Gallstone Pancreatitis: Pathogenesis and Treatment

描述（由申请人提供）：胆石性胰腺炎很常见，可能致命。结石对胆胰液的肠内排斥引起胰腺外分泌的反馈过度刺激，从而诱导胰腺过度产生急性炎症介质。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，目前没有具体的治疗方法，因为致病机制还不清楚。我们已经使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，啮齿动物和人类之间与物种相关的变异可能会限制这些发现的临床相关性和潜在应用。然而，仍然可以从这些研究中获得有用的信息。使用独特的和原始的手术模型，供体大鼠模型，我们表明，肠内胆胰液置换大大改善胰腺的形态学变化在结扎诱导的急性胰腺炎的早期阶段，并抑制胰腺过度生产的急性炎症介质。我们的结论是胆胰液从肠道排出在我们的实验模型中急性胰腺炎的加重中起重要作用。使用我们的供体模型，我们已经表明，大鼠和小鼠胰管结扎后的应激激酶激活改善十二指肠胆胰液置换。我们提出了新的证据，p38和ERK调节NF κ B介导的基因转录在胰腺外分泌（AR42J）细胞系。此外，我们发现，24小时的导管结扎小鼠与肺ERK激活和急性肺损伤。我们推测，胆胰液的肠内排阻会加重胆源性胰腺炎的局部和全身急性炎症反应，从而导致外分泌胰腺的反馈过度刺激，从而在存在梗阻导管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。目标二：探讨结扎诱导的急性胰腺炎早期胰腺细胞因子、趋化因子和活性氧产生的机制。目标3：探讨结扎诱导的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来研究疾病发病机制。肠内胆胰液排除在胆结石性胰腺炎和全身炎症反应综合征发病机制中的作用，可能为这种与相当高的发病率和死亡率相关的疾病急需的治疗措施提供了理论基础，并且没有具体的治疗方法已知。公共卫生相关性。急性胰腺炎是一种常见的胰腺炎性疾病，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。本研究计划探讨胆结石阻塞胰管如何引发胰腺急性炎症。更好地了解这些过程将有助于改善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.