Cell Death Mechanism of Acute Lung Injury in Sepsis

脓毒症急性肺损伤的细胞死亡机制

• 批准号: 9794744
• 负责人: Jie Fan
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9794744
• 关键词: Acute Lung Injury; Address; Affect; Alveolar Macrophages; Apoptosis; Bacteria; CASP1 gene; Cause of Death; Cell Death; Cell membrane; Cells; Cessation of life; Chemotaxis; Development; Disease; Endocytosis; Goals; HMGB1 Protein; Immune System Diseases; Individual; Inflammasome; Inflammation; Inflammatory; Innate Immune Response; Intervention; Kinetics; Ligands; Mediating; Modeling; Molecular; Morphology; Multiple Organ Failure; Mus; Necrosis; Nuclear Protein; Pathogenesis; Patients; Phase; Preventive Intervention; Process; Regulation; Reporting; Role; Rupture; Sepsis; Signal Pathway; Signal Transduction; T-Lymphocyte; TLR2 gene; TLR4 gene; Testing; Therapeutic Intervention; Treatment Efficacy; adaptive immunity; base; cecal ligation puncture; cell type; chemokine; cytokine; effective therapy; extracellular; human disease; in vivo; insight; macrophage; marenostrin; migration; monocyte; mortality; neutrophil; novel; polymicrobial sepsis; prophylactic; public health relevance; receptor for advanced glycation endproducts; response; septic; septic patients; therapeutic target

DESCRIPTION (provided by applicant): Abstract Sepsis affects more than 800,000 people annually with a mortality rate as high as 30% in the US. Severe sepsis complicated with multiple organ dysfunction syndrome (MODS) is a leading cause of death in intensive therapy units with a mortality rate exceeding 50%. Acute lung injury (ALI) is an important component of MODS and often serves as a direct cause of patient death. Nonetheless, few effective therapeutic targets have been identified that predispose an individual to MODS and ALI in sepsis. Alveolar macrophages (AM) are at the center of the pathogenesis of ALI triggered by sepsis. Macrophage (M�pyroptosis is a recently identified caspase-1-dependent programmed cell death, which features rapid plasma-membrane rupture and release of pro-inflammatory intracellular contents. However, the in vivo role of M�yroptosis in the progression of sepsis and the mechanism underlying M�yroptosis remain unclear. We now demonstrate in our preliminary studies that sepsis induces AM and circulating monocytes pyroptosis in a mouse polymicrobial sepsis model of cecal ligation and puncture (CLP). This sepsis-induced pyroptosis is mediated by a novel signaling pathway, in which (RAGE)-dependent endocytosis of HMGB1) activates pyroptosome assembly and cell pyroptosis. Our further observations suggest that induction of AM pyroptosis enhances inflammation by releasing or promoting healthy AM to release pro-inflammatory cytokines and chemokines, augmenting polymorphonuclear neutrophil (PMN) chemotaxis and suppressing T lymphocyte migration. receptor for advanced glycation end products high mobility group box 1 ( Moreover, we have also shown in our previous and preliminary studies that LPS and HMGB1 throughTLR4 upregulate TLR2 in AM, which in turn augments AM pyroptosis in response to bacteria-derived TLR2 ligands. Based on these findings, we hypothesize that: 1) AM pyroptosis may promote the development of ALI in sepsis by amplifying the inflammatory process; 2) HMGB1-RAGE signaling serves as a novel mechanism that induces AM pyroptosis in sepsis; and 3) TLR4 signaling-upregulated TLR2 serves as an important mechanism for augmented AM pyroptosis in sepsis. In order to test these hypotheses, we propose the following three specific aims: Specific Aim #1: to determine the role of AM pyroptosis in the development of ALI following sepsis. Specific Aim #2: to determine the molecular mechanism through which sepsis induces AM pyroptosis. Specific Aim #3: to determine the mechanism of TLR2 signaling-primed AM pyroptosis in sepsis.

描述（由申请人提供）： 摘要脓毒症在美国每年影响超过80万人，死亡率高达30%。严重脓毒症并发多器官功能障碍综合征（MODS）是重症监护病房的主要死亡原因，死亡率超过50%。急性肺损伤（acute lung injury，ALI）是多器官功能不全综合征（MODS）的重要组成部分，是导致患者死亡的直接原因。尽管如此，很少有有效的治疗靶点已被确定，使个体在脓毒症中易患MODS和ALI。肺泡巨噬细胞（AM）是脓毒症引起的急性肺损伤的发病机制的中心。巨噬细胞凋亡（Macrophage pyroptosis）是近年来发现的一种caspase-1依赖的程序性细胞死亡，其特征是质膜迅速破裂并释放促炎细胞内物质。然而，在脓毒症的进展中的体内作用和潜在的机制仍不清楚。 我们现在证明，在我们的初步研究中，脓毒症诱导AM和循环单核细胞焦亡在小鼠多微生物脓毒症模型盲肠结扎和穿孔（CLP）。这种脓毒症诱导的细胞凋亡是由一种新的信号传导途径介导的，其中HMGB 1）的（β-）依赖性内吞作用激活了细胞凋亡小体组装和细胞凋亡。我们进一步的观察表明，诱导AM pyroptosis通过释放或促进健康AM释放促炎细胞因子和趋化因子，增强多形核中性粒细胞（PMN）的趋化性和抑制T淋巴细胞迁移增强炎症。晚期糖基化终产物高迁移率族蛋白1受体（此外，我们在先前和初步的研究中也表明，LPS和HMGB 1通过TLR 4上调AM中的TLR 2，这反过来又增强了AM对细菌来源的TLR 2配体的反应。 基于这些发现，我们推测：1）AM焦亡可能通过放大炎症过程促进脓毒症中ALI的发展; 2）HMGB 1-β信号转导是脓毒症中诱导AM焦亡的新机制; 3）TLR 4信号转导上调的TLR 2是脓毒症中AM焦亡增强的重要机制。为了检验这些假设，我们提出了以下三个具体目标：具体目标#1：确定AM焦亡在脓毒症后ALI发展中的作用。具体目标#2：确定脓毒症诱导AM焦亡的分子机制。具体目标#3：确定脓毒症中TLR 2信号传导引发的AM焦亡的机制。