The role of cigarette smoke toxin and alcohol in pancreatitis

香烟烟雾毒素和酒精在胰腺炎中的作用

基本信息

批准号：
8441513
负责人：
Edwin C Thrower
金额：
$ 14.46万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-10 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8441513
关键词：
Acinar Cell Acute Acute Disease Affinity Agonist Alcohol abuse Alcohol consumption Alcoholic Pancreatitis Alcohols Binding Butanones Calcium Calcium Signaling Cause of Death Cells Cholelithiasis Chronic Disease Cigarette Clinical Data Development Disease Dose Environmental Risk Factor Enzyme Precursors Ethanol Etiology Exocrine pancreas In Vitro Inflammation Inflammatory Lead Long-Term Effects Mediating Mediator of activation protein Modeling Necrosis Nicotine Nicotinic Receptors Other Genetics Pancreas Pancreatitis Pathology Patients Protein Isoforms Protein Kinase C Reporting Research Risk Risk Factors Rodent Role Signal Transduction Smoking Testing Tobacco Toxin Trypsinogen Work acute pancreatitis alcohol abuse therapy alcohol effect alcohol research alcoholic chronic pancreatitis cellular targeting chronic pancreatitis cigarette smoking cigarette smoking citrate carrier in vitro Model in vivo in vivo Model novel premature protein kinase D receptor response smoking prevalence therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Acute pancreatitis is an inflammatory disease that causes death in approximately one-third of patients who develop severe disease. It is most often caused by gallstones and alcohol abuse. The primary mechanism of alcoholic pancreatitis appears to be indirect, acting with other genetic and environmental factors to cause disease. A critical clinical observation made in the last two years is that cigarette smoking substantially increases the risk of developing pancreatitis. In addition, the effects of smoking, when combined with heavy alcohol consumption, further increase the risk of pancreatitis. Although the harmful effects of combining smoking and alcohol on the exocrine pancreas have been established clinically, the cellular mechanisms underlying these responses are unknown. One of the most potent and best studied toxins in cigarette smoke is NNK (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanone). This nicotine metabolite can bind with high affinity to specific cellular receptors that could mediate pancreatitis responses. The studies outlined in this proposal will investigate a previously unexplored disease mechanism: whether the cigarette toxin, NNK, directly mediates or sensitizes to alcoholic pancreatitis responses through specific receptors on the pancreatic acinar cell. The studies in the current proposal will 1) Define the effects of NNK alone, and with ethanol, on acute pancreatitis responses in isolated acinar cells; 2) Investigate potential NNK receptors and related signaling mechanisms alone and with ethanol in pancreatic acinar cells; 3) Define effects of NNK alone, and with ethanol, in in vivo models of pancreatitis. The preliminary studies described in this proposal support each Aim. Since many believe that chronic alcoholic pancreatitis is the result of multiple subclinical bouts of acute disease, it is possible that the mechanisms identified here would be common to both acute and chronic disease forms. Findings from this proposal could be broadly relevant to pancreatitis and other diseases in which smoking and alcohol might act together to cause pathology and could also lead to therapeutic targets.

描述（由申请人提供）：急性胰腺炎是一种炎症性疾病，导致大约三分之一的重症患者死亡。它通常是由胆结石和酗酒引起的。酒精性胰腺炎的主要机制似乎是间接的，与其他遗传和环境因素共同作用导致疾病。过去两年进行的一项重要临床观察是，吸烟会大大增加患胰腺炎的风险。此外，吸烟与大量饮酒相结合会进一步增加患胰腺炎的风险。尽管临床上已确定吸烟和饮酒对外分泌胰腺的有害影响，但这些反应背后的细胞机制尚不清楚。香烟烟雾中最有效、研究最透彻的毒素之一是 NNK（4-[甲基亚硝基氨基]-1-[3-吡啶基]-1-丁酮）。这种尼古丁代谢物可以以高亲和力与可以介导胰腺炎反应的特定细胞受体结合。该提案中概述的研究将调查以前未探索的疾病机制：香烟毒素 NNK 是否通过胰腺腺泡细胞上的特定受体直接介导或敏化酒精性胰腺炎反应。当前提案中的研究将 1) 明确 NNK 单独使用以及与乙醇联合使用对分离腺泡细胞中急性胰腺炎反应的影响； 2）单独和与乙醇一起研究胰腺腺泡细胞中潜在的NNK受体和相关信号传导机制； 3) 确定 NNK 单独使用以及与乙醇一起使用在胰腺炎体内模型中的作用。本提案中描述的初步研究支持每个目标。由于许多人认为慢性酒精性胰腺炎是急性疾病多次亚临床发作的结果，因此这里确定的机制可能是急性和慢性疾病形式所共有的。该提案的发现可能与胰腺炎和其他疾病广泛相关，在这些疾病中，吸烟和酒精可能共同引起病理，也可能导致治疗目标。