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PubMed1988

Alterations induced by phenobarbital, a liver tumor promoter, in hepatocyte receptors for insulin and glucagon and glycogen metabolism.

Exposure of rats to phenobarbital (PB), a tumor promoter in the two-stage hepatocarcinogenesis model, in their diet (0.06%) induces alterations in insulin receptors in the hepatocytes. There is a decrease both in the number of receptors and the dissociation constant (Kd) when compared with animals fed control laboratory diet. The number of insulin receptors/cell and the Kd were respectively: 183,000 +/- 19,000 and 15.3 +/- 2.5 nM for controls; 47,000 +/- 5000 and 2.8 +/- 0.3 nM for PB. The glycogen synthesis in response to insulin was found to be unresponsive in the hepatocytes from rats exposed to PB. Glucagon receptors on hepatocytes, however, were unaltered in animals treated with PB or fed a choline-deficient (CD) diet and the glucagon-stimulated glycogenolytic responses were also comparable to the controls. There is, therefore, a selective alteration in the hepatocyte surface membrane receptors. Both PB and CD have been shown to reduce the hepatic cell membrane receptors for epidermal growth factor, indicating that the two different tumor promoters alter peptide receptors with endogenous protein kinase activities. This similar though selective effect of the tumor promoters on cell surface receptors may be of significance in their action in carcinogenesis by having an effect on the alteration of regulation of cell growth and metabolism.

Animals↗
PubMed2005

Inhibition of adult liver progenitor (oval) cell growth and viability by an agonist of the peroxisome proliferator activated receptor (PPAR) family member gamma, but not alpha or delta.

Multifaceted evidence links the development of liver tumours to the activation and proliferation of adult liver progenitor (oval) cells during the early stages of chronic liver injury. The aim of this study was to examine the role of the peroxisome proliferator activated receptors (PPARs): PPARalpha, delta and gamma, in mediating the behaviour of liver progenitor cells during pre-neoplastic disease and to investigate their potential as therapeutic targets for the treatment of chronic liver injury. We observed increased liver expression of PPARalpha and gamma in concert with expanding oval cell numbers during the first 21 days following commencement of the choline deficient, ethionine supplemented (CDE) dietary model of carcinogenic liver injury in mice. Both primary and immortalized liver progenitor cells were found to express PPARalpha, delta and gamma, but not gamma2, the alternate splice form of PPARgamma. WY14643 (PPARalpha agonist), GW501516 (PPARdelta agonist) and ciglitazone (PPARgamma agonist) were tested for their ability to modulate the behaviour of p53-immortalized liver (PIL) progenitor cell lines in vitro. Both PPARdelta and gamma agonists induced dose-dependent growth inhibition and apoptosis of PIL cells. In contrast, the PPARalpha agonist had no effect on PIL cell growth. None of the drugs affected the maturation of PIL cells along either the hepatocytic or biliary lineages, as judged by their patterns of hepatic gene expression prior to and following treatment. Administration of the PPARgamma agonist ciglitazone to mice fed with the CDE diet for 14 days resulted in a significantly diminished oval cell response and decreased fibrosis compared with those receiving placebo. In contrast, GW501516 did not affect oval cell numbers or liver fibrosis, but inhibited CDE-induced hepatic steatosis. In summary, PPARgamma agonists reduce oval cell proliferation and fibrosis during chronic liver injury and may be useful in the prevention of hepatocellular carcinoma.

Animals↗
PubMed2001

Altered mitochondrial function and overgeneration of reactive oxygen species precede the induction of apoptosis by 1-O-octadecyl-2-methyl-rac-glycero-3-phosphocholine in p53-defective hepatocytes.

The mechanism of induction of apoptosis by the novel anti-cancer drug 1-O-octadecyl-2-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3) was investigated in p53-defective SV40 immortalized rat hepatocytes (CWSV1). Exposure to 12 microM ET-18-OCH3 for 36 h induced apoptosis as determined using classical morphological features and agarose gel electrophoresis of genomic DNA. Increased levels of reactive oxygen species (ROS) were detected spectrophotometrically using a nitroblue tetrazolium (NBT) assay in cells treated with ET-18-OCH3. Both the increased generation of ROS and the induction of apoptosis were inhibited when cells were treated concurrently with ET-18-OCH3 in the presence of the antioxidant alpha-tocopherol. Similar results were achieved when cells were switched acutely to choline-deficient (CD) medium in the presence of the antioxidant. The possible role of mitochondria in the generation of ROS was investigated. Both ET-18-OCH3 and CD decreased the phosphatidylcholine (PC) content of mitochondrial and associated membranes, which correlated with depolarization of the mitochondrial membrane as analyzed using 5,5',6,6'-tetramethylbenzimidazolcarbocyanine iodide (JC-1), a sensitive probe of mitochondrial membrane potential. Rotenone, an inhibitor of the mitochondrial electron transport chain, significantly reduced the intracellular level of ROS and prevented mitochondrial membrane depolarization, correlating with a reduction of apoptosis in response to either ET-18-OCH3 or CD. Taken together, these results suggest that the form of p53-independent apoptosis induced by ET-18-OCH3 is mediated by alterations in mitochondrial membrane PC, a loss of mitochondrial membrane potential, and the release of ROS, resulting in completion of apoptosis.

Animals↗
PubMed2006

Diethanolamine alters neurogenesis and induces apoptosis in fetal mouse hippocampus.

Diethanolamine (DEA) is present in many consumer products such as shampoo. Dermal administration of DEA diminishes hepatic stores of the essential nutrient choline, and we previously reported that dietary choline deficiency during pregnancy reduces neurogenesis and increases apoptosis in the hippocampus of fetal rats and mice. Therefore, DEA could also alter brain development. Timed-pregnant C57BL/6 mice were dosed dermally from gestation day 7 through 17 with DEA at 0, 20, 80, 160, 320, and 640 mg/kg body/day. At doses of DEA > 80 mg/kg body/day, we observed decreased litter size. In fetuses (embryonic day 17) collected from dams treated dermally with 80 mg/kg body/day DEA, we observed decreased neural progenitor cell mitosis at the ventricular surface of the ventricular zone of the hippocampus [to 56+/-14% (se) histone 3 (H3) phosphorylation as compared to controls; P < 0.01]. We also observed increased apoptosis in fetal hippocampus (to 170+/-10% of control measured using TUNEL and to 178+/-7% of control measured using activated caspase 3; P < 0.01). Thus, maternal exposure to DEA reduces the number of neural progenitor cells in hippocampus by two mechanisms, and this could permanently alter memory function in offspring of mothers exposed to this common ingredient of shampoos and soaps.

Administration, Topical↗
PubMed1998

Acute pancreatitis induces cytokine production in endotoxin-resistant mice.

OBJECTIVE: The purpose of this study was to determine whether pathologic progression and cytokine responses in acute pancreatitis (AP) are altered in the absence of endotoxemia. SUMMARY BACKGROUND DATA: Previous studies have demonstrated that AP is characterized by rapid production and release of inflammatory cytokines, which play a major role in the local pancreatic and systemic complications of this disease. Infection and endotoxemia have been implicated as a major source of morbidity and death in AP and as possible stimuli for the overwhelming cytokine response seen in this disease. METHODS: AP was induced by a choline-deficient and ethionine-supplemented diet for 4 days in normal C57BL/6J mice (controls, n = 23) and in CD14 knockout mice (CD14KO, n = 23), which cannot produce circulating cytokines in response to endotoxin. Control and endotoxin-resistant mice were killed at time 0, then at 24, 48, 72, and 96 hours after the start of the diet. At each time point serum was collected for amylase, glucose, and cytokine measurements (tumor necrosis factor-alpha [TNFalpha] and interleukin-1beta [IL1beta]), and the pancreas was removed for histologic examination. TNFalpha was measured with a bioassay using WEHI-2F cells and IL1beta with a bioassay using D10.G4.1 cells. RESULTS: CD14KO mice developed biochemical manifestations of AP with alterations in amylase levels, hypoglycemia, weight loss, and histologic changes of pancreatitis similar to the pattern seen in control mice. TNFalpha and IL1beta production had similar kinetics in both groups, with significant peak TNFalpha serum levels at 72 hours and a progressive rise of IL1beta levels throughout the study period. Histologic changes appeared earlier and were more pronounced in the control versus the CD14KO mice. However, the mortality rate was identical (20% at 96 hours) for both groups. CONCLUSIONS: These results demonstrate that the progression of AP, the cytokine response associated with the disease, and early death are independent of endotoxin action. These findings, which suggest that an uncharacterized stimulus is responsible for triggering the cytokine cascade in this disease, may have significant implications for the management of patients with AP.

Acute Disease↗
PubMed2000

Quantitative measurement of P- and E-selectin adhesion molecules in acute pancreatitis: correlation with distant organ injury.

OBJECTIVE: To determine whether expression of P- and E-selectin molecules is associated with the development of systemic organ manifestations in acute pancreatitis (AP). SUMMARY BACKGROUND DATA: Overproduction of inflammatory cytokines in AP induces expression of adhesion molecules, which may lead to increased leukocytic infiltration and tissue damage. Understanding the temporal expression of these molecules could afford better measures for therapeutic intervention. METHODS: Acute pancreatitis was induced in 30-day-old female C57/ bI/6J mice by feeding a choline-deficient/ethionine-supplemented diet (n = 95). Mice were divided into three groups. Group I (n = 35) was used to study the biochemical and histologic manifestations of AP and to evaluate the neutrophilic infiltration by myeloperoxidase activity and immunofluorescence. Groups II (n = 35) and III (n = 25) were used to evaluate expression of P- and E-selectin by the dual radiolabeled monoclonal antibody technique. RESULTS: Biochemical and histologic evidence of AP developed in all mice. The inflammatory cytokine tumor necrosis factor-alpha gradually increased in serum as early as 18 hours, reaching more than 800-fold background levels by 72 hours. Biphasic P-selectin expression in the lung was seen with peaks at 24 and 48 hours; E-selectin expression peaked at 48 hours. CD18-positive leukocytes and increased myeloperoxidase activity in the lung were demonstrated at 24 hours, correlating with the onset of selectin upregulation. Histologic scoring of lung tissue demonstrated mild damage at 24 hours, with progressive injury occurring from 48 to 72 hours. CONCLUSIONS: In AP, the production of inflammatory cytokines precedes up-regulation of P- and E-selectin, whose expression coincided with the increased infiltration of CD18-positive cells and neutrophil sequestration in lung tissue. Temporally, these events correlate with evidence of histologic pulmonary injury and underscore the role of adhesion molecules as mediators of pathophysiologic events. This mechanistic pathway may afford novel therapeutic interventions in clinical disease by using blocking agents to ameliorate the systemic manifestations of AP.

Acute Disease↗
PubMed2001

Blocking pulmonary ICAM-1 expression ameliorates lung injury in established diet-induced pancreatitis.

OBJECTIVE: To determine whether blocking the cell surface expression of intracellular adhesion molecules (ICAM-1) in established severe acute pancreatitis (AP) would ameliorate pulmonary injury. SUMMARY BACKGROUND DATA: Lung injury in AP is in part mediated by infiltrating leukocytes, which are directed to lung tissue by ICAM-l. The authors' laboratory has previously demonstrated that AP results in overproduction of inflammatory cytokines, upregulation of pulmonary ICAM-1 expression, and a concomitant infiltration of neutrophils, which results in lung injury. METHODS: Young female mice were fed a choline-deficient/ethionine-supplemented diet to induce AP and were treated with a blocking dose of monoclonal antibody specific to the ICAM-1 receptor. Antibody treatment was administered at 72, 96, and 120 hours after beginning the diet, and all animals were killed at 144 hours. The degree of pancreatitis was evaluated by serum biochemical and tumor necrosis factor alpha levels as well as histology. The dual radiolabeled monoclonal antibody method was used to quantitate ICAM-1 cell surface expression in pulmonary tissue. Lung injury was assessed histologically and by determining lung microvascular permeability by measuring accumulated 125I-radiolabeled albumin. Pulmonary neutrophil sequestration was determined by the myeloperoxidase assay. RESULTS: All mice developed severe AP, and pancreatic injury was equally severe in both treated and untreated groups. Pulmonary ICAM-1 expression was significantly upregulated in animals with AP compared with controls. Treatment with a blocking dose of anti-ICAM-1 antibody after the induction of AP resulted in inhibited ICAM-1 cell surface expression to near control levels. Compared to untreated animals with AP, mice treated with anti-ICAM-1 mice had significantly reduced histologic lung injury and neutrophil sequestration, and a decreased microvascular permeability by more than twofold. CONCLUSIONS: These results demonstrate for the first time that treatment targeting the cell surface expression of ICAM-1 after the induction of AP ameliorates pulmonary injury, even in the face of severe pancreatic disease.

Acute Disease↗
PubMed2004

Assessment of phospholipid malabsorption by quantification of fecal phospholipid.

OBJECTIVES: The standard methods for quantifying fat absorption involve extraction of fat from fecal samples with heptane, ether and ethanol. These solvents do not quantitatively recover phospholipids. Malabsorption of dietary and biliary phosphatidylcholine could potentially result in choline deficiency. Therefore, the authors developed a method extracting and quantifying fecal phospholipids. METHODS: Fecal samples were collected for 72 hours from 18 children with cystic fibrosis and 10 control children. Fat was extracted first with hexane/diethyl ether/ethanol and then with chloroform/methanol. Total fat was quantitated gravimetrically. Phospholipids in extracted fat were separated and quantified using high-performance liquid chromatography with evaporative light-scattering detection (HPLC-ELSD). Phospholipid quantification was validated with a phosphomolybdate colorimetric assay. RESULTS: The combination of solvent systems used in this study significantly improved total fat (p < 0.05) and phospholipid (p < 0.001) extraction compared with either hexane/diethyl ether/ethanol or chloroform/methanol alone. Fecal phospholipid measured by HPLC-ELSD was significantly correlated with lipid-soluble phosphorous using the phosphomolybdate assay (r = 0.75, p < 0.001). This method also allows quantification of fecal phosphatidylcholine and lysophosphatidylcholine. CONCLUSIONS: Hexane/diethyl ether/ethanol followed by chloroform/methanol extraction of fecal samples and quantification of phospholipids using HPLC-ELSD is a new method for investigating phospholipid malabsorption.

Case-Control Studies↗
PubMed1989

Xanthine oxidase inhibitor in acute experimental pancreatitis in rats and mice.

It has been suggested that oxygen-derived free radicals play a decisive role in the pathogenesis of acute experimental pancreatitis in a model of edematous pancreatitis. Accordingly, allopurinol, a xanthine oxidase inhibitor, was shown to mitigate the development of nonfatal acute pancreatitis in ex vivo perfusion models using dogs. For further evaluation of allopurinol, its effect was studied in two forms of fatal necrotizing acute experimental pancreatitis: sodium taurocholate-induced pancreatitis in rats and choline-deficient ethionine-supplemented diet-induced pancreatitis in mice. Allopurinol did not affect the mortality rate, pancreatic enzyme elevation in serum and ascites, the enzyme content of the pancreas, or any parameter indicating histopathological damage in the pancreas. Although these experiments did not determine the role oxygen-derived free radicals play in the development of pancreatitis, they show, none the less, the absence of any beneficial therapeutic effect of a xanthine oxidase like allopurinol on the development of the disease once it has begun.

Acute Disease↗
PubMed1990

Growing pancreatic acinar cells (postpancreatitis and fetal) express a ductal antigen.

Monoclonal antibodies specific for luminal plasma membranes of acinar and duct cells of the exocrine pancreas were used to investigate changes in antigen expression during regeneration of the pancreas after acute pancreatitis and during fetal pancreatic development in mice. During regeneration after acute pancreatitis induced by supramaximal injections of cerulein or by a choline-deficient, ethionine-supplemented diet, morphologically identifiable acinar cells expressed the ductal antigen on their luminal surface, but at a lower level than this antigen is expressed on duct cells. As the pancreas regenerated, the ductal antigen was lost from acinar cells and was found only on duct cells. Characteristic tubular complexes formed in both pancreatitis models and were positive for the acinar antigen, demonstrating their acinar origin. In fetal pancreas, acinar cells between prenatal days 3 through 1, when zymogen granules were already abundant, expressed the duct-cell antigen on their luminal surface. By birth duct antigen was mostly present on ducts with only occasional label on acinar cells. The presence of a ductal antigen on acinar cells is associated with acinar-cell growth during regeneration and during fetal development and may reflect a less differentiated state.

Animals↗
PubMed1993

Effect of camostate administration for two weeks on experimental pancreatitis in mice and rats.

The present study investigates the effect of oral pretreatment with the protease inhibitor camostate on the outcome of pancreatitis in three experimental models. In pancreatitis induced by overstimulation with cholecystokinin (CCK) in rats, pancreatic enzymes and the histological degree of pancreatitis were quantified; in pancreatitis induced by a choline-deficient ethionine-supplemented (CDE) diet in mice, the effect on survival was monitored; and in bile-induced pancreatitis in rats, the effect on survival, pancreatic enzymes, and histology was studied. Feeding of camostate (200 mg/kg/day) for 2 weeks worsened the histological degree of pancreatitis induced by overstimulation with CCK or by injection of taurocholate. The concentration of amylase in the pancreas and in serum was significantly lower after pretreatment with camostate, both in cerulein-induced pancreatitis and in bile-induced pancreatitis, while the concentration of trypsin in the pancreas was significantly increased in the camostate-treated animals. Pretreatment with camostate significantly lowered survival. In pancreatitis induced by a CDE diet, 3 of 20 mice survived the observation period, while 9 of 20 control animals survived (p < 0.05). In taurocholate-induced pancreatitis, 5 of 29 rats were alive after 3 days versus 18 of 30 animals in the control group (p < 0.001). CCK levels were not elevated in camostate-treated rats, when pancreatitis was induced 24 h after finishing camostate feeding. It is concluded that camostate induced pancreatic hypertrophy and increased concentration of proteolytic enzymes aggravate experimental panceatitis and that this is not mediated by increased CCK levels.

Administration, Oral↗
PubMed1997

Chloroquine stabilizes pancreatic lysosomes and improves survival of mice with diet-induced acute pancreatitis.

Activation of digestive zymogens by lysosomal enzymes has been suggested as a triggering event in acute pancreatitis (AP). chloroquine (CQ), a weak base that accumulates in the lysosomes and increases their pH, can inhibit the activity of lysosomal enzymes. In the present study, we examined the effect of CQ on choline-deficient, ethionine-supplemented (CDE) diet-induced AP. CQ-diphosphate (15-50 mg.kg-1) or vehicle was given intraperitoneally at 0, 24, and 48 h to female CD1 mice that were fed with either normal diet or CDE diet. For mortality studies, animals were observed for 168 h. Serum and pancreas samples were collected from animals sacrificed 56 h after the start of the CDE diet. Treatment with CQ at 50 mg.kg-1 significantly (p < 0.05) improved the survival of mice with CDE diet-induced AP. In the normal pancreas, CQ decreased the specific activity of lysosomal enzymes cathepsin B1, beta-hexosaminidase, beta-glucuronidase, and acid phosphatase. In the pancreas with AP, CQ did not modify the activity of cathepsin B1, whereas it increased the latency of all enzymes. In conclusion, our results confirm the beneficial effect of CQ on survival of mice with CDE diet-induced AP and suggest that this effect of CQ may be due to its stabilizing action on lysosomes.

Acid Phosphatase↗
PubMed1997

Does recurrent acute pancreatitis lead to chronic pancreatitis? Sequential morphological and biochemical studies.

The pathogenesis of chronic pancreatitis (CP) has been debated as to whether it is a de novo process or the consequence of acute pancreatitis (AP). We investigated whether recurrent AP in rats leads to CP, by sequential morphological and biochemical studies. Thirty male Wistar rats were fed a choline-deficient diet with intraperitoneal ethionine injections twice daily at a dose of 60 mg/100 g body weight twice weekly, and six rats were killed at 4, 6, and 8 weeks; the remaining 12 rats, followed without further treatment, were killed at 12 and 16 weeks. The pancreata from study and control groups were examined by histology, immunohistochemistry, and bio- and immunoassays. Histologically, moderate to severe intra- and perilobular fibrosis and other CP-like lesions appeared maximally at 8 weeks. Immunohistochemically, the earliest extracellular matrix change was strong fibronectin staining at 4 weeks, with a progressive increase to 8 weeks. Collagens I and III came to show strong, and collagen IV moderate, interstitial staining at 6-8 weeks. These morphological changes, however, returned to nearly normal at 16 weeks. Prolyl hydroxylase was significantly elevated at 4 and 6 weeks and normalized after 8 weeks, with no significant change in collagenase. In conclusion, our results suggest that even severe CP-like lesions induced by recurrent AP are reversible in the absence of persistently elevated prolyl hydroxylase and/or suppressed collagenase. The mechanism regulating these changes remains to be studied further.

Acute Disease↗
PubMed2001

Neutrophils, not complement, mediate the mortality of experimental hemorrhagic pancreatitis.

Chemoactivation of the neutrophil (PMN) via the complement system has been observed in many inflammatory conditions and is thought to play a pathogenic role in acute pancreatitis. This study examined the effects of PMN depletion in experimental hemorrhagic pancreatitis and tested the role played by complement. Severe pancreatitis was induced by a choline-deficient, 0.5% ethionine-supplemented diet in female Institute of Cancer Research (ICR) mice weighing 11-13 g. Neutropenia was induced by an antibody injection. Total complement depletion was achieved by tail vein injections of cobra venom factor (CVF). Serum amylase levels and local pancreatic injury were not significantly modulated by either PMN or complement depletion at 72 hours. Systemic and remote organ injury, assessed by the formation of ascites, hematocrit, and serum alanine aminotransferase levels, was significantly reduced in neutropenic mice but failed to be moderated by complement depletion. In addition, liver and lung myeloperoxidase activity was independent of complement depletion. At 5 days, mortality was zero in PMN-depleted mice. There was no improvement in survival in the CVF-treated group. Neutrophils are important in the systemic injury and mortality of severe pancreatitis. PMN chemoactivation involves mechanisms other than complement.

Acute Disease↗
PubMed2002

Peptide YY improves local and systemic parameters and prevents death in lethal necrotizing pancreatitis.

INTRODUCTION: Peptide YY (PYY) is a gastrointestinal hormone with multiple inhibitory effects on the proximal digestive tract, including suppression of secretion by the exocrine pancreas. AIM: To determine whether peptide YY would reduce mortality in a lethal model of necrotizing pancreatitis by improving local and systemic parameters of this disease. METHODOLOGY: Necrotizing pancreatitis was induced in three groups of 30 mice by feeding a choline-deficient ethionine-supplemented diet. Osmotic pumps placed in 10 control mice delivered normal saline. In the two study groups, PYY was delivered at 200 pmol/kg/hr. The prophylactic group received PYY pumps at the onset; the therapeutic group received pumps 24 hours later. Ten mice from each group were followed to assess survival. Remaining mice were killed at 24, 48, 72, and 96 hours. Pancreata were graded on a nine-point histologic scale. Amylasemia was quantified by kinetic determination. Serum interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) values were determined by ELISA. RESULTS: Both prophylactic and therapeutic PYY significantly reduced mortality compared with that seen in controls ( p = 0.05 and p = 0.007). Five-day survival was 33% in controls, 80% in those receiving prophylactic PYY, and 100% in the therapeutic group. Amylasemia was reduced in the therapeutic group by day 3 ( p < 0.02) and in the prophylactic group by day 4 ( p < 0.01). Histologic changes mirrored those in serum amylase. Prophylactic and therapeutic administration of PYY suppressed early circulating levels of IL-6. CONCLUSION: PYY reduces mortality and improves local and systemic parameters in this murine model and may be of clinical benefit in the management of human necrotizing pancreatitis, particularly as this study demonstrates a clear survival benefit when PYY is given after the onset of disease.

Amylases↗
PubMed2002

Acute pancreatitis in transgenic mice expressing human group IIA phospholipase A2.

INTRODUCTION: There is circumstantial and contradictory evidence of the role of group IIA phospholipase A2 (PLA2) in acute pancreatitis. AIM: To examine the severity of acute experimental pancreatitis in transgenic mice expressing human PLA2 compared with mice not expressing PLA2. METHODS: The study involved 12 young female CB57/bl mice not expressing group IIA PLA2 (wild-type mice) and 12 transgenic female CB57/bl mice expressing human group IIA PLA2 (transgenic mice). A choline-deficient, 0.5% ethionine-supplemented diet induced acute pancreatitis for 72 hours after 12 hours of fasting. Mice were killed 4 and 10 days after induction of acute pancreatitis. Pancreas, lung, kidney, and liver were examined histologically, and apoptosis in pancreas and liver was evaluated by DNA nick-end labeling (TUNEL). RESULTS: On day 4, there were no significant differences in pancreatic apoptosis or total pancreatitis score. Liver damage was similar in both groups. On day 10, pancreatic damage was less but apoptosis more severe than on day 4, and neither hepatic damage nor apoptosis was seen. All mice expressing human group IIA PLA2 but none of the mice not expressing human group IIA PLA2 had marked pancreatic fibrosis. No significant pulmonary or renal damage was found at any time. CONCLUSION: Pancreatitis in mice expressing human group IIA PLA2 is not more severe than in normal mice. Expression of group IIA PLA2 per se is not a major determinant of severity in experimental acute pancreatitis.

Acute Disease↗
PubMed1993

A rat fatty liver transplant model.

A rat model of fatty liver transplantation has been developed to study primary nonfunction in fatty liver grafts. ACI rats were fed with a diet deficient in choline and methionine for 7, 14, 28, and 42 days. Fat content in the pretransplant livers was examined by gas chromatography and histology. The main constituent of the fatty droplets was determined to be triglyceride. The triglyceride concentration reached a maximum by day 14 and remained constant for an additional 28 days. Histology revealed an absence of necrosis in 14- and 28-day fatty livers but scattered hepatocytic necrosis and inflammation in 42-day fatty livers. After being given cold (UW stored, 4 degrees C) or warm (37 degrees C) ischemia, the fatty liver was orthotopically transplanted into normal ACI rats. The one-week survival of fatty liver grafts after 6, 12, 18, and 24 hr cold preservation was 5/5, 5/6, 3/8, 0/6 for 14-day fatty liver and 5/5, 4/6, 0/8, 0/6 for 42-day fatty livers. The survival of normal liver grafts was 5/5, 6/6, 5/9, 2/8, respectively. Increased survival rate was correlated with the absence of hepatocytic necrosis. The survival after 15 and 30 min warm ischemia prior to transplant was 5/5, 2/6 for normal liver grafts and 4/7, 0/6 for 28-day fatty liver graft, respectively. Fatty livers were less resistant to damage induced by cold or warm ischemia.

Animals↗
PubMed1999

Morphologic alteration of hepatocytes and sinusoidal endothelial cells in rat fatty liver during cold preservation and the protective effect of hepatocyte growth factor.

BACKGROUND: Fatty liver grafts are considered to be one of the main factors of primary nonfunctioning graft in transplantation. We investigated here, the hepatic damage during cold preservation in a rat fatty liver model by ultrastructural observation, and examined the effect of human recombinant hepatocyte growth factor (hrHGF) on amelioration of the cold-preserved graft condition. METHODS: Wistar rats were fed a choline-deficient diet (CDD) for 7 days. Livers were stored in cold University of Wisconsin (UW) solution for 0, 4, and 24 hr. We evaluated the ultrastructural alteration of the hepatocytes, sinusoidal architecture, and endothelial cells (SECs) by scanning and transmission electron microscopy. Ex vivo, we measured alanine aminotransferase (ALT) in first effluent as an index of hepatocyte injury and the hyaluronic uptake rate (HUR) as that of SEC damage. We injected hrHGF into rats fed CDD for 7 days through the portal vein and also added it to the UW solution to determine whether or not the agent ameliorated the hepatic damage in cold-preserved fatty livers. RESULTS: In rats fed CDD for 7 days, the lesion occupied by fat deposits appeared to enlarge with the duration of cold preservation leading to the disarrangement of sinusoidal architecture. Furthermore, sinusoidal endothelial damage, in which gaps, blebs, microvilli, and sinusoid denudation were detected, appeared to be more severe in these livers than in the corresponding control livers. ALT significantly increased in the 4-hr cold-preserved livers of rats fed CDD for 7 days. HUR decreased with 4-hr cold preservation and/or with CDD feeding. Administration of hrHGF prevented the expansion of fatty droplets and reduced SEC injury as detected by morphological observations. Increase of ALT in first effluent was inhibited to about one fourth the level observed in the 4-hr cold-preserved livers of rats fed CDD. Moreover, HUR significantly increased with the pretreatment of hrHGF. CONCLUSION: The hepatic injury in both hepatocytes and SECs in cold-preserved fatty liver graft developed more rapidly and severely than in the corresponding controls and demonstrated a protective effect of hrHGF.

Animals↗