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.

项目摘要： 在美国，急性胰腺炎（AP）会影响 @ 275,000/年。 AP突然开始，不可预测地无菌 炎症，但在严重的情况下会被感染，导致败血症，长期住院，有时会导致 死亡。败血症本身在美国影响150万人 /年，费用> 200亿美元，导致12-18％的死亡率 并且与AP有很多共同点。虽然被定义为对感染的压倒性反应，但很大一部分 败血症始于诸如AP之类的无菌疾病。 AP已对无菌疾病的进展为感染和 自1992年首次定义败血症以来，败血症。两种疾病都鲜为人知，也没有特定的疾病 靶向疗法。两种疾病，当严重的器官衰竭时，我们已经证明是由于 AP期间，非饱和脂肪酸的过度和不调节的脂解释放。未结合的脂肪酸（UFA） 指的是不绑定其主要载体的小水池（<1％）的游离脂肪酸，即白蛋白 严重的AP经常低。我们的初步数据表明胰腺脂肪酶会生成UFA 严重败血症患者的血清中升高。此外，UFA可以迅速纳入膜 炎症细胞，触发损伤并损害其功能。基于这些，我们假设UFA 由胰腺脂肪酶产生 在AP期间。我们建议研究脂肪毒性炎症细胞损伤的分子机制 通过使用细胞，动物模型（AIM 2）感染，并在人类AP中测试它的相关性，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 通过确定血清UFA的预后价值，脂蛋白毒性细胞损伤在临床AP中的重要性 AP与感染时AP的炎症细胞损伤以及研究关系 在UFA类型之间，感染类型的炎症性损伤性质。在AIM 2中，我们继续确定 使用细胞和动物模型在AP中脂肪毒性细胞损伤的机制和后果。到 这样做，我们将研究炎症细胞损伤对胰腺脂肪酶和脂质环境的依赖性， 确定细菌清除受损的作用，并探索脂肪毒性的机制 发生炎症细胞损伤。通过这样做，我们希望提供广泛相关的，机械性的， 脓毒症的治疗上可及时的新颖解释。这项工作将为概念框架设定 了解无菌疾病感染的发病机理（即通过UFA介导的炎症细胞损伤）， 在临床上相关的是 - 解释为什么白色计数的下降可能表明感染的风险增加了 作为医院感染，因此可能并非总是有利的。它还可以提供改进的诊断工具 基于流量仪，以解释WBC计数，伤害和感染风险，并建议治疗选择 就像早期替代白蛋白一样，审慎的预防性抗生素使用，并将胰腺脂肪酶靶向 一种避免无菌AP发展为严重败血症和死亡的方法。