Gallstone Pancreatitis: Pathogenesis and Treatment

描述(申请人提供)：胆石性胰腺炎很常见，有可能致命。结石对胆胰液的肠道排斥会引起胰腺外分泌的反馈性过度刺激，从而导致胰腺产生大量的急性炎症介质。急性胰腺炎的全身扩散导致多器官功能衰竭，是急性胰腺炎死亡的主要原因。然而，由于致病机制尚不清楚，目前还没有具体的治疗方法。我们用胆管结扎诱导的急性胰腺炎的啮齿动物模型作为实验类比来研究疾病的发病机制。我们承认这样一个事实，即啮齿动物和人类之间的物种相关变异可能会限制这些发现的临床相关性和潜在应用。然而，从这些研究中仍然可以获得有用的信息。利用一种独特的、独创的手术模型--供体大鼠模型，我们发现肠内胆胰液替代显著改善了结扎诱导的急性胰腺炎早期胰腺的形态改变，并抑制了胰腺中急性炎症介质的过度产生。我们得出结论，在我们的实验模型中，胆汁-胰液从肠道排出在急性胰腺炎的加重中起着重要作用。使用我们的供体模型，我们已经证明，十二指肠胆汁胰液置换可以改善大鼠和小鼠胰管结扎后胰腺中应激激酶的激活。我们提出了p38和ERK调控NFkB介导的外分泌胰腺(AR42J)细胞系基因转录的新证据。此外，我们还发现，小鼠导管结扎24小时与肺ERK激活和急性肺损伤有关。我们假设胆石性胰腺炎的局部和全身急性炎症反应是由于肠内隔绝胆胰液而恶化的，胆胰液引起外分泌胰腺的反馈过度刺激，从而在胆囊管阻塞的情况下激活促炎通路。目的1：探讨胰腺腺泡细胞促炎通路的激活机制。目的：探讨急性胰腺炎早期胰腺产生细胞因子、趋化因子和活性氧的机制。目的：探讨急性胰腺炎晚期局部和全身炎症反应的发生机制。我们使用新的方法，如体内基因调控，通过抑制ERK和p38来研究疾病的发病机制。在胆石性胰腺炎和全身炎症反应综合征的发病机制中，肠内胆汁胰液排除法的作用可能为这种与相当高的发病率和死亡率相关的疾病提供了急需的治疗措施的理论基础--对于这种疾病，目前还不知道具体的治疗方法。与公共卫生相关。急性胰腺炎是一种常见的胰腺炎症，具有潜在的致命性。全世界急性胰腺炎最常见的原因是胆结石。这项研究计划调查胆石性胰管梗阻如何引发胰腺的急性炎症。更好地了解这些过程将有助于改进这种潜在致命疾病的治疗。

DESCRIPTION (provided by applicant): Gallstone pancreatitis is common and is potentially fatal. Enteral exclusion of bile-pancreatic juice by the stone causes feedback hyperstimulation of the exocrine pancreas that induces pancreatic overproduction of acute inflammatory mediators. Systemic spread of acute pancreatic inflammation leads to multi-organ failure which is the major cause of death from acute pancreatitis. However, no specific treatment is currently available as the pathogenic mechanisms are not well understood. We have used the rodent model of duct ligation-induced acute pancreatitis as an experimental analogy to investigate disease pathogenesis. We acknowledge the fact that species-related variations between rodents and humans may limit the clinical relevance and potential applications of these findings. However, useful information can still be garnered from these studies. Using a unique and original surgical model, the Donor Rat Model, we showed that enteral bile-pancreatic juice replacement substantially ameliorates pancreatic morphological changes in the early stages of ligation-induced acute pancreatitis and inhibits pancreatic overproduction of acute inflammatory mediators. We concluded that bile-pancreatic juice exclusion from gut plays an important role in exacerbating acute pancreatitis in our experimental model. Using our donor model, we have shown that stress kinase activation in pancreata of rats and mice after duct ligation is ameliorated by duodenal bile-pancreatic juice replacement. We present new evidence that p38 and ERK regulate NFkB-mediated gene transcription in an exocrine pancreatic (AR42J) cell line. Furthermore, we show that 24 h of duct ligation in the mouse is associated with pulmonary ERK activation and acute lung injury. We hypothesize that the local and systemic acute inflammatory response in gallstone pancreatitis is worsened by the enteral exclusion of bile-pancreatic juice that causes feedback hyperstimulation of the exocrine pancreas to activate pro-inflammatory pathways in the presence of an obstructed duct. Aim 1: To determine the mechanism of activation of pro-inflammatory pathways in isolated pancreatic acinar cells. Aim 2: To determine the mechanism of pancreatic production of cytokines, chemokines, and reactive oxygen species in the early stage of ligation-induced acute pancreatitis. Aim 3: To determine the mechanism of development of the local and systemic inflammatory response in the late stage of ligation-induced acute pancreatitis. We use novel approaches, such as in vivo gene modulation, to investigate mechanisms of disease pathogenesis by inhibition of ERK and p38. A role for enteral bile-pancreatic juice exclusion in the pathogenesis of gallstone pancreatitis, and the systemic inflammatory response syndrome, may provide the rationale for much needed therapeutic initiatives for a condition that is associated with considerable morbidity and mortality - and for which no specific therapy is known. PUBLIC HEALTH RELEVANCE. Acute pancreatitis is a common inflammatory condition of the pancreas that is potentially fatal. The commonest cause of acute pancreatitis world-wide is gallstones. This research proposal investigates how gallstone obstruction of the pancreatic duct may initiate acute inflammation of the pancreas. A better understanding of these processes will help to improve the treatment of this potentially fatal condition.