Alcohol Impairs Recovery from Acute Pancreatitis by Dysregulating Immune Response

酒精会导致免疫反应失调，从而损害急性胰腺炎的恢复

• 批准号: 7532814
• 负责人: ILYA GUKOVSKY
• 金额: $ 18.92万
• 依托单位: BRENTWOOD BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-10 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7532814
• 关键词: Acute; Alcohol abuse; Alcohol consumption; Alcoholic Pancreatitis; Alcohols; Animal Feed; Animal Model; Appendix; Atrophic; Cells; Cessation of life; Chronic; Clinical; Cyclosporine; Disease; Environmental Risk Factor; Equilibrium; Exocrine pancreas; Fibrosis; Genetic; Goals; Heavy Drinking; Immune response; Inflammation; Inflammatory; Lead; Mediating; Mediator of activation protein; Modeling; Molecular; Morbidity - disease rate; Mus; Pancreas; Pancreatic Injury; Pancreatitis; Pathogenesis; Pathologic; Pattern; Play; Predisposing Factor; Rattus; Recovery; Resolution; Role; Signal Transduction; Testing; Time; acute pancreatitis; alcohol effect; alcohol induced pancreatic injury; base; chemokine; chronic pancreatitis; cytokine; feeding; human disease; loss of function; mortality; novel; novel strategies; problem drinker; response; therapeutic target

DESCRIPTION (provided by applicant): Alcohol abuse is a major cause of chronic pancreatitis, a severe disorder with considerable morbidity and mortality, the pathogenesis of which remains unknown and specific treatments for which do not exist. The hallmarks of chronic pancreatitis are persistent inflammation, pancreatic fibrosis and death of parenchymal cells, resulting in loss of function and glandular atrophy. Clinical evidence, as well as studies in alcohol-fed animals, suggest that alcohol uniquely promotes the transition from acute to chronic pancreatic injury by predisposing the pancreas to some, yet unknown, genetic and/or environmental factors. A key obstacle to understanding the mechanism of alcoholic chronic pancreatitis (ACP) is the lack of animal models. Recently, we have developed a model of alcohol-mediated pancreatitis in rats that for the first time reproduces the key responses of chronic human disease. In this model (termed "the CsA model of ACP"), a severe post-acute pancreatic injury, characterized by persistent inflammation, widespread fibrosis and massive loss of parenchymal cells, is induced by a synergistic effect of ethanol feeding, an episode of acute cerulein pancreatitis, and cyclosporine A (CsA) treatment. Based on our preliminary findings with this model, we propose a novel hypothesis for the pathogenesis of ACP. The hypothesis states that ACP develops because alcohol impairs the recovery from acute pancreatic injury (e.g., acute pancreatitis) by causing inadequate immunoinflammatory response (IIR). Specifically, we propose that a key molecular signal mediating alcohol- induced dysregulation of IIR in our model is inhibition of the key cytokine IFN-3, associated with inadequate innate immune response and shift in the cytokine/chemokine profile towards mediators of the pro-fibrotic Th2 and pro-inflammatory Th17 responses. These alterations result in deficient resolution of inflammation, exacerbated fibrosis, and perpetuation of the pancreatic injury. Thus, restoring a balanced, adequate IIR (e.g., by IFN-3 administration) may ameliorate alcohol-induced pancreatic injury. The proposed mechanism of ACP suggests novel targets and therapeutic strategies to treat this disorder. Overall goal: Our overall goal in this application is to test the hypothesis that dysregulation of IIR is a key mechanism of ACP, as well as to further develop our model. Specific Aims: 1. Characterize the effect of ethanol feeding on the IIR pattern in the CsA model of ACP (the innate immune response and mediators of Th1/Th2/Th17 responses). 2. Determine the role of IFN-3 in ethanol's effects on the IIR and pancreatic recovery in the CsA model of ACP. PROJECT NARRATIVE Alcohol abuse is a major cause of chronic pancreatitis, a severe disorder the mechanism of which is poorly understood and specific treatments for which do not exist. We have developed a rat model of alcoholic chronic pancreatitis that for the first time reproduces key pathologic changes of the human disease. Based on our preliminary results with this model, we hypothesize that dysregulation of immune response plays a major role in alcoholic chronic pancreatitis. The goal of our application is to test this hypothesis, which may lead to novel strategies to treat chronic pancreatitis.

描述（由申请人提供）：酗酒是慢性胰腺炎的主要原因，慢性胰腺炎是一种具有相当高发病率和死亡率的严重疾病，其发病机制仍然未知，并且不存在具体的治疗方法。慢性胰腺炎的特点是持续炎症、胰腺纤维化和实质细胞死亡，导致功能丧失和腺体萎缩。临床证据以及对酒精喂养的动物的研究表明，酒精通过使胰腺容易受到一些尚不清楚的遗传和/或环境因素的影响，独特地促进从急性到慢性胰腺损伤的转变。了解酒精性慢性胰腺炎（ACP）机制的一个关键障碍是缺乏动物模型。最近，我们在大鼠中开发了一种酒精介导的胰腺炎模型，首次重现了人类慢性疾病的关键反应。在该模型（称为“ACP 的 CsA 模型”）中，乙醇喂养的协同作用诱导了严重的急性后胰腺损伤，其特征是持续炎症、广泛纤维化和实质细胞大量损失，这是急性胰腺炎的一次发作。雨蛙素胰腺炎和环孢素 A (CsA) 治疗。根据我们对该模型的初步发现，我们提出了 ACP 发病机制的新假设。该假设指出，ACP 的发生是因为酒精会导致免疫炎症反应 (IIR) 不足，从而损害急性胰腺损伤（例如急性胰腺炎）的恢复。具体来说，我们提出，在我们的模型中介导酒精诱导的 IIR 失调的关键分子信号是关键细胞因子 IFN-3 的抑制，与先天免疫反应不足以及细胞因子/趋化因子谱向促纤维化介质的转变有关。 Th2 和促炎 Th17 反应。这些改变导致炎症消退不足、纤维化加剧和胰腺损伤持续存在。因此，恢复平衡、足够的 IIR（例如，通过 IFN-3 给药）可能会改善酒精引起的胰腺损伤。 ACP 的拟议机制提出了治疗这种疾病的新靶点和治疗策略。总体目标：我们在此应用中的总体目标是检验 IIR 失调是 ACP 关键机制的假设，并进一步开发我们的模型。具体目标： 1. 表征乙醇喂养对 ACP CsA 模型中 IIR 模式的影响（先天免疫反应和 Th1/Th2/Th17 反应的介质）。 2. 确定 IFN-3 在乙醇对 ACP CsA 模型中 IIR 和胰腺恢复的影响中的作用。项目叙述 酗酒是慢性胰腺炎的一个主要原因，慢性胰腺炎是一种严重的疾病，对其机制知之甚少，并且不存在具体的治疗方法。我们开发了一种酒精性慢性胰腺炎大鼠模型，首次再现了人类疾病的关键病理变化。根据我们对该模型的初步结果，我们假设免疫反应失调在酒精性慢性胰腺炎中起主要作用。我们应用的目标是检验这一假设，这可能会导致治疗慢性胰腺炎的新策略。