Exogenous melatonin treatment reduces hepatocyte damage in rats with experimental acute pancreatitis

Background/purpose

The hormone melatonin affects cellular immunity in particular and the immune system in general both directly and indirectly. We report our evaluation of the effects of decreasing and increasing serum melatonin levels on hepatocyte damage in rats with experimental acute pancreatitis.

Methods

Winstar Albino rats with experimentally induced acute pancreatitis were divided into three groups of ten rats each: (1) control (induced acute pancreatitis only); (2) rats with induced acute pancreatitis plus surgical pinealectomy (no melatonin injections); (3) rats with induced acute pancreatitis plus injections of exogenous melatonin. The effects of melatonin levels were evaluated using biochemical and histopathological parameters.

Results

Rats undergoing the pinealectomy had increased amylase and lactate dehydrogenase (LDH) levels, while those receiving injections of exogenous melatonin had decreased amylase, aspartate transaminase, LDH, and bilirubin levels but increased levels of alanine transferase levels.

Conclusion

Melatonin may have a therapeutic or protective effect on acute pancreatitis and obstructive jaundice.     

Effect of early antibiotic prophylaxis with ertapenem and meropenem in experimental acute pancreatitis in rats

Background

The clinical course in acute necrotizing pancreatitis is mainly influenced by bacterial infection of pancreatic and peripancreatic necrosis. The effect of two antibiotic treatments for early prophylaxis was studied in the taurocholate model of necrotizing pancreatitis in the rat.

Methods

Sixty male Sprague-Dawley rats were divided into three pancreatitis groups (15 animals each) and a sham-operated group (15 animals, control group). Pancreatitis was induced by intraductal infusion of 3% taurocholate under sterile conditions. Animals were placed on one of two different antibiotic regimens (15 mg/kg ertapenem or 20 mg/kg meropenem, one shot) after the induction of pancreatitis or received no antibiotics (control). All animals were sacrificed after 24 h to study pancreatic and extrapancreatic infection.

Results

Early antibiotic prophylaxis with either erapenam or meropenem significantly decreased pancreatic infection from 12/15 (control group) to 4/15 (ertapenem antibiotic group) and 3/15 (meropenem antibiotic group) (P < 0.05).

Conclusions

In our animal model of necrotizing pancreatitis, early antibiotic prophylaxis with ertapenem and meropenem reduced bacterial infection of the pancreas. The efficacy of early antibiotic prophylaxis with ertapenem in the clinical setting should be subject to further research.     

Protective effect of antithrombin III in acute experimental pancreatitis in rats

In the present study we investigated the therapeutic action of antithrombin III (AT III) in taurocholate-induced experimental pancreatitis with high lethality in rats. High-dose AT III treatment greatly improved the survival rate not only when given as pretreatment but also when given 2 hr after induction. No favorable effect on survival rate was observed on administration after 5 hr. Both intravascular and intraperitoneal AT III administration locally restored decreased AT III levels in the peritoneal cavity and increased plasma AT III to supranormal levels. The primary pancreatic insult seemed to be unaffected by the treatment, because neither the rise in plasma lipase nor the development of ascites or the extension of the pancreatic necrosis were diminished. Because heparin pretreatment of the rats was also effective, the mechanism of the beneficial action was probably mediated by inhibition of the proteases of the coagulation cascade, thereby preventing intravascular coagulation in the pancreas and distant organs and subsequent systemic complications. The high efficacy of AT III treatment in this experimental model may stimulate clinical studies evaluating the efficacy of AT III treatment in an early stage of acute pancreatitis.     

Effect of urinary trypsin inhibitor on pancreatic cellular and lysosomal fragility in cerulein-induced acute pancreatitis in rats

We evaluated the protective effect and the mechanism of action of the trypsin inhibitor, urinastatin, extracted from human urine, in experimental acute pancreatitis induced by a supramaximal dose of cerulein (5 g/kg/hr for 3.5 hr). Urinastatin in a dose of 10,000 units/kg/hr was given by three different methods of continuous infusion: (1) 2 hr before and during cerulein infusion, (2) only during cerulein infusion, and (3) starting 1 hr after the beginning of cerulein infusion and continued for 3.5 hr. In protocol 1 and 2 urinastatin was significantly more protective than in 3. In protocol 1 urinastatin was very protective in all parameters tested (serum amylase level, pancreatic water and amylase content, distribution of lysosomal enzymes, cellular and lysosomal fragility). These results suggest that the administration of urinastatin before and during cerulein infusion may suppress the pathogenesis and evolution of pancreatitis by inhibiting the chain reaction of pancreatic enzyme activation closely related to redistribution of lysosomal enzyme and lysosomal fragility.     

MRI shows clodronate-liposomes attenuating liver injury in rats with severe acute pancreatitis

BACKGROUND:Studies have revealed that macrophages play an important role in the development of severe acute pancreatitis(SAP).Activated macrophages can lead to a systemic inflammatory response,induce lipid peroxidation,impair membrane structure,result in injury to the liver and the other extrahepatic organs,and eventually result in multiple organ dysfunction syndrome by promoting excessive secretion of cytokines.Liver injury can further aggravate the systemic inflammatory response and increase mortality by ...     

实验性重症急性胰腺炎细胞因子的变化规律

目的：探讨重症急性胰腺炎（severe acute pancreatitis,SAP)大鼠模型细胞因子的变化规律及其与病情严重度的关系。方法：胰管内塑行注射5％牛磺胆酸钠的方法建立SAP大鼠模型于制模后不同时间获取标本，检测模型大鼠血清中IL－2、IL－8、IL－10、TNF－α的浓度变化。淀粉酶测定采用碘比色法，细胞因子的测定采用ELISA法。结果：制模后大鼠腹水量逐渐增多（由0至14．50ml),胰腺病变评分由0递增至12h的12．83。血和腹水淀粉酶随发病时间而递增。TNF－α、IL－8、IL－10假手术组的浓度很低，制模后上升，第4、5h达到高峰（分别为532．73pg/ml,360.93pg/ml,193.12pg/ml)。IL－2假手术组为297．22pg/ml，模型组制模后1h为209．88pg/ml，后逐渐降低，12h为46．16pg/ml。讨论：大鼠SAP发病后，IL－2浓度随胰腺病变的加重逐渐降低，TNF－α、IL－8、IL－10则逐渐上升，在达到高峰后下降。细胞因子的变化影响了SAP病变的严重度，并随病变严重度的变化而变化。     

Effects of emodin and baicalein on rats with severe acute pancreatitis

AIM: To investigate the therapeutic effects of emodin in combination with baicalein on severe acute pancreatitis (SAP) rats and to explore the mechanism of SAP. METHODS: A total of 112 SAP rats induced by retrograde injection of 5% sodium taurocholate into the biliary-pancreatic duct, randomly assigned to a untreated group and three treated groups emodin group, combined emodin and baicalein group, and sandostatin group. Meanwhile, another 28 other rats were selected as sham operation (SO) group. There were 28 rats in each group, 8 rats were in 3 and 6 h groups respectively, and 12 rats in 12 h group. At each time-points, survival rates,ascites volumes, pathological lesion scores of pancreas tissues,serum amylase, tumor necrosis factor-α and IL-6 levels were determined as the indexes of therapeutic effects. RESULTS: The survival rate at 12 h was significantly higher in three treated groups than in untreated group.The ascites volume at 12 h was remarkably less in combined and sandostatin groups than in emodin group,but there was no difference between combined group and sandostatin group (P>0.05). Serum amylase levels at all time-points were significantly lower in three treated groups than in untreated group. However, they had no difference among treated groups (P>0.05).Serum TNF-α were lower in three treated groups than in untreated group at all time points. Among the three treated groups, at 6 h, the TNF-α levels of combination and sandostatin groups were lower than those of emodin group. These was no difference between combined and sandostantin. Serum IL-6 concentration at 3 h were lower in combined and sandostatin groups than in untreated group, but at 6 and 12 h they were lower in all treated groups than in untreated group and the combined and sandostatin groups and in emodin group, no difference was found between combined and sandostatin groups at all time-points (P>0.05). The pathological scores of pancreas at all time points were significantly lower in three treated groups than in the untreated group, and at 6, 12 h, the scores of combined and sandostatin groups were lower than in emodin group. There was no difference between combined and sandostatin groups (P>0.05). CONCLUSION: Combination of emodin with baicalein has significant therapeutic effects on SAP rats.     

Chronic alcohol consumption intensifies caerulein-induced acute pancreatitis in the rat

Rats were chronically fed either an ethanol-containing diet (36% of total calories derived from alcohol) or a pair-fed, control diet (no alcohol) for 8 wk, and acute pancreatitis (AP) was subsequently induced by a 3-h iv infusion of caerulein (CR) at a dose of 5 μg/kg/hr. CR-induced AP in control rats (no alcohol) was characterized by a significant elevation in serum lipase content, pancreatic interstitial edema, infrequent occurrences of karyorrhexis, and the appearance of vacuoles in acinar cells. Chronic feeding of the ethanol diet followed by treatment with CR resulted in increases in serum lipase content, interstitial edema, karyorrhexis, and acinar vacuolization that were significantly greater than that seen in rats fed the control diet and treated with CR. It is concluded that chronic ethanol intake in the rat intensifies AP that is subsequently induced by CR.     

血浆花生四烯酸代谢紊乱在大鼠急性胰腺炎肝脏损害发病机理中的作用

目的探讨急性胰腺炎肝脏受损与血浆花生四烯酸紊乱的关系．方法同时观察不同程度急性胰腺炎大鼠（ｎ＝１４０）肝脏受损情况和血浆花生四烯酸代谢产物血栓素Ｂ２（ＴＸＢ２）和６酮前列腺素Ｆ１α（６ｋｅｔｏＰＧＦ１α）的变化关系，并对急性胰腺炎时大鼠胰腺和肝脏组织病理学观察．结果发现急性出血坏死性胰腺炎大鼠肝脏发生明显病变，其程度与胰腺病理程度一致，急性出血坏死性胰腺炎时血浆ＴＸＢ２从对照组的１２１ｎｇ／Ｌ±２７ｎｇ／Ｌ上升至ＡＰ后２ｈ的３９９ｎｇ／Ｌ±１３１ｎｇ／Ｌ和４ｈ的６０７ｎｇ／Ｌ±１７４ｎｇ／Ｌ（Ｐ＜００１），ＴＸＢ２／６ｋｅｔｏＰＧＦ１α异常（Ｐ＜００１），而ＴＸＢ２／６ｋｅｔｏＰＧＦ１α比值变化与肝脏病理变化呈正相关（ｒｓ＝０８８９７，Ｐ＜００１）．通过异搏定治疗可明显改善胰腺病理损害和稳定血浆花生四烯酸代谢，明显减轻肝脏的损害．结论急性胰腺炎伴发的肝脏损害的发生发展与血浆花生四烯酸代谢紊乱有关     

血必净对大鼠重症急性胰腺炎的治疗作用

目的:探讨血必净对大鼠重症胰腺炎(severe acute pancreatitis,SAP)的治疗作用.方法:经十二指肠乳头逆行胆胰管注射3.5％牛磺胆酸钠建立SAP模型,给予血必净治疗,观察血清中淀粉酶含量、白介素-6(interleukin-6,IL-6)、丙二醛(malondialdehyde,MDA)、超氧化...     

Pancreatic exocrine function during acute exacerbation in WBN/Kob rats with spontaneous chronic pancreatitis

Summary Conclusion Pancreatic exocrine hypofunction is markedly deteriorated during acute exacerbation in a rat model with chronic pancreatitis. Background Little is known about pancreatic exocrine function during acute exacerbation in patients with chronic pancreatitis. We investigated changes in pancreatic exocrine function after inducing acute pancreatitis in an animal model of spontaneous chronic pancreatitis. Methods WBN/Kob rats with chronic pancreatitis sequentially underwent pancreatic exocrine function test 1–6 d after surgical preparation with external pancreatic fistula. We induced acute pancreatitis in another WBN/Kob rats by iv administration of cerulein at a rate of 10 μg/kg/h for 4 h 4 after surgical preparation. Pancreatic exocrine function test was undertaken in a conscious state 1 d before and after cerulein administration. Results In WBN/Kob rats not given cerulein, pancreatic exocrine function remained almost constant, at 3–6 d after surgery. Marked hyperamylasemia developed immediately after cerulein administration. After its administration, the pancreas microscopcially showed prominent intersitial edema and intracellular vacuolization of acinar cells in addition to the finding of pre-existing chronic pancreatitis. Basal and chole-cystokinin-stimulated flow rate, bicarbonate output, and protein output, which were substantially impaired 1 d before cerulein administration, were further reduced 1 d after its administration.     

Stress kinase inhibition modulates acute experimental pancreatitis

AIM: To examine the role of p38 during acute experimental cerulein pancreatitis. METHODS: Rats were treated with cerulein with or without a specific JNK inhibitor (CEP1347) and/or a specific p38 inhibitor (SB203580) and pancreatic stress kinase activity was determined. Parameters to assess pancreatitis included trypsin, amylase, lipase, pancreatic weight and histology. RESULTS: JNK inhibition with CEP1347 ameliorated pancreatitis, reducing pancreatic edema. In contrast, p38 inhibition with SB203580 aggravated pancreatitis with higher trypsin levels and, with induction of acinar necrosis not normally found after cerulein hyperstimulation. Simultaneous treatment with both CEP1347 and SB203580 mutually abolished the effects of either compound on cerulein pancreatitis. CONCLUSION: Stress kinases modulate pancreatitis differentially. JNK seems to promote pancreatitis development, possibly by supporting inflammatory reactions such as edema formation while its inhibition ameliorates pancreatitis. In contrast, p38 may help reduce organ destruction while inhibition of p38 during induction of cerulein pancreatitis leads to the occurrence of acinar necrosis.     

Erythropoietic protoporphyria with severe liver dysfunction and acute pancreatitis

A case of erythropoietic protoporphyria associated with severe hepatic dysfunction and acute pancreatitis is reported. The patient, a 33-year-old man, was admitted to our hospital complaining of upper abdominal pain, nausea, and vomiting of 3 days' duration. Laboratory tests on admission demonstrated liver dysfunction, anemia, and thrombocytopenia. On the third hospital day, the intensity of the upper abdominal pain increased, concomitantly with elevated levels of serum amylase. Ultrasonography and computed tomography scanning revealed a slightly enlarged pancreas. During this episode, he also complained of various neurological symptoms, including reduced mental alertness, weakness of extremities, constipation, profound sweating, and urinary retention. Porphyrin studies demonstrated markedly elevated erythrocyte and fecal protoporphyrin levels. Laparoscopic findings obtained after the attack subsided were compatible with porphyric liver cirrhosis. We therefore concluded that neurologic disorders and acute pancreatitis could develop in patients with erythropoietic protoporphyria with severe liver dysfunction. Received: July 7, 1999 / Accepted: October 22, 1999     

Histopathologic correlates of serum amylase activity in acute experimental pancreatitis

The association of serum amylase activity with the extent of pancreatic injury in acute pancreatitis is unclear. To clarify this relationship, we induced acute pancreatitis ranging from mild to lethal in 118 Sprague-Dawley rats (350–450 g). This was achieved by controlled intraductal infusion of low- or high-dose bile salt, with or without enterokinase, followed by intravenous cerulein or saline for 6 hr. Serum amylase was measured at baseline and 6 hr. Pancreatic histopathology was evaluated by two blinded pathologists employing total surface scoring (N=118) and morphometric 20-field documentation (N =22). Serum amylase correlated best with edema (r=0.61) and fat necrosis (r=0.58), less well with acinar necrosis (r=0.53) and inflammation (r=0.50), and poorly with hemorrhage (r=0.33) and perivascular infiltrate (r=0.31). Inasmuch as edema and fat necrosis are not important determinants of severity, these observations could explain the poor prognostic value of serum amylase activity in patients with acute pancreatitis.J. Schmidt was supported by grants from Deutsche Forschungsgemeinschaft No. Schm 781/1-1+2 and C. Fernandez-del Castillo was supported by Boehringer Foundation, Mexico.Preliminary results of this research have been presented in part at the Annual Meeting of the American Gastroenterological Association, New Orleans, May 19–22, 1991.     

Exocrine function of caerulein-induced acute pancreatitis in anesthetized rats

Exocrine function was studied in anesthetized rats that had received two specific doses of caerulein (maximal stimulation and supramaximal stimulation). Male Wistar rats (body weight, 200–250 g) were divided into three groups: the control group (4-h saline infusion), the maximal stimulation group (0.25 g/kg per h caerulein for 4 h), and the caerulein pancreatitis group (10g/kg per h for 4 h). Histologically, inter-stitial edema and cytoplasmic vacuolization were observed only in the caerulein pancreatitis group, with no abnormal findings in the other groups. The volume of pancreatic juice was significantly increased in both the maximal stimulation group and the caerulein pancreatitis group. The protein ouput and the amylase output in the 1st h of caerulein infusion were also significantly increased, to 459% and 338% in the maximal stimulation group, and to 925% and 1430% respectively, in the caerulein pancreatitis compared to the baseline values. We also found that the pancreatic juice of the caerulein pancreatitis group contained precipitated protein, and high trypsin activity, and protein degradation was confirmed by electrophoresis. These findings were not observed in the other groups. These results strongly suggest that hypersecretion and the appearance of trypsin activity in pancreatic juice plays an important role in the induction of histological changes in this pancreatitis model in anesthetized rats.     

吡格列酮对急性胰腺炎肝损伤的保护作用研究

目的:探讨吡格列酮对急性胰腺炎(AP)患者肝损伤的保护作用及其机制。方法:选取AP患者144例,使用数字表法随机分为观察组和对照组,每组72例。速率法检测血丙氨酸转氨酶(ALT)、天门冬氨酸氨基转移酶(AST),ELISA法检测外周血炎性因子:肿瘤坏死因子α(TNF-α)、白介素-6(IL-6)、白介素-10(IL-10)。结果:治疗前2组血TNF-α、IL-6和IL-10水平以及ALT和AST等肝功能指标差异无统计学意义(均P0.05),治疗后观察组TNF-α和IL-6水平及ALT和AST均显著低于对照组(均P0.05),观察组血IL-10显著高于对照组(P0.05)。治疗前2组空腹血糖差异无统计学意义(P0.05),治疗后观察组的空腹血糖显著低于对照组(P0.05)。对照组不良反应发生率为5.6%(4/72),观察组不良反应发生率为6.9%(5/72),2组比较无统计学差异(P0.05)。结论:吡格列酮可以升高AP患者血IL-10表达,抑制炎症反应,发挥肝损伤保护作用,临床使用安全。     

Original research: Predictors and outcomes of acute respiratory failure in hospitalised patients with acute pancreatitis

Background and aimAcute pancreatitis (AP) is associated with organ failures and systemic complications, most commonly acute respiratory failure (ARF) and acute kidney injury. So far, no studies have analysed the predictors and hospitalisation outcomes, of patients with AP who developed ARF. The aim of this study was to measure the prevalence of ARF in AP and to determine the clinical predictors for ARF and mortality in AP.MethodsThis is a retrospective cohort study using the Nationwide Inpatient Sample database from the year 2005–2014. The study population consisted of all hospitalisations with a primary or secondary discharge diagnosis of AP, which is further stratified based on the presence of ARF. The outcome measures include in-hospital mortality, hospital length of stay and hospitalisation cost.ResultsIn our study, about 5.4% of patients with AP had a codiagnosis of ARF, with a mortality rate of 26.5%. The significant predictors for ARF include sepsis, pleural effusion, pneumonia and cardiogenic shock. Key variables that were associated with a higher risk of mortality include mechanical ventilation, age more than 65 years, sepsis and cancer (excluding pancreatic cancer). The presence of ARF increased hospital stay by 8.3 days and hospitalisation charges by US$103 460.ConclusionIn this study, we demonstrate that ARF is a significant risk factor for increased hospital mortality, greater length of stay and higher hospitalisation charges in patients with AP. This underlines significantly higher resource utilisation in patients with a dual diagnosis of AP-ARF.