Alcohol and smoking concurrently aggravate chronic pancreatitis

饮酒和吸烟同时加重慢性胰腺炎

基本信息

批准号：
9569575
负责人：
Kusum K. Kharbanda
金额：
$ 21.81万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-22 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9569575
关键词：
Accounting Acetaldehyde Acinar Cell Address Admission activity Alcohols Aldehydes Animals Apoptosis Apoptotic Behavior Binding Biological Models CXCL1 gene Cell secretion Cells Cellular biology Characteristics Cholecystokinin Coculture Techniques Collagen Deposition Diagnosis Diagnostic Diagnostic tests Digestion Disease Disease Progression Early Diagnosis Endocrine Environmental Risk Factor Enzymes Esters Ethanol Etiology Extracellular Matrix Extracellular Matrix Proteins Extracellular Protein Fatty Acids Fibronectins Fibrosis Generations Genetic Goals Growth Growth Factor High Fat Diet Histologic Hospitals IL8RB gene Image Immune Immune response In Vitro Infiltration Inflammation Inflammatory Inflammatory Response Intervention KRAS2 gene Knowledge Laminin Ligands Lymphoid Lysosomes MUC5AC gene MUC5B gene Mediating Metalloproteases Mucin 1 protein Mucins Mutation Myelogenous Nature Necrosis Pain management Pancreas Pancreatic Diseases Pancreatic Function Tests Pancreatitis Pathology Pathway interactions Patients Peptide Hydrolases Play Prognostic Marker Progressive Disease Proliferating Proteins Reactive Oxygen Species Recurrence Research Risk Factors Role SPINK1 gene Severities Signal Pathway Signaling Molecule Smoke Smoking System Therapeutic Intervention Tissues Toxic effect Zymogen Granules acute pancreatitis adduct base cell type chronic pancreatitis cytokine diagnostic biomarker extracellular gastrointestinal immunoreactivity immunoregulation injured mouse model novel diagnostics oxidation prevent prognostic programs recruit stellate cell therapeutic target

项目摘要

Abstract Chronic pancreatitis (CP) is characterized by inflammation, irreversible fibrosis, and necrosis of pancreatic parenchyma, resulting in exocrine and endocrine insufficiencies. Management of CP patients is particularly challenging due to poor understanding of its pathology, lack of reliable and definitive diagnostic markers and complete absence of therapeutics for interventions. The etiology of CP includes multiple genetic and environmental factors including alcohol, smoking, and high fat diet. Alcohol increases the lysosome and zymogen granules fragility and facilitates the pre-mature activation of proteolytic enzymes in acinar cells, resulting in auto-digestion. This recurring damage to parenchyma activates pancreatic stellate cells (PSC), leading to secretion of various cytokines, growth factors and extracellular matrix proteins likecollagens I, III, and IV, fibronectin, and laminin to promote fibrosis. In addition, pancreatic pathologies have characteristic mucin profile. Mucins (MUC) like MUC1, MUC5AC, MUC5B and MUC6 are upregulated during pancreatitis and shown to play critical role in inflammatory response. Studies have established that pancreatic acinar cells can metabolize alcohol both by oxidative and non-oxidative pathways. The products of ethanol oxidation and smoke exposure include aldehyde, reactive oxygen species, and fatty acid ethyl esters, all of which exert multiple toxic effects on pancreas. Aldehydes can make stable adducts with the intra- and extracellular proteins, modulate their function and are suggested to participate in tissue destruction and fibrosis, act as signaling molecules and elicit immunological response. However, the intricate mechanism and the precise contribution of aldehyde- Our preliminary studies have demonstrated the increase immunoreactivity of the aldehyde adducts (4HNE) in the pancreas of alcohol fed animals. Concurrently, smoke exposure significantly increased the activation of the PSC and upregulate the expression of SMA. herefore, the protein adducts in CP pathology remain elusive. T proposed study is based on the hypothesis that aldehyde protein-adducts mechanistically contribute to the progression of CP and can serve as potential diagnostic and prognostic markers. Aim 1: Identification and correlation of aldehyde-adducts with pathobiology of CP using murine models. Using appropriate CP mouse model, we will investigate the generation of protein adducts in the alcohol fed and smoke exposed animals and correlated them with the severity of the CP including necrosis, fibrosis, and extracellular matrix proteins. Simultaneously, we will evaluate the adduct formation on the mucins expressed during CP and will further evaluate their diagnostic and prognostic potential. Aim 2: Investigate the mechanistic contribution of aldehyde- adducts during CP using 3D co-culture system. This aim will comprehend the mechanistic contribution of aldehyde- adducts on acinar and PSC cell biology. Taken together, the proposed studies will delineate the contribution of alcohol and smoking mediated proteins adducts in progression of CP that will provide novel diagnostic, prognostic, and therapeutic targets.

抽象的慢性胰腺炎（CP）的特点是炎症、不可逆的纤维化和坏死。胰腺实质，导致外分泌和内分泌功能不全。脑瘫患者的管理是由于对其病理学了解甚少，缺乏可靠和明确的诊断，因此特别具有挑战性标记物和完全缺乏干预治疗。 CP的病因包括多种遗传因素以及环境因素，包括酒精、吸烟和高脂肪饮食。酒精会增加溶酶体，酶原颗粒脆弱并促进腺泡细胞中蛋白水解酶的过早激活，从而导致自动消化。这种对实质的反复损伤会激活胰腺星状细胞（PSC），导致各种细胞因子、生长因子和细胞外基质蛋白（如胶原蛋白 I、III 和）的分泌 IV、纤连蛋白和层粘连蛋白促进纤维化。此外，胰腺病理学具有特征性粘蛋白轮廓。粘蛋白 (MUC) 如 MUC1、MUC5AC、MUC5B 和 MUC6 在胰腺炎期间表达上调在炎症反应中发挥关键作用。研究表明，胰腺腺泡细胞可以通过氧化和非氧化途径代谢酒精。乙醇氧化和烟雾的产物接触的物质包括醛、活性氧和脂肪酸乙酯，所有这些物质都会产生多种毒性对胰腺的影响。醛可以与细胞内和细胞外蛋白质形成稳定的加合物，调制他们的功能并且是建议参与组织破坏和纤维化，充当信号分子和引发免疫反应。然而，醛的复杂机制和精确贡献我们的初步研究表明，酒精喂养动物胰腺中醛加合物 (4HNE) 的免疫反应性。同时，抽烟暴露显着增加 PSC 的激活并上调 SMA 的表达。因此， CP 病理学中的蛋白质加合物仍然难以捉摸。时间拟议的研究基于这样的假设：醛蛋白加合物在机械上有助于 CP 的进展，可以作为潜在的诊断和预后标志物。目标 1：识别和使用小鼠模型研究醛加合物与 CP 病理学的相关性。使用合适的 CP 鼠标模型中，我们将研究喂食酒精和吸烟的动物中蛋白质加合物的产生，以及将它们与 CP 的严重程度（包括坏死、纤维化和细胞外基质蛋白）相关联。同时，我们将评估 CP 期间表达的粘蛋白上加合物的形成，并进一步评估其诊断和预后潜力。目标 2：研究醛-的机制贡献使用 3D 共培养系统在 CP 期间加合物。这一目标将理解的机械贡献醛加合物对腺泡和 PSC 细胞生物学的影响。总而言之，拟议的研究将描述酒精和吸烟介导的蛋白质加合物在 CP 进展中的作用将提供新的诊断、预后和治疗目标。