Pathogenesis of infection in pancreatitis: from sterile inflammation to sepsis

胰腺炎感染的发病机制：从无菌性炎症到脓毒症

• 批准号: 10328246
• 负责人: Vijay Prem Singh
• 金额: $ 46.2万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328246
• 关键词: ANXA5 gene; Admission activity; Affect; Albumins; Animal Model; Antibiotics; Biological; CASP3 gene; CD14 gene; Cardiac Surgery procedures; Cell model; Cells; Cessation of life; Clinical; Critical Illness; Data; Dependence; Disease; Distant; Drops; Environment; Fatty Acids; Flow Cytometry; Hospitalization; Human; ITGAM gene; Impairment; Infection; Inflammation; Inflammatory; Injury; Length of Stay; Lipase; Lipids; Lipolysis; Malpighian corpuscles; Measurement; Mediating; Membrane; Modeling; Molecular; Mus; Nature; Necrosis; Nonesterified Fatty Acids; Nosocomial Infections; Oleates; Oleic Acids; Operative Surgical Procedures; Organ failure; Pancreas; Pancreatic Injury; Pancreatic enzyme; Pancreatitis; Pathogenesis; Patients; Peripheral; Persons; Process; Rattus; Role; Sepsis; Serum; Signal Transduction; Stains; Sterility; Stroke; Structure of thyroid parafollicular cell; Systemic Inflammatory Response Syndrome; Testing; Therapeutic; Thinness; Time; Triglycerides; Unsaturated Fatty Acids; Ventilator; Visceral; Visceral fat; Work; acute pancreatitis; adverse outcome; aqueous; base; body system; cell injury; clinically relevant; clinically significant; cost; diagnostic tool; improved; infection risk; inhibitor; mortality; novel; orlistat; pathogen; prevent; prognostic value; prophylactic; response; septic; septic patients; sound; targeted treatment

PROJECT SUMMARY: Acute pancreatitis (AP) affects @ 275,000/ year in the USA. AP starts suddenly and unpredictably as sterile inflammation but in severe cases can get infected, resulting in sepsis, prolonged hospitalization and sometimes death. Sepsis itself affects 1.5 million people /year in the USA, costs > $20 billion, results in 12-18% mortality and has a lot in common with AP. While defined as an overwhelming response to infection, a large portion of sepsis starts in sterile diseases like AP. AP has modelled the progression of sterile diseases to infection and sepsis since sepsis was first defined in 1992. Both diseases are poorly understood, and neither has a specific targeted therapy. Both diseases, when severe have distant organ failure, which we have shown to be due to the excessive and unregulated lipolytic release of unsaturated fatty acids during AP. Unbound fatty acids (uFA) refers to the small pool (<1%) of free fatty acids that are not bound to their main carrier, i.e. albumin, which is frequently low in severe AP. Our preliminary data show that pancreatic lipases generate uFA which are increased in the sera of severely septic patients. Additionally, uFA can rapidly incorporate into the membranes of inflammatory cells, trigger injury and impair their function. Based on these we hypothesize that uFA generated by pancreatic lipases cause inflammatory cell injury, impair bacterial clearance and result in sepsis during AP. We propose to study the molecular mechanisms of how lipotoxic inflammatory cell injury causes infections by using cell, animal models (Aim 2), and test the relevance of this in human AP, thus providing evidence to support changes in clinical AP management (Aim 1).In Aim 1 we will determine the clinical significance of lipotoxic inflammatory cell injury in clinical AP by determining the prognostic value of serum uFA and inflammatory cell injury at admission for AP vs. at time of infection, along with studying the relationship between type of uFA, nature of inflammatory injury with the type of infection. In Aim 2, we go on to determine the mechanisms and consequences of lipotoxic inflammatory cell injury in AP using cell and animal models. To do so we will study the dependence of inflammatory cell injury on pancreatic lipases and the lipid environment, determine the role of impaired bacterial clearance, and explore the mechanisms by which lipotoxic inflammatory cell injury occurs. By doing so, we hope to provide a broadly relevant, mechanistically sound, therapeutically amenable, novel explanation for sepsis. This work would set a conceptual framework to understand the pathogenesis of infection in sterile diseases (i.e. via uFA mediated inflammatory cell injury), which is clinically relevant- i.e. explains why a drop in white counts may signal increased risk of infection such as nosocomial infections and thus may not be always favorable. It can also provide improved diagnostic tools based on flow-cytometry to interpret WBC counts, injury and risk of infection, and suggest therapeutic options like the early replacement of albumin, prudent prophylactic antibiotic use, and targeting pancreatic lipases as an approach to avert the progression of sterile AP to severe sepsis and death.

项目概要： 急性胰腺炎（AP）在美国每年影响275，000人。AP突然和不可预测地开始， 炎症，但在严重的情况下可能会受到感染，导致败血症，延长住院时间，有时 死亡脓毒症本身在美国每年影响150万人，花费> 200亿美元，导致12-18%的死亡率 和AP有很多共同点虽然被定义为对感染的压倒性反应， 败血症始于AP等无菌疾病。AP已经模拟了不育疾病到感染的进展， 脓毒症自1992年首次定义以来。这两种疾病都知之甚少，而且都没有一个具体的 靶向治疗这两种疾病，当严重时，都有远处器官衰竭，我们已经证明这是由于 AP期间不饱和脂肪酸的过度和不受调节的脂解释放。游离脂肪酸（乌法） 是指游离脂肪酸的小池（<1%），其不与其主要载体即白蛋白结合， 在严重的AP中经常降低。我们的初步数据表明，胰腺脂肪酶产生乌法， 在严重脓毒症患者的血清中增加。另外，乌法可快速掺入膜中 炎性细胞，触发损伤并损害其功能。基于这些，我们假设乌法 胰腺脂肪酶产生的毒素引起炎性细胞损伤，损害细菌清除并导致脓毒症 在AP。我们建议研究脂毒性炎症细胞损伤如何导致 感染通过使用细胞，动物模型（目的2），并测试这在人类AP的相关性，从而提供 支持临床AP管理变化的证据（目标1）。在目标1中，我们将确定临床 血清乌法对脂毒性炎症细胞损伤的临床意义 AP入院时与感染时的炎症细胞损伤，沿着研究 乌法的类型、炎性损伤的性质与感染的类型有关。在目标2中，我们继续确定 脂毒性炎症细胞损伤的机制和后果在AP使用细胞和动物模型。到 这样做，我们将研究炎性细胞损伤对胰脂肪酶和脂质环境的依赖性， 确定受损的细菌清除的作用，并探讨脂毒性的机制， 发生炎性细胞损伤。通过这样做，我们希望提供一个广泛相关的，机械健全的， 治疗上可行的新解释这项工作将建立一个概念框架， 了解无菌性疾病中感染的发病机制（即通过乌法介导的炎性细胞损伤）， 这是临床相关的-即解释了为什么白色计数下降可能表明感染风险增加， 如医院感染，因此可能并不总是有利的。它还可以提供改进的诊断工具 基于流式细胞术来解释WBC计数、损伤和感染风险，并建议治疗方案 如早期替代白蛋白，谨慎预防性使用抗生素，靶向胰脂肪酶， 一种避免无菌AP进展为严重败血症和死亡的方法。