Macrophage Pyroptosis Mechanism of Post-Trauma Acute Lung Injury

创伤后急性肺损伤巨噬细胞下垂机制的研究 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 功能障碍综合征(MODS)，其中急性肺损伤(ALI)是其重要组成部分。潜在的 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 通过创伤促进ALI，从而潜在地确定预防干预的新靶点。 我们报道了一种新的损伤相关分子模式(DAMP)机制。 分子诱导巨噬细胞(Mφ)下垂，这是一种依赖于caspase-1的程序性细胞死亡。这个 嗜热性细胞的最终渗透溶解释放细胞内的内容物并引起炎症。我们的 以下初步研究进一步表明：1)HMGB1诱导人外周血单核细胞下垂； 2)创伤患者可发生循环单核细胞下垂，细胞内炎性小体。 创伤患者在创伤后四天左右的血清中可以检测到成分的释放；3) M-φ吞噬细胞外Nlrp3炎性小体成分激活炎症反应 在HS/创伤的小鼠模型中，肺泡巨噬细胞(AMφ)松下症是由HMGB1-1诱导的。 AM-φ上睑下垂与肺部炎症加重相关。 基于上述发现，我们假设：1)HMGB1-RAGE信号转导机制可能是一种新颖的 创伤后M-φ上睑下垂的发生机制；2)M-φ上睑下垂促进 创伤后ALI通过影响炎症过程；3)释放的炎性小体成分 来自焦链霉菌的φ是一种新的继发性危险信号，可引起放大的炎症反应。为了测试 在这些假设下，我们提出了以下两个具体目标：具体目标1：确定分子 创伤导致M-φ下垂的机制。具体目标2：确定Mφ的作用 创伤后ALI发展过程中的下垂。

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.