Macrophage Pyroptosis Mechanism of Post-Trauma Acute Lung Injury

创伤后急性肺损伤的巨噬细胞焦亡机制

• 批准号: 10260392
• 负责人: Jie Fan
• 金额: $ 39.13万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10260392
• 关键词: Acute Lung Injury; Alveolar; Alveolar Macrophages; Apoptosis; CASP1 gene; Cell Culture Techniques; Cell Death; Cell Death Process; Cell Differentiation process; Cells; Cytolysis; Development; Dynamin; Early Intervention; Endocytosis; Event; Goals; HMGB1 Protein; Hemorrhagic Shock; Human; In Vitro; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Kupffer Cells; Liver; Lung Inflammation; Modeling; Molecular; Multiple Organ Failure; Mus; Organ failure; Pathogenesis; Pattern; Peripheral; Peritoneal; Phagocytosis; Process; Regulation; Reporting; Role; Signal Transduction; Sterility; Systemic Inflammatory Response Syndrome; Testing; Therapeutic Intervention; Trauma; Trauma patient; base; effective therapy; extracellular; human disease; in vivo; insight; macrophage; monocyte; mortality; mouse model; new therapeutic target; novel; post-trauma; preclinical study; prevent; preventive intervention; prophylactic; uptake

Macrophage Pyroptosis Mechanism of Post-Trauma Acute Lung Injury ABSTRACT Trauma is a major cause of systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS), in which acute lung injury (ALI) is an important component. The underlying mechanism of how trauma leads to SIRS, MODS, and ALI has yet to be fully determined, but understanding these mechanisms is of prime importance as early interventional treatment of trauma patients may prevent organ failure and damage that usually occurs days later. Our long-term goal is to determine the mechanism by which trauma promotes ALI, thereby, potentially identifying novel targets for prophylactic intervention. We have reported a novel mechanism by which damage-associated molecular pattern (DAMP) molecules induce macrophage (Mφ) pyroptosis, a caspase-1-dependent programmed cell death. The ultimate osmotic lysis of pyroptotic cells releases intracellular contents and causes inflammation. Our following preliminary studies further show that: 1) HMGB1 induces human peripheral monocyte pyroptosis; 2) circulating monocyte pyroptosis does occur in trauma patients, and intracellular inflammasome components are released and can be detected in sera of trauma patients about four days after trauma; 3) Mφ phagocytosis of extracellular Nlrp3 inflammasome components activates inflammatory responses in the Mφ; 4) in a mouse model of HS/trauma, alveolar macrophage (AMφ) pyroptosis is induced in a HMGB1- RAGE-dependent manner; and 5) AMφ pyroptosis is associated with augmented lung inflammation. Based on the above findings, we hypothesize that: 1) HMGB1-RAGE signaling serves as a novel mechanism that induces Mφ pyroptosis following trauma; and 2) Mφ pyroptosis promotes the development of ALI after trauma by influencing inflammatory processes; and 3) inflammasome components that are released from pyroptotic Mφ serve as novel secondary danger signals to induce amplified inflammation. In order to test these hypotheses, we propose the following two specific aims: Specific Aim 1: To determine the molecular mechanism through which trauma induces Mφ pyroptosis. Specific Aim 2: To determine the role of Mφ pyroptosis in the development of ALI following trauma.

创伤后急性肺损伤的巨噬细胞热凋亡机制 摘要 创伤是全身炎症反应综合征（SIRS）和多器官损伤的主要原因。 急性肺损伤（ALI）是MODS的重要组成部分。底层 创伤如何导致SIRS、MODS和ALI的机制尚未完全确定，但了解 这些机制是最重要的，因为创伤患者的早期介入治疗可以防止 器官衰竭和损伤通常发生在几天后。我们的长期目标是确定机制 创伤通过其促进ALI，从而潜在地鉴定用于预防性干预的新靶点。 我们已经报道了一种新的机制，通过这种机制，损伤相关分子模式（DAMP） 分子诱导巨噬细胞（Mφ）焦亡，一种半胱天冬酶-1依赖的程序性细胞死亡。的 热解细胞的最终渗透裂解释放细胞内内容物并引起炎症。我们 以下初步研究进一步表明：1）HMGB 1诱导人外周血单核细胞凋亡; 2)循环单核细胞凋亡确实发生在创伤患者中， 在创伤后约四天，释放组分并可在创伤患者的血清中检测到; 3） Mφ吞噬细胞外Nlrp 3炎性体成分激活了小鼠的炎症反应。 Mφ; 4）在HS/创伤小鼠模型中，肺泡巨噬细胞（AMφ）焦亡在HMGB 1- 5）AMφ焦亡与肺部炎症反应增强有关。 基于上述发现，我们假设：1）HMGB 1-β信号通路作为一种新的 创伤后诱导Mφ焦亡的机制;和2）Mφ焦亡促进 创伤后ALI通过影响炎症过程;和3）释放的炎性体组分 作为一种新的次级危险信号，诱导炎症放大。为了测试 根据这些假设，我们提出了以下两个具体目标：具体目标1：确定分子 创伤诱导Mφ焦亡的机制。具体目标2：确定Mφ的作用 在创伤后ALI的发展过程中，