Alcohol and smoking concurrently aggravate chronic pancreatitis

摘要 慢性胰腺炎(CP)的特征是炎症、不可逆转的纤维化和坏死。 胰腺实质，导致外分泌和内分泌不足。脑瘫患者的管理 尤其具有挑战性，因为对其病理了解不深，缺乏可靠和明确的诊断 标记物和完全缺乏干预的治疗方法。脑性瘫痪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。酒精会增加溶酶体和 酶原颗粒的脆性和促进腺泡细胞中蛋白水解酶的提前激活， 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，如胶原蛋白I、III和 纤维连接蛋白和层粘连蛋白促进纤维化。此外，胰腺病变具有特征性的粘液。 侧写。粘蛋白(MUC)如MUC1、MUC5AC、MUC5B和MUC6在胰腺炎过程中上调，并表现为 在炎症反应中发挥关键作用。 研究证实，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。醛可以与胞内和胞外蛋白形成稳定的加合物， 调制 它们的功能 并且是 建议参与组织破坏和纤维化，作为信号分子和 引起免疫反应。然而，醛的复杂机理和精确贡献- 我们的初步研究表明， 饮酒动物胰腺中乙醛加合物(4HNE)的免疫反应性同时，冒烟 暴露可显著增加PSC的活性，上调SMA的表达。因此， CP病理中的蛋白质加合物仍然难以捉摸。 T 拟议的研究是基于这样一个假设，即乙醛蛋白加合物机械地促进了 CP的进展，可作为潜在的诊断和预后标志物。目标1：身份识别和 用小鼠模型研究乙醛加合物与慢性胰腺炎病理生物学的关系。使用适当的CP鼠标 模型，我们将研究酒精和烟雾暴露动物中蛋白质加合物的产生和 它们与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，我们将评估在CP过程中表达的粘蛋白上的加合物形成，并将进一步 评估他们的诊断和预后潜力。目的2：研究乙醛的作用机理。 利用3D共培养系统在CP过程中加成物。这一目标将理解 醛加合物对腺泡细胞和PSC细胞生物学的影响。综上所述，拟议的研究将勾勒出 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、预测和治疗目标。

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.