Mechanism(s) of Alcoholic Pancreatitis

描述（由申请人提供）：慢性胰腺炎是一种严重且疼痛的胰腺外分泌疾病，无有效治疗措施。慢性酒精滥用是慢性胰腺炎的第二大病因，仅次于胆管疾病。胰腺炎的经济和社会影响是毁灭性的，因为该疾病具有不可逆性以及相关的高死亡率和合并症，包括消化不良、糖尿病和胰腺癌。胰腺组织的自身消化由于胰腺外分泌中消化酶原的激活而被认为是胰腺炎的原因。然而，酒精性胰腺炎的代谢基础相对模糊。乙醇代谢物、乙醛（氧化代谢物）和脂肪酸乙酯（FAEE，非氧化脂质代谢物）在胰腺炎发生和进展中的作用”是NIAAA赞助的研究项目的重点领域之一（PA-09-164）。在初步的剂量依赖性研究中，我们发现胰腺损伤沿着血液酒精浓度（BAC）和胰腺脂质、脂肪酸乙酯（FAEE，乙醇的非氧化脂质代谢物）和内质网（ER）应激在肝脏乙醇脱氢酶（ADH）缺陷（ADH-）与正常ADH（ADH+）鹿小鼠喂食3.5%乙醇（最佳耐受剂量）持续2个月（亚慢性暴露）。然而，血液乙醛的水平被发现是相似的两个品系的鹿小鼠喂食乙醇。基于我们在鹿小鼠模型中的初步数据以及我们和其他人报道的FAEE在胰腺腺泡细胞中的细胞毒性作用，我们假设在肝脏ADH抑制下的慢性乙醇暴露诱导ER应激，这是由于乙醇在胰腺外分泌中内源性形成非氧化脂质代谢产物，导致酒精性胰腺炎的发生和进展。在目标1中，我们将描述慢性乙醇暴露3个月和6个月后，抗利尿激素鹿小鼠胰腺中脂质代谢组学变化的进展和FAEE的增加。我们将通过质子和/或31磷核磁共振波谱法评估胰腺中脂肪变化和内源性FAEE水平。在目标2中，我们将检查来自目标1的乙醇喂养的ADH-鹿小鼠中胰腺损伤、ER应激和促炎反应的进展。胰腺损伤将通过形态测量和损伤标志物进行评估，胰腺ER应激通过测量葡萄糖调节蛋白78和相关细胞死亡途径的过表达进行评估，以及炎症反应通过胰腺和/或血浆中的促炎转录因子和细胞因子进行评估。我们关于损伤标志物和脂质代谢组学变化的血浆数据可用于早期检测发育性胰腺炎。两个目标的综合结果应确定FAEE在酒精性胰腺炎发生和进展中的作用/贡献，并确定其生物标志物。这些信息将被用来开发一个翻译研究项目，用于酒精性胰腺炎的早期检测和干预。我们现有的强大的跨学科研究团队和鹿鼠模型的初步数据使我们有资格从事这个项目。 公共卫生相关性：说明：酒精性胰腺炎是一种破坏性疾病，胰腺外分泌的疼痛性疾病通常导致高死亡率，并与消化不良、糖尿病和胰腺癌等并发症相关。本研究旨在建立酒精性胰腺炎的代谢基础，并识别酒精性胰腺损伤的早期标志物，为酒精性胰腺炎的早期检测和预防提供转化研究项目。

DESCRIPTION (provided by applicant): Chronic pancreatitis is a serious and painful disorder of exocrine pancreas with no effective therapeutic measures. After biliary duct disease, chronic alcohol abuse is the second major cause of chronic pancreatitis. The economic and social impact of pancreatitis is devastating due to irreversible nature of the disease and related high mortality and co-morbidities including maldigestion, diabetes, and pancreatic cancer. Autodigestion of pancreatic tissue due to the activation of digestive zymogens in the exocrine pancreas is known to cause pancreatitis. However, metabolic basis of alcoholic pancreatitis is relatively obscure. Role of ethanol metabolites, acetaldehyde (oxidative metabolite) and fatty acid ethyl esters (FAEEs, nonoxidative lipid metabolites) in the initiation and progression of pancreatitis" is one of the focus areas of NIAAA sponsored research programs (PA-09-164). In preliminary dose-dependent studies, we found that pancreatic injury along with substantial increases in blood alcohol concentration (BAC) and pancreatic lipids, fatty acid ethyl esters (FAEEs, nonoxidative lipid metabolites of ethanol) and endoplasmic reticulum (ER) stress in hepatic alcohol dehydrogenase (ADH)-deficient (ADH-) vs. normal ADH (ADH+) deer mice fed 3.5% ethanol (an optimal tolerable dose) for 2 months (subchronic exposure). However, the levels of blood acetaldehyde were found to be similar in both strains of deer mice fed ethanol. Based upon our preliminary data in deer mouse model and the cytotoxic effects of FAEEs reported by us and others in pancreatic acinar cells, we hypothesize that chronic ethanol exposure under hepatic ADH inhibition induces ER stress due to endogenous formation of nonoxidative lipid metabolites of ethanol in the exocrine pancreas resulting in initiation and progression of alcoholic pancreatitis. In Aim 1, we will characterize progression of lipid metabolomic changes and increases in FAEEs in the pancreas of ADH- deer mice after chronic ethanol exposure for 3 and 6 months. We will assess fatty changes and endogenous levels of FAEEs in the pancreas by proton and/or 31phosphorus nuclear magnetic resonance spectroscopy. In Aim 2, we will examine the progression of pancreatic injury, ER stress and proinflammatory responses in ethanol fed ADH- deer mice from Aim 1. Pancreatic injury will be evaluated by morphometry and injury markers, pancreatic ER stress by measuring the over expression of glucose regulated protein 78 and related cell death pathways, and inflammatory responses by proinflammatory transcription factors and cytokines in the pancreas and/or plasma. Our plasma data on markers of injury and changes in lipid metabolome can be utilized for early detection of developmental pancreatitis. The combined results of both aims should determine role/contribution of FAEEs in initiation and progression of alcoholic pancreatitis and identify its biomarkers. This information will be utilized to develop a translational research project for the early detection and intervention of alcoholic pancreatitis. Our strong existing interdisciplinary team of investigators and preliminary data in deer mouse model make us uniquely qualified to pursue this project. PUBLIC HEALTH RELEVANCE: NARRATIVE: Alcoholic pancreatitis is a devastating disease and painful disorder of exocrine pancreas often causes high mortality and associated with co-morbidities including maldigestion, diabetes, and pancreatic cancer. In this project, we will establish metabolic basis of alcoholic pancreatitis, and identify early markers of ethanol-induced pancreatic injury for a translational research project for early detection and prevention of alcoholic pancreatitis.