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PubMed2006

JNK1 but not JNK2 promotes the development of steatohepatitis in mice.

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis and varying degrees of necroinflammation. Although chronic oxidative stress, inflammatory cytokines, and insulin resistance have been implicated in the pathogenesis of NAFLD, the mechanisms that underlie the initiation and progression of this disease remain unknown. c-Jun N-terminal kinase (JNK) is activated by oxidants and cytokines and regulates hepatocellular injury and insulin resistance, suggesting that this kinase may mediate the development of steatohepatitis. The presence and function of JNK activation were therefore examined in the murine methionine- and choline-deficient (MCD) diet model of steatohepatitis. Activation of hepatic JNK, c-Jun, and AP-1 signaling occurred in parallel with the development of steatohepatitis in MCD diet-fed mice. Investigations in jnk1 and jnk2 knockout mice demonstrated that jnk1, but not jnk2, was critical for MCD diet-induced JNK activation. JNK promoted the development of steatohepatitis as MCD diet-fed jnk1 null mice had significantly reduced levels of hepatic triglyceride accumulation, inflammation, lipid peroxidation, liver injury, and apoptosis compared with wild-type and jnk2 -/- mice. Ablation of jnk1 led to an increase in serum adiponectin but had no effect on serum levels of tumor necrosis factor-alpha. In conclusion, JNK1 is responsible for JNK activation that promotes the development of steatohepatitis in the MCD diet model. These findings also provide additional support for the critical mechanistic involvement of JNK1 overactivation in conditions associated with insulin resistance and the metabolic syndrome.

Adiponectin↗

PubMed1995

Effects of cyclosporine and tacrolimus (FK 506) on acute pancreatitis in mice.

OBJECTIVE: To use mice to examine the effects of cyclosporine and tacrolimus (FK 506) on two forms of acute pancreatitis often seen after clinical organ transplantation. METHODS AND DESIGN: In the first experiment, male CD-1 mice received cyclosporine (10 mg/kg), tacrolimus (0.32 mg/kg), or saline solution (control) subcutaneously once a day for 10 days. On the 11th day, acute edematous pancreatitis was induced by ceruletide (cerulein). In the second experiment, female ICR mice were fed with a choline-deficient, ethionine-supplemented (CDE) diet for 72 hours to induce necrotizing pancreatitis. After 30 hours on the CDE diet, the mice received cyclosporine (10 mg/kg), tacrolimus (0.32 mg/kg), or saline solution (control) subcutaneously twice daily for 3 days. RESULTS: The pancreatic dry-to-wet weight ratios after ceruletide injections significantly decreased in mice treated with cyclosporine but did not with tacrolimus. Cyclosporine also significantly increased serum amylase levels, but tacrolimus did not. Cyclosporine or tacrolimus alone did not produce pancreatitis. In the CDE diet groups there was a significant difference in survival among the cyclosporine-treated, the tacrolimus-treated, and the control groups. CONCLUSIONS: Cyclosporine or tacrolimus given alone does not induce acute pancreatitis. In contrast, cyclosporine can adversely affect the course of acute edematous pancreatitis, and both immunosuppressants may worsen the survival of mice with acute hemorrhagic necrotizing pancreatitis. This study also demonstrated that the deteriorating effect of tacrolimus is less potent than that of cyclosporine.

Acute Disease↗

PubMed1999

Does steatohepatitis impair liver regeneration? A study in a dietary model of non-alcoholic steatohepatitis in rats.

BACKGROUND: Impaired liver regeneration is a feature of alcoholic hepatitis, but the relative importance of alcohol, nutritional imbalance and inflammatory mediators in causing this effect is unclear. Non-alcoholic steatohepatitis (NASH) is a form of liver disease with similar morphology to alcoholic hepatitis, but the effect of this disorder on liver regeneration is unclear. We, therefore, examined the status of liver regeneration in a rat nutritional model of hepatic steatosis with inflammation, which is morphologically identical to NASH in humans. METHODS: Male Wistar rats received a methionine-choline-deficient diet (MCDD) for 4 weeks before experiments and both isocaloric pair-fed and ad libitum-fed rats were used as controls. Following partial hepatectomy (68%), the extent of hepatic regeneration was determined 24 h later using [3H]-thymidine incorporation and restitution of liver mass. RESULTS: There was no significant difference of [3H]-thymidine incorporation in MCDD-fed, pair-fed and ad libitum-fed rats (80+/-27, 78+/-11 and 80+/-6.3 d.p.m./microg DNA, respectively). Similarly, restituted liver masses in three groups of rats were not significantly different (17+/-3.8, 18+/-1.8 and 17+/-3.1% initial liver weight, respectively). CONCLUSIONS: The similarities in hepatic histology and cytochrome P450 2E1 induction between this nutritional model of hepatic steatohepatitis and alcoholic steatohepatitis imply that these two disorders share pathogenetic mechanisms. However, liver regeneration is not altered by NASH in rats, indicating that the nutritional and inflammatory changes that appear similar to those of alcoholic liver disease do not cause impairment of liver regeneration.

Animal Feed↗

PubMed1985

Influence of dietary tryptophan on the induction of gamma-glutamyltranspeptidase-positive foci in the livers of rats treated with hepatocarcinogen.

The ingestion of an elevated level (2%) of L-tryptophan (TRP) in a purified diet was investigated to determine whether it would influence the induction of gamma-glutamyltranspeptidase (GGT)-positive foci in the livers of rats exposed to a hepatocarcinogen. Subtotal hepatectomies were performed, and 18 h later, the rats were given injections i.p. of diethylnitrosamine (30 mg/kg). Ten days later, groups of male rats were placed on choline-supplemented (CS), CS + TRP, choline-deficient (CD), or CD + TRP diets for 10 wk. In two separate experiments, the rats fed the CS + TRP diet or the CD diet developed more and larger GGT + foci than did rats fed the CS diet. Rats fed the CD + TRP diet revealed similar changes to those found in rats fed the CD diet. The liver weights of the rats fed the CD or the CD + TRP diet were greater than those of rats fed the CS or the CS + TRP diet. Hepatic GGT activity was somewhat elevated in rats fed the CS + TRP diet and markedly elevated in rats fed the CD or the CD + TRP diet. Hepatic ornithine decarboxylase activity was increased in rats fed the CD + TRP diet. The results suggest that increased dietary tryptophan has a promoting effect on liver carcinogenesis as measured by the induction of GGT + foci in the livers of rats exposed to diethylnitrosamine. A potentiating effect by tryptophan was not observed in the livers of rats fed a CD diet.

Amino Acids↗

PubMed2005

Regional differences in gastrointestinal motility disturbances during acute necrotising pancreatitis.

Patients with acute pancreatitis often suffer from intestinal motility disturbances but the mechanism of this dysfunction is largely unknown. We studied the effect of acute necrotising pancreatitis (ANP) on in vivo gastrointestinal motility and in vitro intestinal contractility in mice. ANP was induced non-invasively by feeding young female mice a choline-deficient ethionine-supplemented (CDE) diet during 72 h. Gastric emptying and intestinal transit were measured in vivo 15 min after intragastric gavage of a semiliquid Evans blue bolus. Gastric and intestinal neuromuscular function was determined in vitro on isolated muscle strips. ANP significantly decreased gastric emptying from 61.2 +/- 9.8 to 34.9 +/- 7.1% and intestinal transit from 63.4 +/- 5.6 to 32.5 +/- 5.4%. ANP did not affect receptor-dependent and receptor-independent gastric muscle contractions except the contractions to substance P, which were slightly inhibited. In intestinal muscle strips, ANP significantly decreased contractions to EFS, carbachol, PGF(2alpha), substance P and KCl. Our results show that ANP delays gastric emptying in vivo, associated with a specific reduction in substance P contractility in vitro. ANP also impairs intestinal transit in vivo, associated with a non-specific reduction of intestinal contractility in vitro. We conclude that ANP impairs gastrointestinal motility in mice with underlying regional differences in the pathogenic mechanisms.

Acute Disease↗

PubMed1999

Effects of hepatic impairment on the metabolism of fructose and 5-fluorouracil, as studied in fatty liver models using in vivo 31P-MRS and 19F-MRS.

The purpose of this study was to observe the effects of hepatic impairment on the metabolism of fructose and 5-fluorouracil (5-FU) in fatty liver models using in vivo 31P-MRS and 19F-MRS and to compare the results. In addition, we compared the results to those of other conventional tests such as laboratory examinations, imaging and pathology. Male SIc:Wistar rats were examined on BEM170/200 (4.7 T, Otsuka Electronics, USA) with 17-mm diameter surface coil. Fatty liver was induced by a choline deficient diet (CD diet) for 2 weeks. 31P-MRS were obtained for 90 min after intravenous (i.v.) injection of 1 g/kg of fructose and 19F-MRS were measured for 100 min after i.v. injection of 100 mg/kg of 5-FU. 1H-MRS and 1H-MRI were also performed. On 31P-MRS, there was no statistical difference in the time course of phosphomonoester (PME), adenosine triphosphate (ATP), and inorganic phosphate (Pi) between CD diet group and control group. On 19F-MRS, we detected high peak of fluoronucleotide (Fnct) and suppressed peak of alpha-fluoro-beta-alanine (FBAL) in CD diet group. We showed the metabolism of fructose and 5-FU by 31P-MRS and 19F-MRS, respectively. There was no difference in fructose metabolism but we observed increased fluoronucleotide and decreased a-fluoro-b-alanine in 5-FU metabolism of fatty liver. We speculate that the effects of hepatic impairment in fatty liver may be more severe on 5-FU metabolism and the increased fluoronucleotide may reflect cell proliferation.

Animals↗

PubMed1982

Pancreatic effects of ethionine: blockade of exocytosis and appearance of crinophagy and autophagy precede cellular necrosis.

Young female mice fed a choline-deficient, ethionine-supplemented (CDE) diet for 24 h develop hemorrhagic pancreatic necrosis with a 5-day mortality rate of approximately 50%. At the end of the diet administration, the in vivo discharge of digestive enzymes is blocked, images of exocytosis and luminal membrane recycling disappear, and zymogen granules accumulate within acinar cells. The general ultrastructure, however, remains well preserved, protein synthesis is normal, and intracellular transport of secretory proteins is only slightly retarded. Thus, the CDE diet does not affect the general phenomenon of membrane fusion-fission but specifically inhibits that associated with exocytosis. Twenty-four hours after withdrawal of the CDE diet, discharge of zymogen granules into lysosomes (crinophagy) can be observed, and, 24 h latr, autophagocytosis is noted. Finally, shortly before the onset of pancreatic necrosis, cells of nearly normal appearance are noted to be scattered among cells showing varying degrees of lesion up to complete disruption. Thus, the CDE-induced pancreatic necrosis results from a sequence of events: blockade of exocytosis evolves to crinophagy and autophagy, which might lead to lysosomal activation of zymogens.

Animals↗

PubMed2005

Liver inflammation and cytokine production, but not acute phase protein synthesis, accompany the adult liver progenitor (oval) cell response to chronic liver injury.

Oval cells are facultative liver progenitor cells, which are invoked during chronic liver injury in order to replenish damaged hepatocytes and bile duct cells. Previous studies have observed inflammation and cytokine production in the liver during chronic injury. Further, it has been proposed that inflammatory growth factors may mediate the proliferation of oval cells during disease progression. We have undertaken a detailed examination of inflammation and cytokine production during a time course of liver injury and repair, invoked by feeding mice a choline-deficient, ethionine-supplemented (CDE) diet. We show that immediately following initial liver injury, B220-expressing leucocytes transiently infiltrate the liver. This inflammatory response occurred immediately before oval cell numbers began to expand in the liver, suggesting that the two events may be linked. Two waves of liver cytokine production were observed during the CDE time course. The first occurred shortly following commencement of the diet, suggesting that it may represent a hepatic acute phase response. However, examination of acute phase marker expression in CDE-fed mice did not support this hypothesis. The second wave of cytokine expression correlated with the expansion of oval cell numbers in the liver, suggesting that these factors may mediate oval cell proliferation. No inflammatory signalling was detected following withdrawal of the injury stimulus. In summary, our results document a close correlation between inflammation, cytokine production and the expansion of oval cells in the liver during experimental chronic injury.

Acute-Phase Proteins↗

PubMed1997

Small molecule inhibition of tumor necrosis factor gene processing during acute pancreatitis prevents cytokine cascade progression and attenuates pancreatitis severity.

The morbidity and mortality associated with acute pancreatitis are primarily a result of pancreatic parenchymal necrosis and the development of marked pulmonary dysfunction. Recent evidence suggests that both of these conditions are propagated by interleukin (IL)-1 beta and tumor necrosis factor (TNF)-alpha, which are produced in large quantities within these organs. Because the generation of these cytokines occurs in a predictable manner early in the development of acute pancreatitis, we aimed to determine whether cytokine gene processing could be inhibited in vivo and what effects this would have on pancreatitis severity. Mild [caerulein, 50 micrograms/kg/hour intraperitoneally (IP) x 4; n = 40] or severe (choline-deficient diet; n = 40) necrotizing pancreatitis was induced in NIH swiss mice. Animals were randomly given a novel small molecule (CNI-1493; 10 mg/kg IP) known to inhibit macrophage production of TNF and IL-1 in vitro by inhibiting translation of TNF mRNA into protein. Control animals received IP vehicle. All animals with acute pancreatitis showed dramatic up-regulation of the IL-1 beta and TNF-alpha genes. Those animals receiving CNI-1493 demonstrated attenuated production of both species of mRNA in pancreatic as well as pulmonary tissue (P < 0.01). Markers of pancreatitis severity such as serum amylase and lipase, as well as pancreatic necrosis, were decreased in animals treated with CNI-1493 (all P < 0.05). Posttranscriptional blockade of TNF production precludes induction of the proinflammatory cytokine cascade that normally occurs during acute pancreatitis. This lack of cytokine gene processing in the pancreas and lungs results in dramatic reductions in tissue damage and pancreatitis severity, which is not model dependent. This is the first time that a small molecule has been shown to influence this disease.

Amylases↗

PubMed2001

Application of the PKCYP-test in cases of altered CYP1A2 for multiple CYP systems in rat models of disease.

Previously, we established a method to assess drug metabolism capacity based on a pharmacokinetic estimation of the quantity of cytochrome P450 (CYP) in vivo (PKCYP-test) by introducing an apparent liver-to-blood free concentration gradient in vivo (qg). The qg values were determined as the ratio of in vivo-in vitro clearance. In this study, we examined the application of the PKCYP-test to the clearance of acetanilide and caffeine mediated by CYP1A2 using rat models in which the levels of CYP enzymes were reduced. Rats fed a choline-deficient diet (CD-fed) and aged rats were used as models for a low level of CYP in the liver. In both rat models, the contribution (fCYP) of CYP1A2 to the in vivo intrinsic clearance values (CLint) of acetanilide and caffeine metabolism was less than unity, suggesting that other metabolic pathways are involved in the CLint. The in vivo clearance for CYP1A2 was estimated by multiplying fCYP by CLint, then the value of qg was determined as the ratio of in vivo-in vitro clearance. We predicted the level of CYP1A2 in CD-fed and aged rats, based on the clearance of acetanilide mediated by CYP1A2, using the qg value of control rats. The clearance of caffeine mediated by CYP1A2 in CD-fed and aged rats, as estimated from the predicted level of CYP1A2, correlated with the observed values. In conclusion, we have demonstrated that the PKCYP-test can be applied to CYP1A2 for drugs metabolized by multiple CYP isozymes, and/or to models involving reduced CYP.

Acetanilides↗

PubMedDate not supplied

Direct effects of interleukin-6 on liver progenitor oval cells in culture.

Following acute injury, liver is usually regenerated from hepatocytes by a process that is dependent on interleukin (IL)-6. If this pathway is impaired, restoration of the liver mass and ultimately the survival of the animal are dependent on recruitment of cells from a precursor cell population, either a stem cell or an oval cell. Importantly, oval cells are also implicated in tumorigenesis. A carcinogenic choline-deficient ethionine supplemented (CDE) diet is capable of inducing substantial numbers of oval cells that we can isolate and utilize to identify cytokines, which affect oval cell proliferation and differentiation. Currently, a putative role of IL-6 in oval cell biology is suggested by the elevation of IL-6 in liver and serum of mice treated with a CDE diet and knockout mouse studies. Also, when IL-6 is injected into the peritoneal cavity of mice on the CDE diet, oval cell numbers are increased compared to mice on the CDE diet alone. We investigated the role of human IL-6 on p53 null immortalized murine oval cell lines (PIL), finding that they express transcripts for the IL-6 receptor and gp 130, STAT-3 is phosphorylated upon IL-6 stimulation, IL-6 induces IL-6 production, and proliferation is induced by IL-6. In addition, we show that mouse primary oval cells also express IL-6 receptor and gp 130 mRNA. These findings suggest that IL-6 directly stimulates oval cells and an autocrine mechanism may sustain oval cell proliferation.

Animals↗

PubMed1989

Effect of FOY-305 (camostate) on severe acute pancreatitis in two experimental animal models.

Two models of severe acute pancreatitis were chosen and pancreatitis induced by sodium taurocholate and by a choline-deficient ethionine-supplemented diet, to evaluate the effectiveness of FOY-305 (camostate), a new synthetic trypsin inhibitor. Prophylactic administration of FOY-305 had a significantly favorable effect on the course of the sodium taurocholate-induced disease and on the survival rate of the treated group. A beneficial effect on the amylase and lipase content in serum and ascites was found, but no effect was observed on enzyme concentration in pancreatic tissue or on the degree of histologically detectable organ destruction. Therapeutic administration of FOY-305 had a significantly positive influence when infused directly, 5 and 30 min after the operation, whereas enzyme increase and organ destruction remained unaffected. FOY-305 showed a beneficial effect when given prophylactically or therapeutically at the beginning of the pancreatitis induced by a CDE diet, with no significant change in enzyme increase and degree of organ destruction. The favorable effect on survival time and rate in the early phase of these two severe experimental forms of pancreatitis may justify an evaluation of FOY-305 in a clinically controlled study.

Acute Disease↗

PubMed1985

Factors that modify the effects of prostaglandin on diet-induced acute pancreatitis in mice.

Considerable disagreement exists as to whether prostaglandins improve survival in animals with experimental pancreatitis. In prior studies we have demonstrated a beneficial effect of prostaglandin in the choline deficient, ethionine supplemented diet model of acute hemorrhagic pancreatitis. In the present study we have examined the effects of 1) delaying treatment with 16,-16-dimethyl prostaglandin E2 (PGE2) till 24 h after introduction of the diet and 2) exposing animals to the test diet for 3 days instead of 2. Following delayed treatment mortality in the saline control group (57%) was significantly higher on the fourth day compared to the PGE2 treatment group (3%). However, the overall mortality on day 7 was not significantly different from that seen in the control group (43% versus 60%). In the second series of experiments, PGE2 no longer had a beneficial effect if animals were fed the CDE diet for 3 days. We would conclude from this study and others that the ability to demonstrate a protective effect of PGE2 on the pancreas is dependent upon the experimental protocol employed. Thus, the ability to demonstrate this effect is dependent upon the dose and type of prostaglandins employed, the length of exposure to the test diet, and the time at which treatment is started relative to the induction of the pancreatitis.

Acute Disease↗

PubMed2004

Curcumin inhibits NF-kappaB activation and reduces the severity of experimental steatohepatitis in mice.

BACKGROUND/AIMS: While oxidative stress is a feature of non-alcoholic steatohepatitis, the causal link between oxidative stress and inflammatory recruitment has yet to be demonstrated. We analysed the role of NF-kappaB redox-sensitive signalling pathway of inflammatory recruitment in experimental steatohepatitis. METHODS: Mice were fed the methionine and choline deficient (MCD) or the control diet, with or without curcumin, an NF-kappaB inhibitor, for up to 4 weeks. Histopathology, lipoperoxides, NF-kappaB/DNA binding and expression of NF-kappaB-regulated genes were assessed. RESULTS: MCD-fed mice developed steatohepatitis accompanied by dramatic accumulation of hepatic lipoperoxides, activation of NF-kappaB and induction of pro-inflammatory ICAM-1, COX-2, MCP-1 and CINC mRNA. Curcumin significantly reduced MCD-induced inflammation but had no effect on steatosis or on the level of hepatic lipid peroxides. Curcumin prevented the MCD-induced activation of NF-kappaB and decreased downstream induction of ICAM-1, COX-2 and MCP-1. However, it failed to reduce activation of AP-1, MAPK pathways or CINC expression. CONCLUSIONS: Curcumin alleviates the severity of hepatic inflammation in experimental steatohepatitis induced by the MCD diet, an effect likely to be mediated via inhibition of NF-kB activation and dependent pro-inflammatory genes. The NF-kappaB pathway is one among several possible signalling pathways by which inflammation is recruited in experimental steatohepatitis.

Animals↗

PubMed1993

The effects of cold preservation on steatotic graft viability in rat liver transplantation.

Clinical experience suggests that grafts obtained from steatotic livers result in primary nonfunction more frequently than those from nonsteatotic livers. To date, however, only a few studies have been done to verify the accuracy of this observation. To investigate the effects of cold preservation on steatotic liver viability, liver grafts obtained from rats fed with a choline-deficient diet were transplanted after periods of cold preservation. Recipient survival rates with normal liver grafts were 8/8 (100%) and those with steatotic liver grafts were 7/8 (88%) (P > 0.05) after 1-hr preservation with UW solution. After 9-hr preservation, however, these rates decreased significantly to 0/8 (0%) with steatotic grafts (P < 0.01), but were not significantly decreased with normal grafts. LDH levels in the effluent at the time of transplantation were 133 IU/L (1-hr) and 512 IU/L (9-hr) in normal livers, but in steatotic livers these were elevated to 598 and 3141 IU/L, respectively (P < 0.01). Recovery rates of hepatic blood flow measured by laser Doppler flowmeter after revascularization were 99% (1-hr) and 96% (9-hr) in normal grafts, but in steatotic grafts they were 98% (1-hr) and 63% (9-hr, P < 0.01). In addition, the oxidative phosphorylation ability of liver mitochondria obtained from steatotic grafts was decreased significantly after cold preservation. The present results suggest that steatotic liver grafts are prone to lose their viability more easily than normal liver grafts after prolonged periods of cold preservation due to a combination of causes.

Animals↗

PubMed1992

Role of bacterial infection in diet-induced acute pancreatitis in mice.

This study was performed to elucidate the role of bacterial infection in acute pancreatitis in young female mice fed a choline-deficient diet supplemented with 0.5% DL-ethionine (CDE diet). Mice were randomly classified into two groups: one had been fed CDE diet alone (nonantibiotic group), the other was fed a CDE diet with oral administration of antibiotics (antibiotic group). Survival rates at 96 and 144 h after introduction of the CDE diet were significantly improved in the antibiotic group, 25.0 and 19.4%, respectively, as compared with 3.6 and 0% in the nonantibiotic group (p, 0.05). Aerobic and anaerobic bacterial cultures of blood, ascites, spleen, and pancreas were taken from living mice 72 h after introduction of the CDE diet. Positive bacterial growth from one or more of the specimens occurred in 29.4% of the nonantibiotic group, and in 10.0% of the antibiotic group. Mice with pancreatic necrosis had a higher positive culture rate, 62.5% in the nonantibiotic group vs 20.0% in the antibiotic group. These results suggest that reduction of intestinal flora in mice inhibits secondary infection caused by bacterial translocation and improves survival in diet-induced hemorrhagic pancreatitis. We believe the development of bacterial infection of gut origin may be a factor influencing mortality in severe pancreatitis.

Acute Disease↗

PubMed1980

Protective effects of PGE2 on diet-induced acute pancreatitis in mice.

Prostaglandins have been noted to have a "protective" effect against gastrointestinal mucosal injury induced by a wide variety of agents although possible protective effects of prostaglandins on injury to other tissues have not been reported. We have tested the effect of prostaglandin E2 (PGE2) on acute experimental pancreatitis induced by feeding young female mice a choline-deficient ethionine-supplemented (CDE) diet for 24 hr. Administration of 0.05--0.20 microgram PGE2/g body wt 1 hr before and 4 hr after institution of the CDE diet lowered the mortality rate of diet-induced pancreatitis from 56% to 31%. Larger and smaller doses of PGE2 were without effect. Administration of PGE2 (0.10 microgram/g body weight) diminished the rise in in-vitro LDH discharge and the increase in "free" Cathepsin D activity which occur during diet-induced pancreatitis. Similarly, PGE2 (0.10 microgram/g body wt) diminished the magnitude of the increase in in-vitro protein discharge and the elevated concentrations of trypsinogen and chymotrypsinogen in pancreas fragments taken from mice given the CDE diet. These findings indicate the PGE2 has a protective effect against CDE diet-induced acute experimental pancreatitis. The Cathespin D and LDH changes noted during CDE diet-induced pancreatitis suggest that this diet may decrease membrane integrity and thus allow these enzymes to leak out of the lysosomes and acinar cell, respectively, during pancreatitis. Although the basis for the protective effect of PGE2 remains unclear, our observations suggest that the prostaglandin may act to reduce the alteration in membrane integrity which occurs during CDE-diet induced pancreatitis.

Amylases↗

PubMed1996

Delineation of antigenic pathways of ethionine-induced liver cancer in the rat.

Although oval cell proliferation is observed prior to the appearance of hepatic nodules and hepatocellular carcinomas during ethionine-induced liver carcinogenesis in the rat, the role of these presumptive hepatic stem cells during the neoplastic process remains controversial. In order to investigate this question, we have used a panel of monoclonal antibodies against antigens associated with normal hepatocytes, oval cells and transplantable hepatocellular carcinomas (THC) to trace antigenic pathways leading to liver cancer. Male ACI rats were fed a choline-deficient diet containing 0.1% DL-ethionine for 4, 16 or 30 weeks. Immunocytochemical analysis of frozen liver sections revealed a subpopulation of hepatic nodules (7/52), carcinomas (8/15) and lung metastases (3/5) containing populations of cells expressing both oval cell, hepatocyte and neoplastic markers. Carcinomas expressing oval cell markers often appeared as a mosaic of well-defined patches composed of phenotypically distinct cells. Many of the phenotypes expressed closely mimicked patterns of expression observed in fetal and neonatal liver. THC derived from primary tumors positive for oval cell antigens (4/5) continued to express these markers. Northern blot analysis and immunocytochemical analysis revealed that 4/5 primary hepatocellular carcinomas (PHC) and THC expressed alpha-fetoprotein (AFP) and albumin transcripts and contained subpopulations expressing AFP together with hepatocyte and oval antigens. In contrast, a well-differentiated PHC and its corresponding THC lacked AFP mRNA and oval cell antigens but showed strong expression of both hepatocyte and neoplastic markers. These results demonstrate that a subpopulation of malignant and metastatic hepatocellular carcinomas are comprised of cells expressing multiple oval cell markers in this model system.

Animals↗