胰岛β细胞参与急性胰腺炎后胰腺再生过程的研究

目的 探讨胰岛β细胞在实验性急性胰腺炎(AP)后胰腺再生过程中的作用.方法 SD大鼠87只,按数字表法随机分为对照组(15只)、糖尿病组(24只)、AP组(24只)和糖尿病+AP组(24只).采用腹腔注射链脲佐菌素(STZ,60 mg/kg体重)或左旋精氨酸(L-Arg,2.5 g/kg体重,2次)方法分别建立糖尿病和AP模型.术后1、3、5、7d分批处死大鼠.检测血淀粉酶和血糖水平;计算胰腺湿重比;胰腺组织常规病理学检查,计算胰腺坏死面积百分比和组织转化区域百分比;免疫荧光检测胰岛β细胞的再生基因( Reg4)和胰岛素的表达.结果 注射STZ后,大鼠血糖明显升高,注射L-Arg后大鼠胰腺组织水肿、坏死、炎细胞浸润,血淀粉酶明显升高,表明制模成功.制模后第3天糖尿病+ AP组的胰腺坏死面积为(71.6±6.0)％,显著大于AP组的(42.3±4.0)％;第7天的组织转化面积为(45.6±5.4)％,显著小于AP组的(78.5±6.4)％.糖尿病+AP组胰岛β细胞的Reg4和胰岛素表达均较AP组明显减少.结论 STZ破坏了胰岛β细胞,加重精氨酸诱导的AP的损伤,并抑制胰腺的再生过程.     

Time course and cellular source of pancreatic regeneration following acute pancreatitis in the rat

The regenerative capacity of the different cell types in the rat exocrine pancreas has been studied in a model of hormone-induced acute pancreatitis in which pancreatic edema, inflammation, and acinar cell destruction were induced within 12 h of infusion of supramaximal concentrations of cerulein (5 micrograms/kg/h). A sequential biochemical and structural analysis of the pancreas in daily intervals was combined with the autoradiographic quantitation of labeling indices of five cell populations following 3H-thymidine injection at days 1-7 after induction of pancreatitis. Desquamation of acinar cell apical cytoplasm and release of cytoplasmic segments into the acinar lumen on the first day following induction of pancreatitis led to formation of duct-like tubular complexes. Enzyme content in the pancreas decreased progressively following the formation of the edema to levels 15-20% of controls and remained reduced during the initial 5 days. Thymidine incorporation into total DNA showed a biphasic pattern with a distinct peak at day 1 and a second broader peak between days 4 and 7. Autoradiographic quantitation of labeling indices demonstrated the exclusive incorporation into intercalated duct cells and interstitial cells during the initial 24 h, while the second peak was predominantly due to labeling of acinar cells. Larger interlobular ducts and islets did not show changes in labeling index. In vivo labeling with 3H-thymidine during the first day and analysis of labeling indices 14 days later showed the persistence of label in intercalated duct cells and interstitial cells and argued against the stem cell hypothesis and against transformation of duct cells into acinar cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Primary pancreatic hydatid disease associated with acute pancreatitis

The Editor welcomes submissions for possible publication in the Letters to the Editor section. Letters commenting on an article published in the Journal or other interesting pieces will be considered if they are received within 6 weeks of the time the article was published. Authors of the article being commented on will be given an opportunity to offer a timely response to the letter. Authors of letters will be notified that the letter has been received. Unpublished letters cannot be returned.     

Evolution of lesions of the pancreatic duct following acute pancreatitis associated with a pseudocyst

AIMS: After an episode of acute pancreatitis, there is usually no sequelae; nevertheless cases of ductal stenosis have been reported. The aim of our study was to evaluate the frequency of pancreatic duct lesions after acute pancreatitis complicated by pseudocyst. PATIENTS AND METHODS: Between 1983 and 2004, 67 patients were admitted for severe acute pancreatitis. Out of these 67 patients, 36 patients were excluded because of chronic pancreatitis (N=12), intraductal papillary mucinous tumors of the pancreas (N=3), carcinoma (N=2), cystadenoma (N=3), alcohol consumption > 40 g/d (N=6), post-traumatic acute pancreatitis (N=3), and a follow-up less than 12 months (N=7). RESULTS: A stenosis of the main pancreatic duct was observed in 52% (16/31) of patients. This stenosis was isolated in 100% of cases, complete for 69% of them (11/16) and associated with upstream dilatation in 69% of cases (11/16). Although the pseudocyst was located in the body of the pancreas in 7/31 cases (48%), the stenosis was located in the head in 9/16 cases (56%). The predictive criteria of pancreatic duct lesions were complications associated with pseudocyst: extra-luminal compression (P=0.01), and vascular thrombosis (P=0.02). CONCLUSION: After an episode of acute pancreatitis complicated by pseudocyst, pancreatic duct stenosis is observed in 52% of the cases. These results show that complete resolution of pancreatic abnormalities after acute pancreatitis is not achieved systematically.     

Cavernous pancreatic ductal ectasia with smooth muscle proliferation causing recurrent acute pancreatitis.

BACKGROUND: Pancreatic cystic lesions have various etiologies, including pseudocyst (inflammatory cyst), retention cyst, congenital cyst, and neoplastic cyst. RESULTS: This report describes a previously unreported, unique pancreatic cyst-like lesion causing recurrent acute pancreatitis. A 23-yr-old man had an 8 x 5 x 3-cm pancreatic head mass which contained multiple 3-7-mm cysts communicating with the main pancreatic duct on imaging studies. Pancreatoduodenectomy with mass excision prevented further attacks of acute pancreatitis. Pathological examination showed multiple cystic dilatations of branch pancreatic ducts surrounded by proliferating smooth muscle tissue, probably associated with hamartomatous changes. CONCLUSION: We consider the present lesion to represent cavernous pancreatic ductal ectasia with smooth muscle proliferation because of its striking cholangiopancreatographic similarity to Caroli disease.     

Involvement of tubular complexes in pancreatic regeneration after acute necrohemorrhagic pancreatitis.

Localized acute necrohemorrhagic pancreatitis was induced in rats by multiple trypsin injections. Morphological alterations were monitored by light and electron microscopy until complete recovery. In the acute phase, typical pictures of focal acute necrohemorrhagic pancreatitis were observed. In the postacute phase, fibrosis and tubular complexes are characteristic of damaged areas. Tubular complexes appear from the dedifferentiation of acinar cells. They are characterized by duct-like cells bordering wide, empty luminae. In the recovery phase, cellular proliferation was accompanied by differentiation, with progressive acquisition of the morphological characteristics of acinar cells at the periphery of the tubular complexes. In that instance, cellular proliferation was concomitant with the development of collagen septa in tubular complexes. In these structures both duct-like and acinar-like cells presented mitoses. Cell division persisted in the dedifferentiated cells until tubular complexes disappeared. A very similar process was observed in the embryonic pancreas, where organized parenchyma originated from proliferation and differentiation of protodifferentiated cells. We concluded that pancreatic repair following necrohemorrhagic pancreatitis involves proliferation of cells from intact acini and from tubular complexes, at variance with edematous pancreatitis, where regeneration is exclusively due to acinar cell proliferation.     

Involvement of endogenous cholecystokinin in pancreatic regeneration after cerulein-induced acute pancreatitis.

This study was undertaken to determine the involvement of endogenous cholecystokinin (CCK) in the regeneration of pancreatic tissue after cerulein-induced acute pancreatitis treated by the CCK receptor antagonist L364,718. Acute pancreatitis was induced in rats by s.c. injections of cerulein in gelatin (12 micrograms/kg) three times a day for 2 days with controls receiving saline in gelatin. Rats were then divided into four treatment groups: saline-dimethyl sulfoxide (DMSO) (SD), saline-L364,718 (SA), cerulein-pancreatitis-DMSO (CD), and cerulein-pancreatitis-L364,718 (CA). In the first experiment, rats were treated for 3 or 10 days with DMSO or L364,718 (0.1 mg/kg, twice a day). In the second experiment, rats were treated for 13 days with DMSO or L364,718 (1.0 mg/kg, twice a day). After the rats were killed, pancreata were weighed and evaluated for their total protein, amylase, chymotrypsin, RNA, and DNA. We found that destruction of the pancreatic tissue occurred after cerulein-induced pancreatitis and that regeneration of the tissue was in progress but incomplete after 10 days; the low dose of L364,718 did not prevent regeneration. After 13 days, regeneration was still incomplete but the 1-mg dose of L364,718 strongly inhibited spontaneous regeneration. These data suggest that endogenous CCK is an important and potent trophic factor in the regeneration process of pancreatic tissue following an episode of acute pancreatitis.     

5-脂氧合酶在大鼠急性坏死性胰腺炎组织中的表达

目的:研究5-脂氧合酶(5-lipoxygenase, 5-LOX)在急性坏死性胰腺炎(ANP)病程中的表达.方法:将SD大鼠54只随机分为3组:假手术组、ANP组和齐留通组. 经十二指肠行胆胰管逆行加压注射50 g/L牛磺胆酸钠, 诱导大鼠ANP模型. 各组大鼠分别于6、12、24 h处死. 用RTPCR、免疫组化和Western blot免疫印迹法检测胰腺组织5-LOX mRNA及相应蛋白的表达.ELISA方法检测血清LTB4水平. 应用全自动生化分析仪检测各组大鼠血清淀粉酶水平.结果:与ANP组相比较, 齐留通组各个时点5-LOX蛋白及mRNA表达均显著降低, 差异具有统计学意义(1.333%±0.516% vs 2.667%±0.516%, 3.000%±0.632% vs 4.500%±0.548%,3.833%±0.753% vs 5.833%±0.408%; 0.285%±0.005% vs 0.366%±0.004%, 0.608%±0.005% vs 0.949%±0.013%, 0.297%±0.002%vs 0.400%±0.006%, 均P<0.05). 假手术组血清淀粉酶、LTB4水平很低, ANP组和齐留通组水平都明显升高, 且齐留通组每个时点都较ANP组水平降低, 差异有统计学意义(血清淀粉酶:1967.50±41.21 IU/L vs 2123.50±49.11IU/L, 3242.33±87.76 IU/L vs 3531.17±74.14IU/L, 2286.83±93.91 IU/L vs 2903.33±90.90IU/L, 均P<0.05).结论:急性胰腺炎时, 5-LOX表达明显增加, 使用齐留通后, 5-LOX表达明显减少.     

Expression patterns and action analysis of genes associated with blood coagulation responses during rat liver regeneration

INTRODUCTION The liver is the main site where coagulation factors are synthesized[1]. Tissue damage is often companied with angiorrhexis, bleeding and blood coagulation. Blood coagulation is a complex hemostatic process in which zymogens convert into coag…     

Expression patterns and action analysis of genes associated with drug-induced liver diseases during rat liver regeneration

INTRODUCTION The liver has a very strong capacity to regenerate[1]. Liver cells proliferate rapidly to compensate for lost liver tissues after liver injury or drug stimulus, which is called liver regeneration (LR)[2]. The LR process is usually categorized…     

Expression patterns and action analysis of genes associated with hepatitis virus infection during rat liver regeneration

INTRODUCTIONThe liver can regenerate and precisely regulate its size. Hepatocytes maintain the ability to proliferate in response to hepatectomy, liver damage caused by viruses or chemicals, liver cell death, etc[1,2]. The remaining liver may compensate f…     

Exocrine pancreatic changes following acute attack of biliary pancreatitis

Following the Cambridge and Marseilles Symposia, functional recovery of the pancreas occurs if the primary cause and complications of the disease have been eliminated. However, recent research showed contradictory results, owing to the difference in diagnostic methods and the proportion of patients studied in relation to the etiologic factor and severity of the disease, as well as the differences in the tests utilized. Sixty-three consecutive patients with acute biliary pancreatitis were prospectively studied. Seventeen were men (27%) and 46 were women (73%), with an average age of 62.3 years, 45 were mild cases and 18 were severe. All patients underwent a cholecystectomy. No patient in this series underwent necrosectomy. During the acute phase, severity was evaluated following the Atlanta criteria as well as the existence of necrosis and its percentage by means of dynamic computed tomography (CT). During the follow-up, different tests were used to assess the pancreatic exocrine function, 1 month, 6 months and 1 year after the acute pancreatitis (AP) episode. The possible existence of pancreatic exocrine insufficiency following biliary origin AP as well as whether this possible deficit was relat- ed to the severity of the episode was investigated. We found no such insufficiency 1 year after the episode, and no link with the severity of the episode.     

Redifferentiation and apoptosis of pancreatic cells during acute pancreatitis

Summary The pancreatic cells reorganize their genetic program in a rapid and precise manner during the course of pancreatitis. These phenotypic changes probably confer increased resistance to acute pancreatitis. Then, understanding the mechanism and the finality of these changes can allow us to act earlier and more efficiently against acute pancreatitis with the development of rational therapeutic strategies. Two major phenotypic changes that occur during acute pancreatitis are the appearance of stem cells and activation of the apoptotic program of the acinar cells. In this article I discuss a recent observation about origin and pluripotency of the tubular complex-forming cells during the postacute period of pancreatitis. In addition, I summarize our knowledge on apoptosis in the pancreatic cells, particularly during acute pancreatitis.     

Factors and outcomes associated with pancreatic duct disruption in patients with acute necrotizing pancreatitis

Background and aimsAcute necrotizing pancreatitis (ANP) can affect main pancreatic duct (MPD) as well as parenchyma. However, the incidence and outcomes of MPD disruption has not been well studied in the setting of ANP.MethodsThis retrospective study investigated 84 of 465 patients with ANP who underwent magnetic resonance cholangiopancreatography and/or endoscopic retrograde cholangiopancreatography. The MPD disruption group was subclassified into complete and partial disruption.ResultsMPD disruption was documented in 38% (32/84) of the ANP patients. Extensive necrosis, enlarging/refractory pancreatic fluid collections (PFCs), persistence of amylase-rich output from percutaneous drainage, and amylase-rich ascites/pleural effusion were more frequently associated with MPD disruption. Hospital stay was prolonged (mean 55 vs. 29 days) and recurrence of PFCs (41% vs. 14%) was more frequent in the MPD disruption group, although mortality did not differ between ANP patients with and without MPD disruption. Subgroup analysis between complete disruption (n = 14) and partial disruption (n = 18) revealed a more frequent association of extensive necrosis and full-thickness glandular necrosis with complete disruption. The success rate of endoscopic transpapillary pancreatic stenting across the stricture site was lower in complete disruption (20% vs. 92%). Patients with complete MPD disruption also showed a high rate of PFC recurrence (71% vs. 17%) and required surgery more often (43% vs. 6%).ConclusionsMPD disruption is not uncommon in patients with ANP with clinical suspicion on ductal disruption. Associated MPD disruption may influence morbidity, but not mortality of patients with ANP. Complete MPD disruption is often treated by surgery, whereas partial MPD disruption can be managed successfully with endoscopic transpapillary stenting and/or transmural drainage. Further prospective studies are needed to study these items.     

Expression pattern and action analysis of genes associated with the responses to chemical stimuli during rat liver regeneration

INTRODUCTION The liver has tremendous capacity to regenerate itself[1,2]. Liver cells proliferate rapidly to compensate the lost liver tissues after liver injury or chemical stimulus, which is called liver regeneration (LR)[1,3]. Generally, based on the c…     

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

Background: 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. Methods: 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. Results: 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. Conclusions: 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. Received: January 8, 2002 / Accepted: September 6, 2002 Reprint requests to: J. Niikawa Editorial on page 305     

胰腺腺泡细胞凋亡与急性胰腺炎及其治疗策略

细胞凋亡是由基因控制的细胞自主的有序的死亡,包含了复杂的调控机制,与细胞坏死有着本质区别,不引起炎症刺激.在实验性及临床急性胰腺炎中均观察到胰腺腺泡细胞的凋亡,研究表明其可能是机体有利的保护性反应,与病情严重程度呈负相关关系.本文总结了近年来对急性胰腺炎胰腺腺泡细胞凋亡机制的研究进展,并对治疗方面的相关研究和探索进行了归纳和阐述.     

Pancreatic acinar cell regeneration following copper deficiency-induced pancreatic necrosis

Rats maintained on a diet deficient in copper for up to 8-10 weeks exhibit marked necrosis and depletion of acinar cells in the pancreas. When these animals are subsequently fed a copper-supplemented diet, foci of hepatocyte differentiation emerge by about 12 weeks. The present study deals with pancreatic changes during copper depletion and determines the extent of regenerative capacity of the pancreas during the early phases of copper supplementation. During the period of copper depletion, the pancreas gradually decreased in size, and by eight weeks of deficiency weighed approx. 30% as much as the control pancreas. Light-microscopic examination showed focal necrosis of acinar cells at 4 weeks, loss of lobular architecture by six weeks and loss of 85-90% of acinar tissue by eight weeks. Regeneration of the pancreas was initiated by feeding copper-supplemented diet at the end of eight weeks of copper deficiency. The wet weight of the pancreas increased gradually, and by 17 days it weighed 50% more than on the first day of regeneration. Mitotic activity was observed mainly in the acinar cells, beginning at 24 h and reaching a maximum of 19 +/- 1/1000 acinar cells at 72 h, and decreasing steadily thereafter. [3H]Thymidine autoradiography showed a labeling index of 51 +/- 1.7/1000 acinar cell nuclei at 24 h, reaching a peak value of 261 +/- 5.5/1000 acinar cells at 96 h. By 17 days, pancreatic regeneration was only partially complete; however, the proliferative activity was still persistent, albeit at a slower pace. Morphometric analysis of the pancreas on the 17th day of regeneration showed that acinar tissue occupied only 37% of the volume, as compared to 84% in the normal pancreas. These studies clearly demonstrate that acinar tissue of the pancreas following copper deficiency is capable of regeneration, but that the recovery of the pancreas is only partial. Additional studies are necessary to establish the role of this early acinar cell regeneration in pancreatic hepatocyte differentiation.