Alcohol and smoking concurrently aggravate chronic pancreatitis

饮酒和吸烟同时加重慢性胰腺炎

• 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
• 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

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.

摘要 慢性胰腺炎（CP）的特征是炎症、不可逆的纤维化和坏死。 胰腺实质，导致外分泌和内分泌不协调。CP患者的管理是 由于对其病理学的了解不足，缺乏可靠和明确的诊断， 标记物和完全缺乏用于干预的治疗剂。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， 酶原颗粒脆性并促进腺泡细胞中蛋白水解酶的过早激活， 导致自动消化。这种对实质的反复损伤激活了胰腺星状细胞（PSC）， 导致分泌各种细胞因子、生长因子和细胞外基质蛋白，如胶原I、III， IV、纤连蛋白和层粘连蛋白以促进纤维化。此外，胰腺病理具有特征性粘蛋白 profile.粘蛋白（MUC）如MUC 1、MUC 5AC、MUC 5 B和MUC 6在胰腺炎期间上调，并显示 在炎症反应中起关键作用。 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。乙醇氧化产物和烟气 接触包括醛、活性氧和脂肪酸乙酯，所有这些都会产生多种毒性 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 它们的功能 并且 建议参与组织破坏和纤维化，作为信号分子， 引发免疫反应。然而，复杂的机制和醛的精确贡献- 我们的初步研究表明 图1显示了在酒精喂养的动物的胰腺中醛加合物（4 HNE）的免疫反应性。同时，烟雾 暴露显著增加PSC的活化并上调SMA的表达。因此， CP病理学中的蛋白加合物仍然难以捉摸。 不 提出的研究是基于这样的假设，即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：确定和 使用鼠模型的环糊精加合物与CP的病理生物学的相关性。使用适当的CP鼠标 模型，我们将研究蛋白质加合物的产生，在酒精喂养和烟雾暴露的动物， 与CP的严重程度相关，包括坏死、纤维化和细胞外基质蛋白。 同时，我们将评估CP期间表达的粘蛋白上的加合物形成，并将进一步 评估其诊断和预后潜力。目的2：研究醛类化合物的作用机理。 使用3D共培养系统在CP期间加合物。这一目标将理解机械的贡献， 醛加合物对腺泡和PSC细胞生物学的影响。总的来说，拟议的研究将描述 酒精和吸烟介导的蛋白加合物在CP进展中的作用， 诊断、预后和治疗靶点。