Cell Priming, Receptor Cross-talk and Acute Lung Injury

描述（由申请人提供）：严重创伤引起的失血性休克（HS）通过激活和启动炎症过程，促进全身性炎症反应综合征（SIRS）的发展，其机制尚不清楚。急性肺损伤（ALI）是SIRS的主要组成部分，往往是患者死亡的直接原因。肺血管内皮是一个活跃的器官，通过合成和释放一些炎症介质在ALI的发展中起着核心作用。IL-12是在肺部炎症过程中具有多重作用的关键细胞因子。肺内皮细胞（EC）是响应HS损伤的IL-12的一个重要来源。相反，肺EC是IL-12的靶点，在IL-12刺激下引起一系列炎症分子的产生，包括IL-12本身。因此，肺EC通过与IL-12的相互作用形成了一种反馈机制，放大了HS的肺部炎症。活性IL-12的产生受到炎性小体的严格控制。尽管IL-12在SIRS的发展中起着核心作用，但旨在阻断IL-1受体的抗IL-12治疗尚未成功。然而，靶向炎性体可能为创伤后SIRS提供一种新的抗il -12策略。然而，HS在肺和EC中引发炎性体的机制尚不清楚。我们观察到两种可能介导HS激活和炎性体启动的受体串扰机制。我们发现TLR4信号上调I型IL-1受体（IL-1RI），从而使细胞对IL-12刺激敏感；HS增强toll样受体（TLR）4信号在肺内皮细胞中TLR2的上调，从而增加IL-12对TLR2配体的释放。在本研究中，我们将验证以下假设：1)HS通过靶向肺EC炎性体促进ALI的发展；2) TLR4- IL-1RI串扰是放大HS肺部炎症的一种新的反馈机制；3) TLR4-TLR2的串扰是介导hs引发炎性小体活化的重要机制。

DESCRIPTION (provided by applicant): Hemorrhagic shock (HS) resulting from severe trauma promotes the development of systemic inflammatory response syndrome (SIRS) by activating and priming the inflammatory process through as of yet unclear mechanisms. Acute lung injury (ALI) is a major component of SIRS and often serves as a direct cause of death to patients. The lung vascular endothelium is an active organ and plays a central role in the development of ALI through synthesis and release of a number of inflammatory mediators. IL-12 is a key cytokine with multiple effects on lung inflammatory processes. Lung endothelial cells (EC) are one important source of IL-12 in response to HS insult. Conversely, lung EC is targets of IL-12, causing the production of a range of inflammatory molecules, including IL-12 itself, in response to IL-12 stimulation. Thus, lung EC through interacting with IL-12 forms a feedback mechanism to amplify lung inflammation in HS. The production of active IL-12 is tightly controlled by Inflammasome. Despite the central role of IL-12 in the development of SIRS, anti-IL-12 therapy aimed at blocking IL-1 receptor has not been successful. Targeting at inflammasome, however, may present a novel anti-IL-12 strategy for post-trauma SIRS. However, the mechanism underlying HS initiation of inflammasome in the lung and EC is unclear. We have observed two receptor cross-talk mechanisms that might mediate HS activation and priming of inflammasome. We found that TLR4 signaling upregulates type I IL-1 receptor (IL-1RI), and thereby sensitizing the cells to IL-12 stimulation; and HS enhances Toll-like receptor (TLR)4 signaling upregulation of TLR2 in lung EC, which in turn augments IL-12 release in response to TLR2 ligands. In the proposed study we will test the hypotheses that: 1) HS through targeting lung EC inflammasome promotes the development of ALI; 2) cross-talk of TLR4- IL-1RI is a novel feedback mechanism amplifying lung inflammation in HS; and 3) cross-talk of TLR4-TLR2 serves as an important mechanism mediating HS-primed inflammasome activation.