosis of this type. Contribution of neutrophils seems less likely.

Role of adhesion molecules in the development of massive hepatic necrosis in rats

Massive hepatic necrosis develops after endotoxin administration in rats pretreated with heat-killed Propionibacterium acnes as a result of microcirculatory disturbance caused by endothelial cell destruction by activated macrophages in the hepatic sinusoids. Immunohistochemical hepatic expression of intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen 1 alpha (LFA-1 alpha) and the effect of monoclonal antibodies against both adhesion molecules on liver necrosis provoked after endotoxin administration was studied in these rats. There were increased stains of ICAM-1 in endothelial cells and LFA-1 alpha in macrophages in the hepatic sinusoids in Propionibacterium acnes-pretreated rats compared with normal rats. Such stains were further increased soon after endotoxin administration, followed by development of hepatic necrosis. Monoclonal antibodies against both adhesion molecules significantly attenuated the extent of liver injury compared with controls, without affecting the infiltration and activation of hepatic macrophages. Polyclonal antibodies against polymorphonuclear leukocytes eradicated circulating neutrophils, but did not change such liver injury, although gum arabic, which suppressed macrophage activation, attenuated the extent of liver injury. Thus, adhesion between endothelial cells and activated macrophages in the hepatic sinusoids via ICAM-1 and LFA-1 alpha is essential for the initiation of massive hepatic necrosis of this type. Contribution of neutrophils seems less likely. (Hepatology 1996 Feb;23(2):320-8)

Role of adhesion between activated macrophages and endothelial cells in the development of two types of massive hepatic necrosis in rats.

Sinusoidal endothelial cell damage is produced by activation of hepatic macrophages after endotoxin administration in rats pretreated with Cornyebacterium parvum or undergoing 70% hepatectomy. Such damage causes fibrin deposition in the hepatic sinusoids leading to massive hepatic necrosis. In the C. parvum model, cytotoxic mediators, such as tumour necrosis factor (TNF)alpha and superoxide anions released from activated hepatic macrophages directly destroy sinusoidal endothelial cells. In contrast, in the partial hepatectomy model, endothelial cell damage occurs as a result of fibrin deposition due to derangement of the coagulation equilibrium regulated by tissue factor and thrombomodulin expressed on hepatic macrophages and sinusoidal endothelial cells, respectively. Immunohistological examination revealed that the expression of ICAM-1 in sinusoidal endothelial cells and LFA-1 in hepatic macrophages was greater in both models than in normal rats preceding the development of hepatic necrosis. The extent of liver injury was significantly attenuated by treatment with monoclonal antibodies against both adhesion molecules in the C. parvum model, but aggravated in the partial hepatectomy model, compared to control rats. We conclude that adhesion of activated macrophages to endothelial cells via LFA-1 and ICAM-1 in the hepatic sinusoids is essential for endothelial cell destruction in the C. parvum model, but can act protectively against provocation of fibrin deposition in the hepatectomy model.

Misoprostol protection against acetaminophen-induced hepatotoxicity in the rat.

The hepatoprotective effects of misoprostol on acetaminophen (APAP)-induced toxicity were studied in the rat. Liver injury was evaluated at 36 hr after APAP administration by measuring serum ornithine carbamoyltransferase (OCT) and alanine aminotransferase (ALT) levels, by using tetranitroblue tetrazolium (TNBT) staining and by histological analysis. After APAP administration, peak serum levels of the drug were detected at 15 min. Liver GSH was depleted from control levels of 448 +/- 48 micrograms/g to 82 +/- 2 micrograms/g (P < 0.01) within 3 hr. Serum ALT levels increased significantly after 16 hr and H&E staining revealed significant hepatic necrosis after 12 hr. Rats treated with misoprostol before and after APAP administration showed reduced OCT and ALT levels at 36 hr of overdose (454 +/- 446 IU/liter and 2571 +/- 2944 IU/liter, respectively) compared to those without misoprostol treatment (1348 +/- 480 IU/liter and 6077 +/- 3025 IU/liter, respectively, P < 0.01). TNBT staining showed a reduced area of damage from 28.6 +/- 22.3% to 7.3 +/- 8.9% (P < 0.01), and H&E staining also showed less extensive hepatic necrosis in rats treated with misoprostol before and after the overdose. In a time sequence study, misoprostol treatment starting within 10 hr of overdose showed the same protective effect as when it was given before and after APAP ingestion. No protection was detected when the treatment was started during the development of hepatic injury. However, misoprostol given when injury was established seemed to be protective. Our results show that misoprostol protects the liver against APAP-induced injury if given within 10 hr of overdose.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of OP-2507, a prostacyclin analogue, on endotoxin-induced extensive hepatic necrosis in rats following partial hepatectomy.

The effect of OP-2507, a prostacyclin analogue, on endotoxin-induced extensive hepatic necrosis in rats following partial hepatectomy.

The role of adhesion between activated macrophages and sinusoidal endothelial cells via LFA-1 and ICAM-1 in the development of massive hepatic necrosis in rats

The role of adhesion between activated macrophages and sinusoidal endothelial cells via LFA-1 and ICAM-1 in the development of massive hepatic necrosis in rats

Inhibition of Corynebacterium parvum–primed and lipopolysaccharide-induced hepatic necrosis in rats by selective depletion of neutrophils using a monoclonal antibody

To examine whether neutrophils are involved in the pathogenesis of experimental liver dysfunction, we observed the effect of selective in vivo neutrophil depletion by a monoclonal antibody (RP-3) on the pathogenesis of acute experimental hepatic necrosis in rats induced by a preparative injection of heat-killed Corynebacterium parvum and a challenging dose of lipopolysaccharide (LPS) (positive control group). The serum transaminase titer 8 h after LPS injection was reduced by selective depletion of peripheral blood neutrophils as a result of RP-3 treatment (RP-3 group). A kinetic study showed that the serum transaminase titer of the RP-3 group was significantly lower than that of the positive control group from 4 to 24 h after LPS injection. The transaminase level was significantly lower in the group with less than 400/mm3 peripheral blood neutrophils than in the group with a greater number. The effect of RP-3 on the transaminase level was due neither to the injection of cancer ascites nor to RP-3 injection with the accompanying decrease in complement titer. These results suggest that neutrophils play an important role in the induction of liver dysfunction in this system.

Protection by 16,16-dimethyl prostaglandin E2 and dibutyryl cyclic AMP against complement-mediated hepatic necrosis in rats

16,16-Dimethyl prostaglandin E2, a known cytoprotective agent, was examined for its ability to protect the liver against complement-mediated necrosis induced by an intravenous injection of a monoclonal antibody against a rat liver-specific antigen in rats. The hepatic injury induced by the antibody was characterized by (a) rapid development of numerous massive hemorrhagic foci of necrotic liver cells, (b) marked increases in serum liver enzyme activities and (c) pronounced reduction in the CH50 level, presumably as a result of complement consumption in the liver. Pretreatment with 16,16-dimethyl prostaglandin E2 at intraperitoneal doses of 20 and 100 micrograms/kg suppressed the hepatic injury, as evidenced by markedly mitigated liver-cell necrosis and much smaller increases in the serum-enzyme activities compared with the values in diseased control animals. The prostaglandin analogue failed to prevent serum complement consumption in response to the antibody injection or affect the CH50 level at the preinjury stage, indicating that neither complement inactivation nor interference with the antigen-antibody reaction was involved in the hepatic protection. The hepatoprotective doses of 16,16-dimethyl prostaglandin E2 produced a significant increase in liver cyclic AMP content in a dose-related manner. In addition, intravenous dibutyryl cyclic AMP at 3 and 10 mg/kg dose-dependently prevented histological and biochemical changes in the hepatic damage without altering the rate of reduction in serum complement activity. Like 16,16-dimethyl prostaglandin E2, dibutyryl cyclic AMP did not affect the preinjury CH50 level.(ABSTRACT TRUNCATED AT 250 WORDS)

Protection by 16,16-dimethyl prostaglandin E2 and dibutyryl cyclic AMP against complement-mediated hepatic necrosis in rats

Protection by 16,16-dimethyl prostaglandin E2 and dibutyryl cyclic AMP against complement-mediated hepatic necrosis in rats

P-573 - Protection by 16, 16-dimethyl prostaglandin E2 and dibutyryl cyclic AMP against complement-mediated hepatic necrosis in rats.

P-573 - Protection by 16, 16-dimethyl prostaglandin E2 and dibutyryl cyclic AMP against complement-mediated hepatic necrosis in rats.

Human hepatic regenerative stimulator substance: Partial purification and biological characterization of hepatic stimulator substance from human fetal liver cells

Current support or replacement therapies for fulminant acute hepatic failure are frequently very disappointing. In this study, human hepatic stimulator substance--a liver-specific growth factor--was partially purified from human fetal liver cells and characterized by its biological effects. Almost 70-fold protein content was purified with an approximately 80-fold increase in specific growth stimulator activity. Human hepatic stimulator substance proved to be heat-stable, protease-sensitive, organ-specific and species-nonspecific. Human hepatic stimulator substance produced a two- to threefold increase of 3H-thymidine incorporation into hepatic DNA when injected intraperitoneally into growing weanling mice (nonhepatectomized) or regenerating rats (34% hepatectomy). The effects of hHSS in reversing the lethality of D-galactosamine (1.6 gm/kg body weight)-induced hepatic necrosis in rats were further evaluated. A survival rate of 4% (n = 24), 41% (n = 12, p less than 0.05), 33% (n = 12, p less than 0.05), 31% (n = 13, p less than 0.05) and 18% (n = 11, p greater than 0.05) was observed when the rats were injected with 4 ml of saline intraperitoneally, 4 ml of human intact fetal hepatocytes (2.4 x 10(8] intraperitoneally, 4 ml of human hepatic stimulator substance intraperitoneally, 2 ml of twofold concentrated human hepatic stimulator substance intravenously and 1 ml of fourfold human hepatic stimulator substance intramuscularly, respectively, 20 hr after poisoning.(ABSTRACT TRUNCATED AT 250 WORDS)

Halothane induced hepatic necrosis in rats: the role of in vivo lipid peroxidation.

Hepatic damage was induced in phenobarbitone pretreated male Fischer 344 rats by the administration of 1% halothane in 14% oxygen for either 1 or 2 hours. Ethane production during the exposure period was not significantly different between the halothane and non-halothane exposed groups. Animals were sacrificed 1, 2, 6 and 24 hrs from commencement of anaesthesia and the hepatic microsomal fraction analyzed for diene conjugates, lipid hydroperoxides, total lipid content and fatty acid composition. Animals exposed to halothane and sacrificed at 2 and 24 hrs had significantly elevated levels of diene conjugates (P less than 0.05), while lipid hydroperoxide concentration and serum alanine aminotransferase increased in only those animals sacrificed at 24 hrs. Alterations in total lipid content and hepatic microsomal fatty acid composition were not observed in animals sacrificed after 1 and 2 hrs. A significant reduction in total lipid and arachidonic acid content occurred only in those animals sacrificed 24 hrs after exposure, however a concomitant increase in the saturated fatty acid fraction was not observed. It is proposed that alterations in fatty acid composition in vivo and evidence of lipid peroxidation occur as a result of cell death rather than an initiating event in halothane induced hepatic necrosis in rats.