Pancreatic Weight Research Articles

Protective effects of rhubarb on experimental severe acute pancreatitis.

To investigate the effects of rhubarb on severe acute pancreatitis (SAP) in rats. Severe acute pancreatitis was induced by two intraperitoneal injections of cerulein (40 microg/kg body weight) plus 5-h restraint water-immersion stress. Rhubarb (75-150 mg/kg) was orally fed before the first cerulein injection. The degree of pancreatic edema, serum amylase level, local pancreatic blood flow (PBF), and histological alterations were investigated. The effects of rhubarb on pancreatic exocrine secretion in this model were evaluated by comparing with those of somatostatin. In the Cerulein+Stress group, severe edema and diffuse hemorrhage in the pancreas were observed, the pancreatic wet weight (11.60+/-0.61 g/Kg) and serum amylase (458 490+/-43 100 U/L) were markedly increased (P<0.01 vs control). In the rhubarb (150 mg/kg) treated rats, necrosis and polymorphonuclear neutrophil (PMN) infiltration in the pancreas were significantly reduced (P<0.01), and a marked decrease (50%) in serum amylase levels was also observed (P<0.01). PBF dropped to 38% (93+/-5 mL/min per 100 g) of the control in the Cerulein+Stress group and partly recovered in the Cerulein+Stress+Rhubarb 150 mg group (135+/-12 mL/min per 100 g) (P<0.01). The pancreatic exocrine function was impaired in the SAP rats. The amylase levels of pancreatic juice were reduced in the rats treated with rhubarb or somatostatin, comparing with that of untreated SAP group. The bicarbonate concentration of pancreatic juice was markedly elevated only in the rhubarb-treated group (P<0.01). Rhubarb can exert protective effects on SAP, probably by inhibiting the inflammation of pancreas, improving pancreatic microcirculation, and altering exocrine secretion.

Calcineurin mediates pancreatic growth in protease inhibitor-treated mice.

CCK acts on pancreatic acinar cells to increase intracellular Ca(2+) leading to secretion of digestive enzymes and, in the long term, pancreatic growth. Calcineurin (CN) is a serine/threonine-specific protein phosphatase activated by Ca(2+) and calmodulin that recently has been shown to participate in the growth regulation of cardiac and skeletal myocytes. We therefore tested the effect of two different CN inhibitors, cyclosporine A (CsA) and FK506, on mouse pancreatic growth induced by oral administration of the synthetic protease inhibitor camostat, a known stimulator of endogenous CCK release. Mice were fed a powdered diet with or without 0.1% camostat. Pancreatic wet weight, protein, and DNA were increased in response to camostat in a time-dependent manner over 10 days in ICR mice but not in CCK-deficient mice. Both CsA (15 mg/kg) and FK506 (3 mg/kg) given twice daily blocked the increase in pancreatic wet weight and protein and DNA content induced by camostat. The increase in plasma CCK induced by camostat was not blocked by CsA or FK506. Camostat feeding also increased the relative amount of CN protein, whereas levels of MAPKs, ERKs, and p38 were not altered. In summary, 1) CCK released by chronic camostat feeding induces pancreatic growth in mice; 2) this growth is blocked by treatment with both CsA and FK506, indicating a role for CN; 3) CCK stimulation also increases CN protein. In conclusion, activation and possibly upregulation of CN may participate in regulation of pancreatic growth by CCK in mice.

Regulation of Hypoxia-Inducible Factor-1α, Vascular Endothelial Growth Factor, and Angiogenesis by an Insulin-Like Growth Factor-I Receptor Autocrine Loop in Human Pancreatic Cancer

Activation of the insulin-like growth factor-I receptor (IGF-IR) was recently shown to modulate angiogenesis by up-regulating the expression of vascular endothelial growth factor (VEGF). We hypothesized that inhibiting IGF-IR function would inhibit angiogenesis and growth of pancreatic cancer in vivo and sought to identify major signaling pathways regulated by IGF-IR in pancreatic cancer cells. Human pancreatic cancer cells (L3.6pl) were stably transfected with a dominant-negative form of IGF-IR (IGF-IR DN) or an empty vector (pcDNA). In vitro, IGF-IR DN cells exhibited a decrease in both constitutive and inducible phosphorylation of IGF-IR and Erk1/2. Constitutive expression of nuclear hypoxia-inducible factor-1alpha and secreted VEGF (P < 0.01) protein levels also were significantly lower in IGF-IR DN cells than in pcDNA cells. In vivo, IGF-IR inhibition led to decreases in pancreatic tumor volume and weight, vessel density, and tumor cell proliferation (P < 0.01 for all) and increases in tumor cell apoptosis (P < 0.02). Our results suggest that autocrine activation of the IGF-IR system significantly affects VEGF expression and angiogenesis in human pancreatic cancer. Thus, IGF-IR may be a valid target in the treatment of pancreatic cancer.

Candesartan, an angiotensin II receptor antagonist, suppresses pancreatic inflammation and fibrosis in rats.

Angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists attenuate fibrosis in the kidney, heart, and liver by suppressing transforming growth factor-beta1 mRNA and decreasing production of extracellular matrix proteins. We recently demonstrated that lisinopril, an angiotensin-converting enzyme inhibitor, alleviates pancreatic inflammation and fibrosis in male Wistar Bonn/Kobori rats. The involvement of angiotensin II receptor and its receptor interaction in the pathogenesis of spontaneous chronic pancreatitis was assessed in this model. Candesartan, an angiotensin II receptor antagonist, was administered in drinking water (10.5, 42, or 125 mg/l) to 10-week-old male WBN/Kob rats for 10 weeks and inflammatory parameters, fibrosis, and gene expression of renin-angiotensin system components and transforming growth factor-beta1 were assessed in the pancreas. Immunostaining for alpha-smooth muscle actin was also performed. Candesartan significantly suppressed decrease in pancreatic weight and increases in pancreatic myeloperoxidase activity, hydroxyproline content, ratio of fibrous tissue, histologic scores, and ratio of alpha-smooth muscle actin-positive cells (activated pancreatic stellate cells) at 20 weeks. The high dose enhanced the expression of angiotensinogen and angiotensin II receptor type 2 mRNA and suppressed the overexpression of transforming growth factor-beta1 mRNA. The conclusion is that candesartan alleviates chronic pancreatitis and fibrosis by suppressing the overexpression of transforming growth factor-beta1, resulting in prevention of activation of pancreatic stellate cells in male WBN/Kob rats. We propose that angiotensin II receptor type 1 antagonists may be useful for the treatment of chronic pancreatitis involving angiotensin II interaction with its receptor.

Effects of ethanol and folic acid consumption during pregnancy and lactation on basal enzymatic secretion in the duodenal juice of offspring rats

Objective Studies on duodenal juice enzyme activities were carried out on suckling Wistar rats born to dams given ethanol during gestation and suckling. The results were compared with offspring of dams given diets containing no ethanol. Comparisons were also made with offspring of dams given ethanol and folic acid supplementation to observe whether a folate supplement could sufficiently reverse the negative effect of ethanol consumption. Methods The dams were fed increased amounts of ethanol (5% to 20%, vol/vol) in tap water for 4 wk. The maximum quantity, 20% ethanol, was given to the dams during pregnancy and lactation. Offspring animals were randomized into three groups: control (CG), ethanol treated (EG), and ethanol plus folic acid (EFG). Results Body weight at birth and at 21 d after birth and pancreatic weight were lower in offspring after ethanol treatment. Folic acid supplement increased these parameters in the EFG. Under basal conditions, decreases in amylase, lipase, and chymotrypsin activities in the duodenal juice after ethanol treatment were detected. Serum and urine amylase activities also decreased in the EG and EFG. These changes were different in the ethanol-treated progenitors. In these progenitors, ethanol treatment increased serum amylase levels. In the offspring, amylase activities in the EFG decreased with respect to the CG; however, an increase in the EG was observed. In dams the folic acid supplement did not significantly alter the serum amylase activities. Lipase and chymotrypsin activities in the EFG were similar to those in the EG. An increase of serum and urine amylase in the EFG with respect to the EG was found. Conclusion Our findings indicated that, under basal conditions, ethanol treatment during gestation and lactation negatively affects the digestive function in offspring. The effects of ethanol were slightly attenuated in rats supplemented with folic acid for amylase activities. Although extrapolation from animal studies can be tenuous, the present findings may explain the use of folic acid in the prevention of damage induced by ethanol to increase the amylase levels to physiologic concentrations.

Anti-nutritional effects of a moderate dose of soybean agglutinin in the rat

This study was conducted to investigate the effects of a moderate dose of purified soybean agglutinin on performance and nitrogen digestibility in rats as well as to determine its effects on the protein, DNA and RNA content of the small intestine and pancreas. Twenty-four Sprague - Dawley rats were randomly allotted into one of four groups for a 10-day nitrogen balance experiment. The four groups of rats were fed 7 g of a casein-cornstarch based diet or a similar diet supplemented with 0.1, 0.2 or 0.4 mg/g purified soybean agglutinin. All experimental diets were adjusted to an identical nutrient level. Dose of soybean agglutinin had no significant effect on rat performance. Incorporation of soybean agglutinin in the diet reduced apparent protein digestibility and the utilization of dietary protein by increasing nitrogen loss from the faeces and urine. Fresh pancreatic weight increased in rats fed soybean agglutinin at a level of 0.4 mg/g in the diet compared to the control, but the dry pancreatic weight and the protein content of the pancreas did not differ among the four groups. However the DNA and RNA content of the pancreas had a tendency to increase with a higher level of soybean agglutinin. The weight of the jejunum and its protein, DNA and RNA content were not significantly affected by soybean agglutinin, but the dry weight and the RNA of the jejunum tended to increase with higher levels of soybean agglutinin in the diet. In conclusion, purified soybean agglutinin, at moderate levels in the rats diet, had negative effects on digestive function, such as nitrogen digestibility, nitrogen retention and nitrogen balance. As the level of soybean agglutinin increased, the effects became more pronounced. Meanwhile, hypertrophy of the pancreas was observed with higher doses of soybean agglutinin incorporation in the diets.

Pancreatic regeneration after ethionine-induced acute pancreatitis in rats lacking pancreatic CCK-A receptor gene expression.

We examined the effects of cholecystokinin (CCK) on the development of ethionine-induced pancreatitis and pancreatic recovery. We used Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model lacking pancreatic CCK-A receptor gene expression. Ethionine-induced pancreatitis was induced in the 7-week-old male OLETF rats and in a control group that does not lack the pancreatic CCK-A receptor, Long-Evans Tokushima Otsuka (LETO) rats. The two groups were maintained on a low-protein diet for 11 days. During the last 4 days of the low-protein diet, dl-ethionine 20 mg/100 g body weight was administered intraperitoneally once daily. Histologic and biochemical examinations of the pancreas were performed, and plasma CCK concentrations were measured on days 1, 4, and 7 after the last ethionine administration. Pancreatic histologic scores for inflammation, hemorrhage, and necrosis in the LETO and OLETF rats were highest on days 1 and 4, respectively. Pancreatic weight, DNA content, and protein level per DNA content in both groups decreased during the low-protein diet, and recovery signs were delayed in the OLETF rats. The highest plasma CCK concentrations in the LETO and OLETF rats were reached on days 1 and 4, respectively. Ethionine-induced pancreatitis developed in the OLETF rats, and their pancreatic regeneration was delayed in comparison to that in the LETO rats. Our results suggested that CCK plays an important role in the development of pancreatitis as well as in the pancreatic repair process.

The free radical scavenger edaravone suppresses experimental closed duodenal loop-induced acute pancreatitis in rats

Recent studies suggest that the enhanced release of reactive oxygen species (ROS) plays an important role in the pathogenesis of clinical acute pancreatitis. In the present study, we investigated the effects of the free radical scavenger edaravone, which is used clinically as an anti-stroke agent, in the development of experimental closed duodenal loop (CDL)-induced acute pancreatitis. In the CDL-pancreatitis model, after edaravone and vehicle saline were injected intravenously, pancreatitis was induced for 7 h by the CDL technique. The subsequent ascites volume, wet pancreatic weight, serum amylase levels, and pancreatic tissue lipid peroxide levels were evaluated. Pancreatic tissue damage was also evaluated histologically. In this CDL-induced pancreatitis model, edaravone treatment tended to reduce the ascites volume and inhibit the increases in the wet pancreatic weight. Edaravone also tended to reduced the microscopic mucosal damage scores and pancreatic tissue lipid peroxide levels. In particular, the serum amylase levels in the edaravone-treated rats (1-20 mg/kg i.v.) were significantly reduced as compared to the vehicle-treated rats. These results strongly support the involvement of ROS in the pathogenesis of CDL-induced acute pancreatitis and cytoprotective effects of free radical scavender against pancreatic acinar cells. A clinical effect for edaravone against acute pancreatitis is strongly expected.

Differential mechanism and site of action of CCK on the pancreatic secretion and growth in rats.

Recent studies demonstrated that cholecystokinin (CCK) at physiological levels stimulates pancreatic enzyme secretion via a capsaicin-sensitive afferent vagal pathway. This study examined whether chemical ablation of afferent vagal fibers influences pancreatic growth and secretion in rats. Bilateral subdiaphragmatic vagal trunks were exposed, and capsaicin solution was applied. Pancreatic wet weight and pancreatic secretion and growth in response to endogenous and exogenous CCK were examined 7 days after capsaicin treatment. Perivagal application of capsaicin increased plasma CCK levels and significantly increased pancreatic wet weight compared with those in the control rats. Oral administration of CCK-1 receptor antagonist loxiglumide prevented the increase in pancreatic wet weight after capsaicin treatment. In addition, continuous intraduodenal infusion of trypsin prevented the increase in plasma CCK levels and pancreatic wet weight after capsaicin treatment. There were no significant differences in the expression levels of CCK-1 receptor mRNA and protein in the pancreas in capsaicin-treated and control rats. Intraduodenal administration of camostat or intravenous infusion of CCK-8 stimulated pancreatic secretion in control rats but not in capsaicin-treated rats. In contrast, repeated oral administrations of camostat or intraperitoneal injections of CCK-8 significantly increased pancreatic wet weight in both capsaicin-treated and control rats. Present results suggest that perivagal application of capsaicin stimulates pancreatic growth via an increase in endogenous CCK and that exogenous and endogenous CCK stimulate pancreatic growth not via vagal afferent fibers but directly in rats.

Treatment for hyperglycemia promotes pancreatic regeneration in rats without CCK-1 receptor gene expression.

Recent studies have suggested that CCK is not essential for normal pancreatic growth in mice. We examined whether the treatment of hyperglycemia participates in a non-CCK-1-receptor-mediated mechanism of pancreatic regeneration after partial (30%) pancreatectomy (Px) with use of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model for type 2 diabetes mellitus without CCK-1 receptor gene expression. Male OLETF rats were divided into five groups at 24 weeks of age. The first group was killed to examine the pancreas at 24 weeks of age (PrePx). The second group underwent a midline laparotomy and received a standard rat chow (ShamPx). The remaining three groups of rats received one of the following three treatments after Px: a standard rat chow (PxC), a diet containing acarbose (PxA), or a standard rat chow and once-daily subcutaneous injection of insulin (PxI) for 8 weeks. PxC rats had significantly higher serum glucose levels than did PxA and PxI rats. Pancreatic weight and pancreatic contents of protein in PxA and PxI rats were significantly higher than in PxC rats. The pancreas in PxC rats was atrophic, and marked inflammatory cell infiltration was observed in the pancreas. In addition, tumor necrosis factor-alpha (TNFalpha) was expressed in the inflammatory cells, acinar cells, and islets in PxC rats. However, histologic alterations, including expression of TNFalpha, remained at a minimum in PxA and PxI rats. We conclude that the control of serum glucose levels plays an important role in preventing pancreatic atrophy and participates in the non-CCK-1-receptor-mediated mechanisms of pancreatic growth in rats.

Angiotensin-converting enzyme inhibitor attenuates pancreatic inflammation and fibrosis in male Wistar Bonn/Kobori rats

Background & Aims: Pancreatic stellate cells have some similarities to hepatic stellate cells and an intrinsic renin-angiotensin system is present in the pancreas and is enhanced in acute pancreatitis and chronic pancreatic hypoxia. We assessed the effects of lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, on spontaneously occurring chronic pancreatitis. Methods: Lisinopril in drinking water (20, 50, or 200 mg/L) was administered to 10-week-old male Wistar Bonn/Kobori (WBN/Kob) rats for 10 weeks and then the inflammatory parameters, fibrosis, serum and pancreatic ACE activity, and expression of transforming growth factor-β1 (TGF-β1) messenger RNA (mRNA) as well as positive immunostaining for α-smooth muscle actin (α-SMA) were assessed. Results: Lisinopril attenuated gross alterations in the pancreas. This protective effect was confirmed quantitatively by significant increases in pancreatic weights and decreases in pancreatic myeloperoxidase (MPO) activity (an index of granulocyte infiltration), pancreatic hydroxyproline content (an index of collagen deposition), ratio of fibrous tissue, and histologic scores. Lisinopril significantly reduced serum ACE activity but it did not affect pancreatic activity. High doses of lisinopril suppressed the overexpression of TGF-β1 mRNA measured by reverse-transcription polymerase chain reaction (RT-PCR) and decreased the number of α-SMA-positive cells (activated pancreatic stellate cells) in the pancreas. Conclusions: Lisinopril alleviated chronic pancreatitis and fibrosis in male WBN/Kob rats. It suppressed the expression of TGF-β1 mRNA, resulting in the prevention of pancreatic stellate cell activation, which may be involved in the observed protection. We propose that an ACE inhibitor may be useful for treating chronic pancreatitis.

Effects of early decompression and cholecystokinin inhibition in rats with acute pancreatitis induced by bile-pancreatic-duct obstruction

Biologic data related to pancreatic regeneration and acinar-cell homeostasis after ductal decompression would be useful in clinical settings to elucidate the time at which obstructions in human biliary acute pancreatitis (AP) should be removed. Our aim was to evaluate the outcome of AP after early removal of bile-pancreatic-duct obstruction (BPDO) and to ascertain whether cholecystokinin (CCK) blockade accelerates recovery from the disease. We conducted analysis of apoptosis and cell cycle, as well as measurements of enzyme and calcium load, in acinar cells using flow cytometry to ascertain the capability of the pancreas to regain its function after AP. Male Wistar rats were subjected to AP by means of BPDO for 6 hours and 24 hours. In other groups, the BPDO was opened 24 hours after induction; 3 days and 7 days later they were killed. Half of the rats in which the BPDO was opened were administered L364,718, a CCK-receptor antagonist (0.1 mg/kg/12 hours), 30 minutes before the induction of BPDO. Plasma amylase activity, hematocrit, and pancreatic weight returned to control values after BPDO opening. The highest degree of oxidative stress was found in the pancreases of rats subjected to BPDO for 6 hours, as indicated by the decrease in pancreatic glutathione content, but it was not restored 7 days after BPDO opening. Cell-cycle distribution, as measured with propidium iodide DNA staining, showed increases in the proportion of acinar cells in S-phase from 3 days after BPDO opening in L364,718-treated and nontreated rats. Annexin V-fluorescein isothiocyanate labeling revealed deletion of acinar cells by way of apoptosis 3 days after BPDO opening. However, it may be compensated 7 days after BPDO opening because regardless of whether rats were treated with L364,718, significant increases in synthesis and mitosis were detected. Accumulation of digestive enzymes and calcium in acinar cells was found during BPDO, but this appeared to have normalized 3 days after BPDO opening and onward in both L364,718-treated and nontreated rats. In conclusion, early removal of obstruction allowed rapid cell proliferation and prevented the progression of severe alterations within acinar cells induced by BPDO. CCK blockade does not accelerate pancreatic recovery after BPDO opening.

Effect of IS-741 on ethionine-induced acute pancreatitis in rats: relation to pancreatic acinar cell regeneration.

Tissue destruction arising from neutrophil infiltration of the pancreas and other organs in acute pancreatitis is supposed to be suppressed by IS-741. We studied the effect of IS-741 on acute pancreatitis induced by DL-ethionine in rats. Rats fed with a low protein diet for 11 days received daily intraperitoneal administration of DL-ethionine (20 mg/100 g) for the last 4 days of the diet. To evaluate the therapeutic effect on ethionine-induced pancreatitis, IS-741 (10 mg/kg s.c.) was administered every 8 h beginning after the second ethionine injection (IS group). An equal volume of saline was used for control rats as alternative to IS-741 (control group). The rats were killed 1, 3, 5, and 7 days after the last injection of ethionine. Blood was collected to measure concentrations of the inflammatory cytokine, interleukin-8. Histologic and biochemical examinations of the pancreas were performed. The pancreatic weight, DNA content, and protein levels were determined. The pancreas was histologically examined. Pancreatic tissue in the control group showed marked infiltration of inflammatory cells, and acinar cell necrosis was widespread 1 day after the last injection of ethionine (day 1). The severity of acute pancreatitis was alleviated in rats treated with IS-741 (IS group). Pancreatic wet weight and DNA content in the IS group were higher than those in the control group on day 1. Pancreatic protein level per DNA in the IS group was higher than that in the control group on day 7. The plasma interleukin-8 level in the control group was higher than that in the IS group on day 5. Therapeutic administration of IS-741 ameliorated ethionine-induced acute pancreatitis in rats, and IS-741 could be a useful drug to treat patients with severe acute pancreatitis.

Duodenal-preserving resection of the head of the pancreas and pancreatic head resection with second-portion duodenectomy for benign lesions, low-grade malignancies, and early carcinoma involving the periampullary region.

Duodenal-preserving resection of the head of the pancreas (DPRHP) and pancreas head resection with segmental duodenectomy (PHRSD) can be alternatives to standard pancreaticoduodenectomy for benign periampullary lesions. Retrospective analysis of patients requiring surgery for benign and borderline malignant tumors of the periampullary region. Tertiary care referral center. Duodenal-preserving resection of the head of the pancreas (n = 8) and PHRSD (n = 7) were performed in 15 patients with a preoperative diagnosis of benign and borderline malignant tumors of the periampullary region (ie, 11 pancreas head lesions [2 intraductal papillary mucinous tumors, 4 serous cystadenomas, 2 insulinomas, 1 epidermal cyst, 1 metastatic renal cell carcinoma, 1 nonfunctioning islet cell tumor/parapaillary] and 4 duodenal lesions [3 adenomas and 1 adenocarcinoma]). Surgical factors (operation time and blood loss), postoperative complication, postoperative pancreatic insufficiency (eg, development of diabetes mellitus and steatorrhea or elevated stool elastase values), weight change, and recurrence of disease. No differences were noted in the mean operation time and estimated blood loss between the 2 procedures. Major postoperative complication constituted the following: bile duct stricture (n = 1) in DPRHP and delayed gastric emptying (n = 1) and postoperative bleeding (n = 1) in PHRSD. Newly developed diabetes mellitus occurred in 1 patient. Exocrine pancreatic insufficiency (steatorrhea) was observed in 1 patient after PHRSD. Patients with early duodenal carcinoma and intraductal papillary mucinous tumors with a borderline malignancy are still alive without evidence of recurrence. There was no hospital or long-term mortality. Duodenal-preserving resection of the head of the pancreas is recommended first for a benign or low-grade, early malignant pancreatic head lesion; PHRSD can be an option for a lesion of the ampullary-parapapillary duodenal area as well as the pancreatic head. Duodenal-preserving resection of the head of the pancreas can be converted to PHRSD if ischemia of the second portion of the duodenum occurs. We found benign periampullary lesions could be conservatively treated with DPRHP and PHRSD, which could substitute for classic pancreaticoduodenectomy.

A mouse model of severe acute pancreatitis induced with caerulein and lipopolysaccharide

To establish a non-traumatic, easy to induce and reproducible mouse model of severe acute pancreatitis (SAP) induced with caerulein and lipopolyasccharide (LPS). Thirty-two healthy mature NIH female mice were selected and divided at random into four groups (each of 8 mice), i.e., the control group (NS group), the caerulein group (Cn group), the lipopolysaccharide group (LPS group), and the caerulein+LPS group (Cn+LPS group). Mice were injected intraperitoneally with caerulein only, or LPS only, and caerulein and LPS in combination. All the animals were then killed by neck dislocation three hours after the last intraperitoneal injection. The pancreas and exo-pancreatic organs were then carefully removed for microscopic examination. And the pancreatic acinus was further observed under transmission electron microscope (TEM). Pancreatic weight, serum amylase, serum nitric oxide (NO) concentration, superoxide dismutase (SOD) and malondialdehyde (MDA) concentration of the pancreas were assayed respectively. (1) NS animals displayed normal pancreatic structure both in the exocrine and endocrine. In the LPS group, the pancreas was slightly edematous, with the infiltration of a few inflammatory cells and the necrosis of the adjacent fat tissues. All the animals of the Cn group showed distinct signs of a mild edematous pancreatitis characterized by interstitial edema, infiltration of neutrophil and mononuclear cells, but without obvious parenchyma necrosis and hemorrhage. In contrast, the Cn+LPS group showed more diffuse focal areas of nonviable pancreatic and hemorrhage as well as systemic organ dysfunction. According to Schmidt's criteria, the pancreatic histologic score showed that there existed significant difference in the Cn+LPS group in the interstitial edema, inflammatory infiltration, parenchyma necrosis and parenchyma homorrhage in comparison with those of the Cn group, LPS group and NS group (P<0.01 or P<0.05). (2) The ultrasturcture of acinar cells was seriously damaged in the Cn+LPS group. Chromatin margination of nuclei was present, the number and volume of vacuoles greatly increased. Zymogen granules (ZGs) were greatly decreased in number and endoplasmic reticulum exhibited whorls. The swollen mitochondria appeared, the crista of which was decreased in number or disappeared. (3) Pancreatic weight and serum amylase levels in the Cn +LPS was significantly higher than those of the NS group and the LPS group respectively (P<0.01 or P<0.05). However, the pancreatic wet weight and serum amylase concentration showed no significant difference between the Cn+LPS group and the Cn group. (4) NO concentration in the Cn+LPS group was significantly higher than that of NS group, LPS group and Cn group(P<0.05 or P<0.01). (5) The SOD and MDA concentration of the pancreas in the Cn+LPS group were significantly higher than those of NS, LPS and Cn groups (P<0.05 or P<0.01). The mouse model of severe acute pancreatitis could be induced with caerulein and LPS, which could be non-traumatic and easy to induce, reproducible with the same pathological characteristics as those of SAP in human, and could be used in the research on the mechanism of human SAP.

Effect of dietary protein level, amino acid balance and feeding level on growth, gastrointestinal tract, and mucosal structure of the small intestine in broiler chickens

In a factorial experiment, two series of feeds containing excess dietary protein, differing in amino acid balance (i.e. balanced (BPS) and unbalanced (UPS) amino acid mixture), and with a range of protein contents (400, 300 and 200 g CP·kg -1 ) at the same energy content of 13 MJ AME·kg -1 were offered at two levels of feeding (ad libitum or 0.75 of ad libitum intake) to 4320 broiler chickens between 10 and 24 days of age. Growth rate was significantly lowered by feed restriction. There was also a significant (P < 0.001) effect of dietary protein on the combined weight of the proventriculus and gizzard but only for the birds on the restricted feeding regime. Relative pancreatic weight in- creased (P < 0.001) with an increase in dietary protein level for the birds fed restricted amounts of BPS. The crypt depth of chicks on the ad libitum feeding regime was higher (P < 0.01) for the chicks on the BPS than for those on the UPS diet. The protein content of the jejunal mucosa was higher (P < 0.001) for birds fed ad libitum on the UPS diet than on the BPS diet. Daily feed allocation had a significant (P < 0.01) effect on jejunal protein content in birds that received the BPS diet, this being reduced in birds on restricted feeding. Maltase (P < 0.001) and sucrase (P < 0.01) activities were sig- nificantly reduced in chicks offered ad libitum access to the UPS diet. At high dietary CP, the specific activity of alkaline phosphatase was lower (P < 0.001) in chicks on the UPS diet than in those fed the BPS diet.

Cerulein-induced acute pancreatitis in the rat is significantly ameliorated by treatment with MEK1/2 inhibitors U0126 and PD98059.

Both cerulein and cholecystokinin activate mitogen-activated protein (MAP) kinase (ERK1/2) in vivo and in isolated pancreatic acini. ERK1/2 in pancreas homogenates was activated in rats rendered pancreatitic by subcutaneous injections of cerulein (5 microg/kg per hour). To determine if blocking ERK1/2 activity might rescue cerulein-induced acute pancreatitis, the "MAP kinase kinase" (also known as MEK1/2) inhibitors PD98059 and U0126 were administered in vivo. In rats pretreated with PD98059 (10 mg/kg per i.v. injection) or U0126 (5 mg/kg per i.v. injection) 30 minutes before and then together with hourly cerulein injections for 3 hours, pancreatitis was significantly attenuated on the basis of pancreatic wet weight and histology. Serum amylase concentration was significantly reduced when PD98059 was administered intraperitoneally (10 mg/kg per intraperitoneal injection). PD98059 also ameliorated pancreatitis over a 6-hour cerulein time course. The phosphorylation of pancreatic ERK1/2 was attenuated in PD98059- and U0126-treated animals at both 30 minutes and 3 hours after cerulein injection. Rats rendered neutropenic with vinblastine and pretreated with U0126 still showed attenuated manifestations of cerulein-induced acute pancreatitis, a finding suggesting that pancreatic ERK1/2 is mostly responsible for the effect, rather than infiltrating neutrophils. Inhibition of pancreatic ERK1/2 in vivo affords significant protection against inflammatory sequelae following cerulein-induced acute pancreatitis.

Preterm Birth Affects the Intestinal Response to Parenteral and Enteral Nutrition in Newborn Pigs

Maturation of gastrointestinal (GI) function in neonates is stimulated by enteral nutrition, whereas parenteral nutrition induces GI atrophy and malfunction. We investigated whether preterm birth alters the GI responses to parenteral and enteral nutrition. Pigs were delivered either preterm (107 d gestation) or at term (115 d gestation) and fed total parenteral nutrition (TPN) or enteral sow's milk (ENT) for 6 d after birth. Immaturity of the preterm pigs was documented by reduced blood pH, oxygen saturation and neutrophil granulocyte function, impaired intestinal immunoglobulin G uptake from colostrum, and altered relative weights of visceral organs (small intestine, liver, spleen, pancreas, and adrenals). For both ages at delivery, increases occurred in pancreatic weight (30-75%) and amylase activity (0.5- to 13-fold) after birth, but much more in ENT than in TPN pigs (P < 0.05). Six days of TPN feeding was associated with reduced intestinal weight for both delivery groups (60% of values in ENT, P < 0.001), but only in term TPN pigs was the weight lower than at birth (-20%, P < 0.05). Likewise, it was only in term TPN pigs that intestinal maltase activity increased, compared with ENT, and the absorption of glucose and proline decreased. Only in preterm pigs did TPN feeding increase lactase activity (+50% compared with ENT, P < 0.05). For both delivery ages, the mRNA of lactase-phloridzin hydrolase and sodium-coupled glucose transporter 1 (SGLT-1) were increased in TPN, compared with ENT. In conclusion, the trophic effect of enteral vs. parenteral nutrition on the GI tract is also present after preterm birth, but the postnatal maturation of many GI functions is modified, compared with term birth. The effects of nutritional regimen on the maturation of the gut epithelium in neonates depend on gestational age at birth.

Dietary lectins can stimulate pancreatic growth in the rat.

Lectins are proteins or glycoproteins of nonimmune origin, which bind specifically to carbohydrate structures. They are widespread in the human diet, and many are resistant to digestion. High doses of lectins have been shown to stimulate intestinal and pancreatic growth. The aim of the present study was to investigate the long-term actions of low doses of lectins on the rat intestine and pancreas. A long-term carcinogenesis study was performed using low levels (40 micro g/rat/day) of peanut (PNA) or mushroom lectin (ABA) which bind to O-linked (mucin-type) oligosaccharides in the gut. While this was primarily designed as a colon carcinogenesis study, the pancreas was also investigated. No significant changes in colon carcinogenesis were seen, however, the colons were slightly heavier in the lectin treated groups. The weight of the pancreas was significantly greater (by 18 and 23%) in both lectin treated groups (P < 0.03/0.001). The weights of the acini and septal tissue were also increased by 39-46% in PNA and ABA fed animals, respectively (P < 0.002); there was no significant change in the endocrine pancreas. In conclusion, long-term feeding of low doses of lectin can influence pancreatic growth, and this trophic action may have potential adverse implications for the development of pancreatic cancer in humans.

Neonatal hypoxia in the rat: effects on exocrine pancreatic development.

Glucocorticoids profoundly affect pancreatic development during the suckling period. Increases in circulating glucocorticoids during exposure to hypoxia may alter the normal pattern of pancreatic enzyme development. Rats were exposed to hypoxia from birth to 7 days (suckling) or from 28 to 35 days of age (weaned at day 21). Hypoxia in neonatal rats (0-7 days) led to decreased pancreatic weight, and trypsin, lipase, and amylase activity compared with normoxic controls. In contrast, rats exposed to hypoxia from 28 to 35 days of age had decreased lipase activity but no change in other pancreatic parameters. Two weeks after hypoxia (0-7 days) pups were returned to normoxia, and their body weights remained smaller than the age-matched, previously normoxic controls. Pancreatic enzyme activities were decreased in the group recovering from hypoxia compared with controls. Recovery of enzyme activities was observed 3 weeks after hypoxic rats were returned to normoxia. Normoxic pups were given dexamethasone to simulate the hyperglucocorticoid state in hypoxia at 7-day olds. Dexamethasone administration led to decreased body weight, but increased pancreatic weight and enzyme activity compared with normoxic, age-matched controls. Hypoxia in newborn rats delays the maturation of pancreatic exocrine enzymes. The mechanism is not related to increased serum glucocorticoids.