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，这是一种严重的发病率和死亡率的严重疾病，其发病机理仍然未知，并且不存在特定的治疗方法。慢性胰腺炎的标志是持续性炎症，胰腺纤维化和实质细胞死亡，导致功能和腺体萎缩的损失。临床证据以及对饮酒动物的研究表明，酒精独特地促进了从急性到慢性胰腺损伤的过渡，这是通过使胰腺诱发到某些但未知的遗传和/或环境因素的转变。了解酒精性慢性胰腺炎（ACP）机制的关键障碍是缺乏动物模型。最近，我们开发了一种大鼠酒精介导的胰腺炎模型，该模型首次再现了慢性人类疾病的关键反应。在该模型（称为“ ACP的CSA模型”）中，严重的急性后胰腺损伤，其特征是持续性炎症，广泛的纤维化和实质细胞的大规模丧失，是由乙醇喂养的协同作用诱导的，是急性Cerules pancreules Pancreules Pancreatiation的一发。基于我们对该模型的初步发现，我们提出了一个新的假设ACP发病机理。该假设指出，ACP会发展是因为酒精会损害急性胰腺损伤（例如，急性胰腺炎），导致免疫炎症反应不足（IIR）。具体而言，我们建议在模型中介导酒精诱导的IIR失调的关键分子信号是抑制关键的细胞因子IFN-3，与先天性免疫反应不足以及细胞因子/趋化因子谱的变化相关的是对产物纤维化TH2的介体和促炎性TH17的介体的转移。这些改变导致炎症，加剧的纤维化和胰腺损伤的延续不足。因此，恢复平衡，足够的IIR（例如，通过IFN-3给药）可以改善酒精诱导的胰腺损伤。提出的ACP机制提出了治疗这种疾病的新靶标和治疗策略。总体目标：我们在此应用程序中的总体目标是检验IIR失调是ACP的关键机制的假设，以及进一步开发我们的模型。具体目的：1。表征乙醇对ACP的CSA模型（先天免疫反应和TH1/TH2/TH17反应的介体）中IIR模式的影响。 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。项目叙事性酗酒是慢性胰腺炎的主要原因，这是一种严重的疾病，其机制知之甚少，并且不存在特定的治疗方法。我们已经开发了酒精性慢性胰腺炎的大鼠模型，该模型首次再现了人类疾病的关键病理变化。基于我们的初步结果，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。我们应用的目的是检验这一假设，这可能导致治疗慢性胰腺炎的新策略。