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来促进全身炎症反应综合征(SIRS)的发展，其机制尚不清楚。急性肺损伤(ALI)是全身炎症反应综合征(SIRS)的主要组成部分，常常是患者死亡的直接原因。肺血管内皮细胞是一个活跃的器官，通过合成和释放多种炎症介质，在ALI的发生发展中起着核心作用。IL-12是一种重要的细胞因子，在肺部炎症过程中具有多方面的作用。肺内皮细胞(EC)是HS损伤后产生IL-12的重要来源之一。相反，肺内皮细胞是IL-12的靶标，导致一系列炎症分子的产生，包括IL-12本身，以响应IL-12的刺激。因此，肺内皮细胞通过与IL-12相互作用形成一种反馈机制，放大HS的肺部炎症反应。活性IL-12的产生受到炎症体的严密控制。尽管IL-12在SIRS的发生发展中起着核心作用，但以阻断IL-1受体为目的的抗IL-12治疗并不成功。然而，针对炎症小体，可能为创伤后SIRS提供一种新的抗IL-12策略。然而，HS启动肺和EC炎症小体的机制尚不清楚。我们观察到了两种受体串扰机制，它们可能介导HS的激活和炎症小体的启动。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信号上调TLR2在肺内皮细胞中的表达，进而增加TLR2配体对IL-12的释放。在拟议的研究中，我们将检验以下假设：1)HS通过靶向肺EC炎症体促进ALI的发展；2)TLR4-IL-1RI的串扰是放大HS肺部炎症的一种新的反馈机制；以及3)TLR4-TLR2的串扰是介导HS启动的炎症性小体激活的重要机制。

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.