Cell Death Mechanism of Acute Lung Injury in Sepsis

描述(由申请人提供)： 摘要脓毒症每年影响80多万人，在美国死亡率高达30%。严重脓毒症合并多器官功能障碍综合征(MODS)是重症监护室死亡的主要原因，死亡率超过50%。急性肺损伤(ALI)是多器官功能障碍综合征(MODS)的重要组成部分，也是患者死亡的直接原因。然而，在脓毒症中，几乎没有有效的治疗靶点被确定为易患MODS和ALI的个体。肺泡巨噬细胞(AM)在脓毒症所致ALI发病机制中处于中心地位。巨噬细胞(M�)松下症是新近发现的一种依赖半胱氨酸天冬氨酸蛋白酶1的程序性细胞死亡，其特征是质膜快速破裂和细胞内促炎物质的释放。然而，M-�上睑下垂在脓毒症进展中的体内作用和M-�上睑下垂的机制尚不清楚。我们现在在我们的初步研究中证明，在盲肠结扎和穿孔(CLP)的小鼠多菌败血症模型中，脓毒症诱导AM和循环单核细胞下垂。这种脓毒症诱导的下垂是通过一条新的信号通路介导的，在该信号通路中，依赖RAGE的HMGB1内吞作用激活了裂殖体组装和细胞下垂。我们的进一步观察表明，AM焦下症的诱导通过释放或促进健康AM释放促炎细胞因子和趋化因子，增强中性粒细胞(PMN)的趋化作用和抑制T淋巴细胞迁移来增强炎症。晚期糖基化终末产物受体高迁移率族蛋白1(此外，我们在以前和初步的研究中也表明，内毒素和HMGB1至TLR4上调AM中的TLR2，进而增加AM的嗜热症，以响应细菌来源的TLR2配体。基于这些发现，我们推测：1)AM上睑下垂可能通过放大炎症过程而促进脓毒症时ALI的发展；2)HMGB1-RAGE信号通路可能是导致脓毒症AM下垂发生的新机制；3)TLR4信号上调的TLR2可能是脓毒症AM上睑下垂加重的重要机制。为了验证这些假说，我们提出了以下三个具体目标：具体目标1：确定AM下垂在脓毒症后ALI发生发展中的作用。具体目的#2：确定脓毒症引起AM下垂的分子机制。具体目的#3：确定脓毒症时TLR2信号启动AM上睑下垂的机制。

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.