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: 9884764
• 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/9884764
• 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; Diagnostic; 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; 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; improved; infection risk; inhibitor/antagonist; mortality; novel; orlistat; pathogen; prevent; prognostic value; prophylactic; response; septic; septic patients; sound; targeted treatment; tool

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： 在美国，急性胰腺炎 (AP) 每年影响 275,000 人。 AP 突然开始且不可预测地表现为无菌状态 炎症，但在严重的情况下可能会被感染，导致败血症、长期住院，有时甚至 死亡。在美国，脓毒症本身每年影响 150 万人，造成的损失超过 200 亿美元，导致 12-18% 的死亡率 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 AP 等无菌疾病。 AP 模拟了无菌性疾病到感染的进展过程 自 1992 年首次定义脓毒症以来，人们对脓毒症的了解甚少，而且都没有具体的治疗方法 靶向治疗。这两种疾病，严重时都会出现远处器官衰竭，我们已经证明这是由于 AP 期间不饱和脂肪酸过度且不受调节的脂肪分解释放。游离脂肪酸 (uFA) 指未与其主要载体（即白蛋白）结合的少量（<1%）游离脂肪酸， 严重 AP 时通常较低。我们的初步数据表明，胰脂肪酶产生的 uFA 是 严重脓毒症患者血清中升高。此外，uFA 可以快速融入膜中 炎症细胞，引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，导致炎症细胞损伤，损害细菌清除并导致败血症 AP期间。我们建议研究脂毒性炎症细胞损伤如何引起的分子机制 通过使用细胞、动物模型进行感染（目标 2），并测试其在人类 AP 中的相关性，从而提供 支持临床 AP 管理变革的证据（目标 1）。在目标 1 中，我们将确定临床 AP 管理 通过测定血清uFA的预后价值探讨脂毒性炎症细胞损伤在临床AP中的意义 AP 入院时与感染时的炎症细胞损伤，并研究其关系 uFA 类型、炎症损伤性质与感染类型之间的关系。在目标 2 中，我们继续确定 使用细胞和动物模型研究 AP 中脂毒性炎症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，并探索脂毒性的机制 发生炎症细胞损伤。通过这样做，我们希望提供一个广泛相关的、机制上合理的、 对脓毒症的治疗上可行的新颖解释。这项工作将建立一个概念框架 了解无菌疾病感染的发病机制（即通过 uFA 介导的炎症细胞损伤）， 这具有临床相关性，即解释了为什么白细胞计数下降可能表明感染风险增加，例如 作为医院感染，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白细胞计数、损伤和感染风险，并建议治疗方案 例如早期更换白蛋白、谨慎预防性使用抗生素以及针对胰腺脂肪酶 一种避免无菌性 AP 进展为严重败血症和死亡的方法。