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.

巨噬细胞凋亡机制，急性肺损伤 抽象的 创伤是系统性炎症综合征（SIR）和多器官的主要原因 功能障碍综合征（MODS），其中急性肺损伤（ALI）是重要组成部分。基础 创伤如何导致SIRS，MODS和ALI的机制尚未完全确定，但要理解 这些机制至关重要，因为创伤患者的早期介入治疗可能会阻止 器官故障和通常几天后发生的损害。我们的长期目标是确定机制 通过哪种创伤促进ALI，从而有可能识别预防性干预的新靶标。 我们报道了一种新型机制，通过该机制，损伤相关的分子模式（潮湿） 分子诱导巨噬细胞（Mφ）凋亡，caspase-1依赖性程序性细胞死亡。这 凋亡细胞的最终渗透裂解可释放细胞内含量并引起炎症。我们的 遵循初步研究进一步表明：1）HMGB1诱导人类外周单核细胞凋亡； 2）创伤患者确实发生了循环的单核细胞凋亡，细胞内炎症体确实发生 释放成分，可以在创伤后四天的创伤患者血清中检测到； 3） 细胞外NLRP3炎性组成分的Mφ吞噬作用激活了炎症反应 mφ; 4）在HS/创伤的小鼠模型中，HMGB1-诱导肺泡巨噬细胞（AMφ） - 依赖愤怒的方式；和5）AMφ凋亡与增强的肺注射有关。 基于上述发现，我们假设：1）HMGB1-RAGE信号作为一种新颖 创伤后影响Mφ凋亡的机制； 2）Mφ凋亡促进了 因影响炎症过程而受创伤后的ALI； 3）释放的炎症组件 从凋亡中，Mφ是诱导扩增注射的新型次要危险信号。为了测试 这些假设，我们提出以下两个特定目的：特定目的1：确定分子 创伤诱导Mφ凋亡的机制。特定目标2：确定Mφ的作用 创伤后ALI的发展中的凋亡。