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PubMed1999

Potential role of cholecystokinin in the development of acute pancreatitis.

Evidence based on animal studies suggests that cholecystokinin (CCK) is involved in the induction and development of acute experimental pancreatitis. However, the results obtained with CCK or CCKA receptor antagonists in different species (rats, mice) and different models of acute pancreatitis (cerulein pancreatitis, hemorrhagic pancreatitis induced by choline-deficient, ethionine-supplemented diet, arginine-induced pancreatitis, sodium taurocholate-induced pancreatitis) produced variable results. The route of administration, the specificity and potency of compounds and the design of the study are predictive for the outcome. Based on the available information, CCK appears to play a contributory role in the development of acute experimental pancreatitis in mice and rats. No conclusions can be drawn from these results with respect to the human disease.

Acute Disease↗
PubMed1982

Acute hemorrhagic pancreatic necrosis in mice. Effects of proteinase inhibitors on its induction.

An acute hemorrhagic pancreatitis with fat necrosis (AHPN) was induced in female mice fed a choline-deficient diet containing 0.5% DL-ethionine. The effect of various proteinase inhibitors on the induction of the pancreatitis was evaluated using three parameters, the mortality of the animals, the appearance before death of a shock-like state, and the severity of the pancreatic pathology. Treatment of the animals with leupeptin, pepstatin, chymostatin and/or antipain, proteinase inhibitors of microbial origin, resulted in a distinct attenuation of the severity of the induced process, whereas aprotinin and chloroquine had no effect. The results indicate that use of the microbial proteinase inhibitors should be considered as potential therapeutic agents in cases of pancreatitis.

Acute Disease↗
PubMed1989

Acute hemorrhagic pancreatitis in mice: improved survival after indomethacin administration.

This study was designed to test whether indomethacin given in drinking water attenuates the severity of the acute hemorrhagic pancreatitis induced in mice fed a choline-deficient ethionine diet (CDE), and improves their survival. Three doses of indomethacin were tested, 20, 10 and 5 mg of indomethacin/l of drinking water, and their effects on the histopathology of the pancreas and liver, serum amylase activity levels, and mortality were determined. Even though 20 and 10 mg/l suppressed pancreatic injury, and the accompanying shock-like state, the mice died due to indomethacin hepatotoxicity. Hepatotoxicity was minimal at a dose of 5 mg/l, which resulted in preservation of significant amounts of normal pancreatic parenchyma, subsequent regeneration of acinar cells, and an increased survival of the mice. The results suggest that prostaglandins may play an important role in the pathogenesis of acute hemorrhagic pancreatitis, and that indomethacin attenuates the severity of the induced disease.

Acute Disease↗
PubMed1988

Intracellular vacuoles in experimental acute pancreatitis in rats and mice are an acidified compartment.

The appearance of vacuoles inside acinar cells characterizes an early stage of development in different models of acute pancreatitis and, possibly, also in human disease. The vacuoles have been shown to contain both digestive and lysosomal enzymes. This abnormal admixture may have important implications for the pathogenesis of pancreatitis because the lysosomal enzyme cathepsin B can activate trypsinogen and may, by this way, trigger pancreatic autodigestion. For the activation process of trypsinogen by cathepsin B, however, an acidic pH is required. This study, therefore, looked for evidence of vacuole acidification in two different models of acute pancreatitis. Edematous pancreatitis was induced in rats by hyperstimulation with cerulein and hemorrhagic pancreatitis was induced in mice by feeding a choline-deficient, ethionine-supplemented diet. Pancreatic acinar cells were isolated at different times after induction of pancreatitis and incubated with 50 microM of acridine orange to identify acidic intracellular compartments. As shown in previous work, zymogen granules are the main acidic compartment of normal acinar cells; they remained acidic throughout the course of pancreatitis in both models. Vacuoles became increasingly more frequent in both models as pancreatitis progressed. Throughout development of pancreatitis, vacuoles accumulated acridine orange indicating an acidic interior. Addition of a protonophore (10 microM monensin or 5 microM carbonyl cyanide m-chlorophenylhydrazone [CCCP] or a weak base (5 mM NH4Cl) completely and rapidly abolished acridine orange fluorescence inside both zymogen granules and vacuoles providing further evidence for an acidic interior. The acidification of vacuoles seen in two different models of pancreatitis may be an important requirement for activation of trypsinogen by cathepsin B and thus for the development of acute pancreatitis.

Acute Disease↗
PubMed2005

Hemin-activated macrophages home to the pancreas and protect from acute pancreatitis via heme oxygenase-1 induction.

Hemin upregulates heme oxygenase-1 (HO-1), a stress-induced enzyme implicated in protection from a variety of injuries while its related isoform HO-2 is constitutively expressed. The role of hemin or HO-1 in the pancreas and their potential modulation of pancreatic injury are unknown. We show that HO-1 is induced in pancreatitis caused by caerulein and more prominently in severe pancreatitis caused by feeding a choline-deficient diet (CDD). Intraperitoneal hemin administration dramatically increases peritoneal and pancreas macrophages that overexpress HO-1 in association with pancreatic induction of the chemoattractants monocyte chemotactic protein-1 and macrophage inflammatory protein-1alpha but not RANTES or macrophage inflammatory protein-2. Hemin administration before CDD feeding protected 8 of 8 mice from lethality while 7 of 16 controls died. Protection is mediated by HO-1-overexpressing macrophages since hemin-primed macrophages home to the pancreas after transfer to naive mice and protect from CDD-induced pancreatitis. Suppression of hemin-primed peritoneal cell HO-1 using HO-1-specific small interfering RNA prior to cell transfer abolishes protection from CDD-induced pancreatitis. Similarly, hemin pretreatment in caerulein-induced pancreatitis reduces serum amylase and lipase, decreases pancreatic trypsin generation, and protects from lung injury. Therefore, hemin-like compounds or hemin-activated macrophages may offer novel therapeutic approaches for preventing acute pancreatitis and its pulmonary complication via upregulation of HO-1.

Acute Disease↗
PubMed1987

Complementarity between two rat liver tumor promoters.

A delay in the exposure of initiated rats to orotic acid (OA) beyond a specific time frame results in a progressive loss of promotional effect in liver carcinogenesis. The current study was designed to ascertain whether the loss of promotional effect could be counteracted by pre-exposing the initiated animals to other rat liver promoting regimens such as a diet deficient in choline (CD). Male Fischer 344 rats (150 g) were initiated with diethylnitrosamine (200 mg/kg, ip); 1 week later they were given either a CD diet or a CD diet supplemented with choline for 5 weeks. Animals from these two groups were then fed either a 1% OA diet or the basal diet for another 20 weeks. The results indicated that the loss of OAs promotion efficacy from delaying the start of the promoting regimen can be counteracted by pre-exposing the initiated rats to a CD diet. Thus in rats exposed to OA from the first week of initiation, 7% of the liver developed as nodular areas, whereas only 0.8% of liver was nodular when OA feeding was delayed by 5 weeks. This loss was abolished when initiated rats were fed a CD diet for 5 weeks prior to feeding OA for 20 weeks. These results suggest that in a rat liver tumor promotion model, two tumor promoters, OA and CD, show some degree of complementarity when given sequentially.

Animals↗
PubMed1976

Role of age and sex in chronic thyroiditis in rats fed 3'-methyl-4-dimethylaminoazobenzene.

Inbred male and female Buffalo strain rats were started at 4, 8, 12, 24, or 52 weeks of age on 0.06% 3'-methyl-4-dimethylaminoazobenzene in a low-protein, choline-deficient diet. Eight-week-old males and females were the most susceptible to the development of chronic thyroiditis, but females were more susceptible than the males. Female rats of other ages developed a slightly higher incidence of thyroiditis than the male rats, the difference being most noticeable for rats 12 weeks old.

Age Factors↗
PubMed1996

[Effect of KSG-504, a new CCK-A-receptor antagonist, on experimental acute pancreatitis in rats and mice].

We investigated the protective and/or therapeutic effects of a new cholecystokinin receptor antagonist, KSG-504, on different types of experimental pancreatitis in the rat and mouse. The intravenous injection of KSG-504 (10, 25, 50 and 100 mg/kg) before caerulein administration to the rat inhibited the increases in plasma amylase, lipase and of pancreatic wet weight in a dose-dependent manner. The histological changes due to caerulein-induced acute pancreatitis were also decreased by KSG-504 when KSG-504 (25, 50 and 100 mg/kg) was administered after the induction of acute pancreatitis; the increases in plasma amylase, lipase and pancreatic wet weight were reduced, but the histological changes of the pancreas were not decreased significantly. In the second experiment, acute pancreatitis was induced in rats by injecting 0.3 ml of 6% sodium taurocholate into the pancreatic interstitial tissue. KSG-504 administered immediately and 1.5 hr after sodium-taurocholate injection at 100 mg/kg reduced the increases of pancreatic enzymes in the plasma, pancreatic wet weight and ascites. Moreover, KSG-504 (50 and 100 mg/kg, i.v., x 2) mitigated the histological changes of taurocholate-induced acute pancreatitis. Another type of acute pancreatitis was induced in mice by dl-ethionine (0.5 g/kg, p.o., x 4) and a choline-deficient diet. KSG-504 (10, 30 and 100 mg/kg) was subcutaneously administered five times every 12 hr during the experiment. KSG-504 elongated the survival of mice in a dose-dependent manner. These findings suggest that KSG-504 has potent protective and/or therapeutic effects against acute pancreatitis and that cholecystokinin may be involved in the development of pancreatitis.

Acute Disease↗
PubMed2003

[Pharmacological study on the effects of the adenosine uptake inhibitor KF24345 on inflammatory diseases].

Adenosine protects against cellular damage and dysfunction under several adverse conditions, including inflammation. We examined the effects of KF24345, a novel adenosine uptake inhibitor, on inflammatory diseases to investigate whether the adenosine uptake inhibition is useful for the treatment of inflammation. KF24345 inhibited adenosine uptake into washed erythrocytes (in vitro) and sampled blood cells from mice after its oral administration (in vivo). KF24345 significantly suppressed lipopolysaccharide-induced tumor necrosis factor-alpha production and leukopenia in mice, and the effects of KF24345 were abolished by the treatment with a non-selective or an A(2A)-selective adenosine receptor antagonist. In the experimental glomerulonephritis induced in mice by anti-glomerular basement membrane antiserum, KF24345 significantly inhibited proteinuria and glomerular damage without exhibiting the side effects observed following the treatment with prednisolone and cyclophosphamide. In addition, KF24345 ameliorated the severity of experimental acute pancreatitis induced by cerulein or choline-deficient and ethionine-supplemented diet in mice, and it decreased mortality accompanying severe acute pancreatitis. The anti-pancreatitis effects of KF24345 were abolished by the treatment with a non-selective or an A(2A)-selective adenosine receptor antagonist. These results suggest that KF24345 and adenosine uptake inhibitors can be a new therapeutic approach for various inflammatory diseases, including glomerulonephritis and acute pancreatitis.

Acute Disease↗
PubMed2000

Isolation of liver oval cells from hamsters treated with diethylnitrosamine and 2-acetyl aminofluorene.

Recently, cholangiocellular carcinoma (CCC) was successfully induced in the hamster by infecting with Clonorchis sinensis following hepatocarcinogen treatment and has been proposed as a suitable model to study the pathogenesis of human CCC. In this hamster model, oval cells are suggested to be cells of origin of CCC. More direct analysis of histogenesis of CCC would become possible if large numbers of highly purified oval cells of hamster origin are obtained. In this study, we describe successful isolation of highly purified oval cells from hamsters. Oval cells were induced by diethylnitrosamine and 2-acetylaminofluorene treatment under choline deficient diet and isolated by centrifugal elutriation method. This isolated cells were highly homogenous in size (10.9+/-1.1 microm in diameter) and had a high nuclear to cytoplasmic ratio, an oval-shaped nucleus and a few cytoplasmic organelles. Immunocytochemically, 85.4+/-1.6%, 75.1+/-2.0%, 62+/-1.5% and 25.6+/-2.7% of the isolated cells were positive for cytokeratin 19, OV-6, albumin and alpha-fetoprotein, respectively, indicating that these cells had phenotypic characteristics of both hepatocytes and bile duct epithelium. The isolated cells were therefore considered to be hamster oval cells.

2-Acetylaminofluorene↗
PubMed2002

Malnutrition interferes with the unique lymphadenopathy induced in Lewis rats by metallic tin.

Metallic tin powder injected into Lewis rats caused marked enlargement of draining lymph nodes with prominent hyperplasia of plasma cells. A low level of dietary protein (8%) or deficiency of choline interfered with the cellular proliferation and reduced the size of the nodes by nearly one-third compared to a normal protein diet (20%). A high level of protein in the diet (50%) did not augment the effect of metallic tin powder beyond that achieved by a level usually considered adequate (20%).

Animals↗
PubMed1992

Intrahepatic cholestasis: a review of biochemical-pathological mechanisms.

Intrahepatic cholestasis involves impaired excretion of bile via the hepatobiliary system as a consequence of one or more lesions within the liver. In humans, intrahepatic cholestasis most often results as a side-effect of drug therapy and the clinical manifestation of this condition, jaundice, has been estimated to account for hospitalization in 2 to 5% of the cases for the general population and approaches as much as 20% in the elderly. With the aging of the population and the common occurrence of poly-drug therapy in geriatric patients, it is to be expected that jaundice due to drug-induced intrahepatic cholestasis will become even more prevalent, and accordingly the need to understand the basic mechanisms of this disease condition will become more urgent. The list of culprit agents implicated in the induction of intrahepatic cholestasis in humans is continually expanding. These include various steroid hormones, bile acids, drugs and other chemicals. Experimentally, a wide spectrum of agents has been shown to precipitate intrahepatic cholestasis. Over the years, a number of hypotheses on the biochemical and pathological mechanisms of intrahepatic cholestasis has emerged, including the following: impaired sinusoidal membrane function; interference with the distribution and binding of cytoplasmic endogenous carrier proteins; interference with mitochondrial energy supply; defects in the canalicular membrane including altered Na+/K+ -ATP-ase activity; impairment of microfilament and microtubule functions; interference with bile secretion involving bile acid dependent and independent fractions, and altered bile acid metabolism due to "hypoactive hypertrophic smooth endoplasmic reticulum". In partial agreement with the latter hypothesis, our studies indicated that impairment of the endoplasmic reticulum might represent one of the early stages in the development of intrahepatic cholestasis. Various experimental conditions that induce intrahepatic cholestasis to different degrees resulted in an interference of the synthesis of microsomal phospholipids and altered microsomal function. The conditions included the administration of various hepatotoxic compounds or steroids, pregnancy, delayed development of the endoplasmic reticulum in neonates, and dietary methyl donor or choline deficiency. This review reports the biochemical-pathological mechanisms postulated to be involved in the genesis of intrahepatic cholestasis with specific reference to experimental models of drug-induced intrahepatic cholestasis. The important practical implications of cholestasis are also briefly surveyed.

Animals↗
PubMed2007

Monounsaturated fat decreases hepatic lipid content in non-alcoholic fatty liver disease in rats.

AIM: To evaluate the effects of different types of dietary fats on the hepatic lipid content and oxidative stress parameters in rat liver with experimental non-alcoholic fatty liver disease (NAFLD). METHODS: A total of 32 Sprague-Dawley rats were randomly divided into five groups. The rats in the control group (n = 8) were on chow diet (Group 1), rats (n = 6) on methionine choline-deficient diet (MCDD) (Group 2), rats (n = 6) on MCDD enriched with olive oil (Group 3), rats (n = 6) on MCDD with fish oil (Group 4) and rats (n = 6) on MCDD with butter fat (Group 5). After 2 mo, blood and liver sections were examined for lipids composition and oxidative stress parameters. RESULTS: The liver weight/rat weight ratio increased in all treatment groups as compared with the control group. Severe fatty liver was seen in MCDD + fish oil and in MCDD + butter fat groups, but not in MCDD and MCDD + olive oil groups. The increase in hepatic triglycerides (TG) levels was blunted by 30% in MCDD + olive oil group (0.59 +/- 0.09) compared with MCDD group (0.85 +/- 0.04, P < 0.004), by 37% compared with MCDD + fish oil group (0.95 +/- 0.07, P < 0.001), and by 33% compared with MCDD + butter group (0.09 +/- 0.1, P < 0.01). The increase in serum TG was lowered by 10% in MCDD + olive oil group (0.9 +/- 0.07) compared with MCDD group (1.05 +/- 0.06). Hepatic cholesterol increased by 15-fold in MCDD group [(0.08 +/- 0.02, this increment was blunted by 21% in MCDD + fish oil group (0.09 +/- 0.02)]. In comparison with the control group, ratio of long-chain polyunsaturated fatty acids omega-6/omega-3 increased in MCDD + olive oil, MCDD + fish oil and MCDD + butter fat groups by 345-, 30- and 397-fold, respectively. In comparison to MCDD group (1.58 +/- 0.08), hepatic MDA contents in MCDD + olive oil (3.3 +/- 0.6), MCDD + fish oil (3.0 +/- 0.4), and MCDD + butter group (2.9 +/- 0.36) were increased by 108%, 91% and 87%, respectively (P < 0.004). Hepatic paraoxonase activity decreased significantly in all treatment groups, mostly with MCDD + olive oil group (-68%). CONCLUSION: Olive oil decreases the accumulation of triglyceride in the liver of rats with NAFLD, but does not provide the greatest antioxidant activity.

Animals↗
PubMed1996

An evaluation of hepatic ultrasound speed in injury models in rats: correlation with tissue constituents.

The speed of sound through the livers of 32 male Sprague-Dawley rats was measured. The study population consisted of four experimental groups: control, acute liver injury induced by carbon tetrachloride, fatty liver induced by a choline-deficient diet, and liver cirrhosis induced by administration of N-diethylnitrosamine. To examine possible correlations between the speed of sound and liver histology, biochemical measurements of the water, fat, and collagen content were made. The aim of the present study was to determine the effects of the characteristics of diseased liver tissue on the speed of sound, by studying the tissue constituents biochemically and by using a more accurate measurement of the speed of sound. The sound speed was 1591.6 +/- 6.7 m/s in the acute liver injury group, 1531.4 +/- 18.4 m/s in the fatty liver group, and 1624.9 +/- 6.7 m/s in the liver cirrhosis group. No significant correlation existed between the speed of sound and the water content in all groups taken together, whereas a good correlation was found in the fatty liver group (P < 0.0001, r = -0.858) and in cirrhosis (P < 0.0001, r = 0.760) when the groups were examined separately. These results indicate that the speed of sound is useful for diagnosing fatty liver for predicting the fat content.

Animals↗
PubMed2000

Differentiation of rat oval cells after activation of peroxisome proliferator-activated receptor alpha43.

Peroxisome proliferators (PPs) act as nongenotoxic tumor promoters in rodents. Their hepatocarcinogenicity requires the presence of the PP-activated receptor alpha (PPARalpha); however, the exact role played by this transcription factor in the liver, more precisely in liver cell growth and differentiation, is not known. The aim of this study was to investigate the role of PPARalpha in oval cells, which are considered to be closely related to liver stem cells, act as bipotential progenitors for the two main hepatic lineages, and have been implicated as playing a role in several models of liver carcinogenesis. We studied the PPARalpha-mediated response of primary oval cells isolated from rats fed a choline-deficient ethionine-supplemented diet (CDE diet, a regimen commonly used for the induction of oval cell proliferation in rodents) with or without cotreatment with WY14,643, a prototype PPARalpha-activator. PPARalpha was expressed at relatively low levels in primary oval cells from rats fed the CDE diet alone. In vivo treatment with WY14,643 for 2-6 weeks induced, in the oval cells, the expression of PPARalpha as well as that of the PPARalpha-responsive genes encoding fatty acyl-CoA oxidase and cytochrome P450 4A1. Moreover, the oval cell response to WY14,643 was accompanied by an overall phenotypic modulation toward the hepatocyte lineage. In addition, the PPARalpha activator induced, among the oval cells, a subpopulation of transitional cells showing features of maturing hepatocytes expressing the oncofetal marker, alpha-fetoprotein. These results show that oval cells are responsive to PPs and strongly argue for a role of PPARalpha in the differentiation/maturation of rat oval cells. In the absence of the CDE diet regimen, 9-week treatment with WY14,643 lead to the appearance of a population of large-sized cells somewhat similar to the transitional cells. However, these cells showed little expression of markers of mature hepatocytes, consistent with a block during their maturation process, i.e., they are resistant to PPARalpha-mediated differentiation. Interestingly, the phenotype of these cells resembled that of the cells usually found in neoplastic foci induced by PPs. Our results, together with previous reports, suggest the involvement of oval cells in the hepatocarcinogenicity of PPs.

Animals↗
PubMed2002

Reactive Oxygen and Nitrogen Oxide Species-induced Stress, a Major Intrinsic Factor Involved in Carcinogenic Processes and a Possible Target for Cancer Prevention.

Reactive oxygen and nitrogen oxide species and their inducing stress are involved in a variety of physiological and pathological phenomena in aerobes, including humans. For multistage carcinogenic processes, reactive oxygen and nitrogen oxide species-induced stress (RONOSS) serves as a major intrinsic factor and is involved in every step. This means that free radicals, RONOSS and their inducing downstream events may be targets for cancer prevention. It is therefore of importance to elucidate the mechanisms underlying the participation of RONOSS in carcinogenesis and to apply the obtained results for establishment of strategies to control cancer development. Despite the large body of accumulated knowledge due to worldwide efforts dealing with this research field, there still remain numerous uncertainties. In this mini-review, we introduce two examples of such efforts, one concerning a renal carcinogen KBrO(3) and the other dealing with hepatocarcinogenesis caused by a choline-deficient, L-amino acid-defined diet, in order to give some idea about the current understanding of the roles of RONOSS in carcinogenesis.

Journal Article↗
PubMed2000

Promotion of Liver Lesion Development in the Syrian Hamster by Dietary Fat Following Multi-organ Initiation is Inhibited by DHEA-S Administration.

The influence of dietary supplementation with dehydroepiandrosterone-sulphate (DHEA-S) at 0.6% was investigated in male Syrian golden hamsters initiated by treatments with azoxymethane(AOM), and dihydroxy-di-n-propyl nitrosamine (DHPN), timed after transfer from a choline-deficient to a normal diet. These carcinogens respectively target the colon, and the respiratory tract, the liver and pancreas. A total of 75 animals were divided into 6 groups, 1-3 (20 animals each) receiving the initiation protocol of during the first 8 weeks, and 4-6 (5 animals each) given the vehicles alone. The hamsters in groups 2,3 and 5,6 then received a high fat diet (20% corn oil) while DHEA-S was given in addition for 20 weeks to groups 3 and 6. Groups 1 and 4 served as controls on the basal diet. Assessment of development of preneoplastic and neoplastic lesions, after sacrifice at week 28, revealed increase in hepatocellular liver nodules and the index of BrdU incorporation in the hepatocellular cells of the liver in the initiated animals given the high fat diet. This was significantly reduced by the DHEA-S supplementation. Non-significant tendencies for high fat enhancement and hormone protection were also observed for lung and colon tumors.

Journal Article↗
PubMedDate not supplied

Experimental observations and clinical implications of fasting and diet supplementation in fatty livers.

Fatty accumulation per se does not appear to affect liver function; however, interest has recently renewed to fatty liver because of the clinical relevance of non alcoholic steato-hepatitis (NASH) and for the increased risk of post-transplant failure in grafted livers with steatosis. Clinical and experimental studies have doubtless demonstrated that oxidative stress ensues in steatotic livers. Mitochondria represent the preferential target of the oxidative injury associated to fatty degeneration and show reduced content of glutathione, higher levels of oxidative products and damages to enzymes involved in the process of ATP synthesis, which become more evident under stressing conditions. Although obese patients with fatty liver are advantaged by weight loss, clinical and experimental observations suggest that fatty livers poorly tolerate excessive food deprivation. These observations represent the rationale for treatment strategies based on the supplementation of antioxidants and energetic substrates rather than solely a diet restriction. This review focuses on data emerging from a series of investigations performed in rats with fatty livers induced by a choline-deficient diet, which resembles human steatosis due to an excessive intake of carbohydrates, and aims to give the cue for the development of therapeutic options able to preserve hepatic function after transplantation of steatotic organs.

Animals↗