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

• 批准号: 8224403
• 负责人: Edwin C Thrower
• 金额: $ 18.82万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-10 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8224403
• 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

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. PUBLIC HEALTH RELEVANCE: Smoking and alcohol abuse increase the risk of developing acute pancreatitis, an inflammatory condition that can cause death in 1/3 of those with severe disease. The findings from this project will lead to a better understanding of how a potent cigarette toxin and alcohol act together to cause this disease at a cellular level. This could lead to development of a therapy for alcohol and smoking-related pancreatitis.

描述（由申请人提供）：急性胰腺炎是一种炎症性疾病，可导致大约三分之一的患有严重疾病的患者死亡。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，它与其他遗传和环境因素作用，引起疾病。在过去两年中，一个关键的临床观察结果是，吸烟大大增加了患胰腺炎的风险。此外，吸烟的影响与大量饮酒相结合，进一步增加了胰腺炎的风险。尽管在临床上已经建立了吸烟和酒精对外分泌胰腺的有害影响，但这些反应的基础机制尚不清楚。香烟中最有效，最有效的毒素之一是NNK（4- [甲基硝基氨基] -1- [3-吡啶基] -1-丁酮）。这种尼古丁代谢产物可以与特定的细胞受体具有高亲和力结合，以介导胰腺炎反应。该提案中概述的研究将研究先前未开发的疾病机制：香烟毒素，NNK是否直接通过胰腺腺泡细胞上的特定受体介导或对酒精性胰腺炎反应进行介导或敏感。当前建议中的研究将1）仅定义单独的NNK和乙醇对孤立腺泡细胞中急性胰腺炎反应的影响； 2）单独研究潜在的NNK受体和相关的信号传导机制，并在胰腺腺泡细胞中使用乙醇； 3）在体内胰腺炎模型中，仅定义NNK和乙醇的影响。该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种亚临床疾病的结果，因此急性和慢性疾病形式都可能是常见的机制。该提案的发现可能与胰腺炎和其他疾病广泛有关，其中吸烟和酒精可能会共同起作用以引起病理，也可能导致治疗靶标。 公共卫生相关性：吸烟和酗酒会增加患急性胰腺炎的风险，炎症性疾病可能导致患有严重疾病的1/3死亡。该项目的发现将使人们更好地了解有效的香烟毒素和酒精如何在细胞水平上引起这种疾病。这可能导致开发用于酒精和吸烟相关胰腺炎的疗法。