Alcohol Impairs Recovery from Acute Pancreatitis by Dysregulating Immune Response

描述(申请人提供)：酒精滥用是慢性胰腺炎的主要原因，这是一种具有相当高的发病率和死亡率的严重疾病，其发病机制尚不清楚，也没有针对其的具体治疗方法。慢性胰腺炎的特征是持续性炎症、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动物的研究表明，酒精通过使胰腺易于受到一些尚不清楚的遗传和/或环境因素的影响，独特地促进了从急性胰腺损伤到慢性胰腺损伤的转变。了解酒精性慢性胰腺炎(ACP)发病机制的一个关键障碍是缺乏动物模型。最近，我们开发了一种酒精介导的大鼠胰腺炎模型，首次复制了慢性人类疾病的关键反应。在这个模型(称为ACP的CsA模型)中，酒精喂养、急性胰腺炎发作和环孢素A(CsA)治疗的协同作用导致了以持续炎症、广泛的纤维化和大量实质细胞丢失为特征的严重急性胰腺损伤。基于我们对该模型的初步发现，我们对ACP的发病机制提出了一个新的假说。该假说认为，ACP的发生是因为酒精通过引起免疫炎症反应(IIR)不足而损害了急性胰腺损伤(如急性胰腺炎)的恢复。具体地说，我们认为，在我们的模型中，介导酒精诱导的IIR失调的一个关键分子信号是抑制关键细胞因子干扰素-3，这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Th2和促炎Th17反应的介体转移有关。这些改变导致炎症消退不足，纤维化加重，胰腺损伤永久化。因此，恢复平衡、充足的IIR(例如，通过注射干扰素-3)可能会减轻酒精诱导的胰腺损伤。提出的ACP机制为治疗这种疾病提供了新的靶点和治疗策略。总体目标：我们在这项应用中的总体目标是检验IIR调节失调是ACP的关键机制这一假设，并进一步发展我们的模型。具体目的：1.研究酒精喂养对ACP CsA模型IIR模式(Th1/Th2/Th17反应的先天免疫应答和介体)的影响。2.探讨干扰素-3在乙醇对环孢素A所致急性胰腺炎大鼠IIR及胰腺功能恢复中的作用。酗酒是慢性胰腺炎的一个主要原因，这是一种严重的疾病，其机制尚不清楚，也不存在具体的治疗方法。我们已经建立了一种酒精性慢性胰腺炎的大鼠模型，这是第一次复制人类疾病的关键病理变化。基于我们对该模型的初步研究结果，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。我们的应用程序的目标是检验这一假设，这可能导致治疗慢性胰腺炎的新策略。

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.