Relative Contribution of Trypsin and Inflamation in Acute and Chronic Pancreatitis

摘要 胰腺炎是一种胰腺炎症性疾病，导致超过30万人入院 仅在美国。尽管进行了几十年的研究，但目前还没有针对胰腺炎的特效疗法。 虽然急性胰腺炎期间的炎症始于腺泡细胞，但在疾病过程中 炎症会扩散到全身循环。急性发作期全身炎症失控 胰腺炎可导致全身炎症反应综合征(SIRS)和多器官衰竭， 这是导致发病率和死亡率的主要原因。因此，控制炎症的策略将导致 为开发治疗急性胰腺炎的特异性治疗方法而努力。在目前的提案中，我们将评估 胰腺炎早期腺泡内事件导致介导局部信号通路的激活 炎症，最终导致疾病发展。在第一个目标中，我们将评估 亚当斯，特别是ADAM-10/17将这种局部炎症扩散到全身水平。亚当斯是 依赖于锌离子的蛋白水解酶能裂解多种膜结合蛋白。 其中，ADAM-10和-17与多种炎症性疾病有关，但它们的作用 尚未在胰腺炎中进行评估。有趣的是，我们的初步数据显示， ADAM-10/17抑制剂在治疗环境中，即在损伤开始后，导致 重症急性胰腺炎模型的胰腺和肺损伤及炎症反应。就像大多数 急性胰腺炎的研究进行了预防性干预，这在临床上没有意义， 目前的提案集中于评估这一与翻译相关的观察结果，这可能 发展成为治疗胰腺炎的策略。在下一个目标中，我们将研究 胰腺炎的诱导可能导致腺泡细胞内质网应激的激活，以及这可能如何导致 激活AP-1和NF-kB等已知与之相关的信号通路 发炎。我们还将评估抗微生物‘中性粒细胞胞外陷阱’或网络的作用，在 第三个目标是腺泡细胞损伤，这将有助于我们理解炎症和炎症的恶性循环 胰腺炎中的损伤。由于我们拥有独特的T7 KO小鼠，我们将能够 评估胰酶在这些早期腺泡内事件中的作用，这些事件最终将帮助我们 了解胰腺损伤背景下的局部和全身炎症。

Abstract Pancreatitis, an inflammatory disease of pancreas, leads to more than 300,000 admissions to hospitals in the United States alone. Despite decades of research there is no specific therapy for pancreatitis. While the inflammation during acute pancreatitis is initiated in acinar cells, over disease course the inflammation spills into systemic circulation. Uncontrolled systemic inflammation during acute pancreatitis can lead to Systemic Inflammatory Response Syndrome (SIRS) and multi-organ failure, which is the primary cause of morbidity and mortality. Thus strategies to control inflammation will lead to development of specific therapy for acute pancreatitis. In the current proposal we will evaluate the early intra-acinar events in pancreatitis that lead to activation of signaling pathways that mediate local inflammation, eventually resulting in disease development. In the first aim, we will evaluate the role of ADAMs, specifically ADAM-10/17 in spreading this local inflammation to systemic levels. ADAMs are Zn2+ - dependent proteases that proteolytically cleave a wide variety of membrane-bound proteins. Among these, ADAM-10 and -17 have been implicated in multiple inflammatory disorders but their role has not been evaluated in pancreatitis. Intriguingly, our preliminary data suggest that treatment with ADAM-10/17 inhibitor in a therapeutic setting, i.e. after initiation of injury, leads to decrease in pancreatic and lung injury and inflammation in caerulein model of severe acute pancreatitis. As most of the studies in acute pancreatitis perform prophylactic intervention, which is not clinically significant, the current proposal is focused on evaluating this translationally relevant observation that has the potential of being developed into a therapeutic strategy for pancreatitis. In the next aim, we will study how induction of pancreatitis may result in activation of ER stress in the acinar cells and how this may lead to activation of signaling pathways like AP-1 and NF-kB that are known to be associated with inflammation. We will also evaluate the role of anti-microbial `Neutrophil Extracellular Traps' or NETs, in acinar cell injury in the third aim, which will help us understand the vicious cycle of inflammation and injury in pancreatitis. Since we are in possession of the unique T7 KO mice, we will be in a position to evaluate the role of trypsin in these early intra-acinar events that will eventually help us in understanding the local and systemic inflammation in the context of pancreatic injury.