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: 9593050
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9593050
• 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; Preventive Intervention; 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; preclinical study; prevent; 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焦亡机制 抽象的 创伤是全身炎症反应综合征 (SIRS) 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）是一个重要组成部分。底层的 创伤导致 SIRS、MODS 和 ALI 的机制尚未完全确定，但了解 这些机制至关重要，因为创伤患者的早期介入治疗可能会预防 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 创伤可促进 ALI，从而有可能确定预防性干预的新目标。 我们报道了一种新的机制，通过损伤相关分子模式（DAMP） 分子诱导巨噬细胞 (Mφ) 焦亡，这是一种依赖于 caspase-1 的程序性细胞死亡。这 焦亡细胞的最终渗透裂解释放细胞内内容物并引起炎症。我们的 以下初步研究进一步表明：1）HMGB1诱导人外周单核细胞焦亡； 2）外伤患者确实会发生循环单核细胞焦亡，且细胞内炎症小体 创伤后四天左右，成分被释放并可在创伤患者的血清中检测到； 3） Mφ吞噬细胞外Nlrp3炎症小体成分激活炎症反应 Mφ； 4) 在 HS/创伤小鼠模型中，HMGB1- 诱导肺泡巨噬细胞 (AMφ) 焦亡 RAGE依赖方式； 5) AMφ焦亡与肺部炎症加剧有关。 基于上述发现，我们假设：1）HMGB1-RAGE信号作为一种新型的信号通路。 创伤后诱导Mφ焦亡的机制； 2）Mφ焦亡促进发育 通过影响炎症过程而导致创伤后 ALI； 3) 释放的炎症小体成分 来自焦亡的 Mφ 可作为新的次要危险信号来诱导放大的炎症。为了测试 根据这些假设，我们提出以下两个具体目标： 具体目标 1：确定分子 创伤诱发 Mφ 焦亡的机制。具体目标 2：确定 Mφ 的作用 创伤后 ALI 发展中的细胞焦亡。