Role Of p120 Catenin In Sepsis-Induced Lung Injury

描述（由申请人提供）：细菌内毒素（脂多糖，LPS）可引发全身高炎症反应，随后导致多器官功能障碍综合征。LPS结合toll样受体4 （TLR4）可诱导丝裂原活化蛋白激酶（MAPK）和核因子B （NF-(B)）的活化，从而产生促炎细胞因子。当这种生产失控和过量时，就会导致感染性休克的发展。p120-连环蛋白是内皮细胞和其他极化贴壁细胞粘附连接的一个组成部分，最近被认为与炎症的内在调节有关。无p120-catenin的表皮细胞表现出NF-(B)和促炎性NF-(B)靶点活性增加。在初步实验中，我们做了一个有趣的观察，肺血管中p120的特异性siRNA缺失使小鼠对LPS高度敏感，这表明p120是宿主对败血症反应的关键因素。我们的支持数据进一步证明，LPS刺激后小鼠肺中的p120-catenin表达迅速降低。此外，肺血管内皮和培养的肺微血管内皮细胞中p120-catenin的缺失通过激活NF-(B)和MAPK信号，显著增加lps诱导的细胞间粘附分子-1 （ICAM-1）、中性粒细胞粘附和跨内皮中性粒细胞迁移的表达。总的来说，这些数据表明p120-catenin可以抑制lps诱导的肺部炎症反应。本研究拟明确p120-catenin的抗炎作用，确定LPS诱导p120-catenin降解的机制，探讨p120-catenin通过干扰tlr4激活的信号通路减轻肺部炎症损伤的可能性。该提案将涉及以下具体目标：探讨lps诱导肺损伤后肺内皮细胞p120-catenin表达的调控机制。在这里，我们将剖析在LPS刺激下导致肺微血管p120丢失的信号通路。2. 探讨内皮细胞p120-catenin表达在lps诱导的肺炎性损伤中的调控作用。3. 确定内皮p120调节TLR4信号介导的肺部炎症的信号通路。确定p120-连环蛋白激活的途径调节lps诱导的脓毒症将对设计治疗或预防急性肺损伤的治疗策略有很大的兴趣。

DESCRIPTION (provided by applicant): The bacterial endotoxin (lipopolysaccharide, LPS) can trigger systemic hyper-inflammatory response that subsequently leads to multiple organ dysfunction syndrome. LPS binding to toll-like receptor 4 (TLR4) induces the activation of mitogen-activated protein kinase (MAPK) and nuclear factor (B (NF-(B) resulting in production of pro-inflammatory cytokines. When this production becomes uncontrolled and excessive, it leads to the development of septic shock. p120-catenin, a component of adherens junctions in endothelial cells and other polarized adherent cells, has recently been implicated in the intrinsic regulation of inflammation. p120-catenin null epidermal cells exhibited increased activity of NF-(B and proinflammatory NF-(B targets. In preliminary experiments, we made the intriguing observation that deletion of p120 in the lung vasculature with specific siRNA rendered the mice highly susceptible to LPS, suggesting that p120 is a crucial element of the host response to sepsis. Our supporting data further demonstrate that p120-catenin expression in the mouse lung is rapidly reduced after LPS challenge. Also, deletion of p120-catenin in pulmonary vasculature endothelium and cultured pulmonary microvascular endothelial cells significantly increased LPS-induced expression of intercellular adhesion molecule-1 (ICAM-1), neutrophil adhesion, and transendothelial neutrophil migration via activation of NF-(B and MAPK signaling. Collectively, these data suggest that p120-catenin serves to dampen the LPS-induced inflammatory response in lungs. The objectives of the proposed studies are to define the anti-inflammatory role of p120-catenin, determine the mechanism of p120-catenin degradation induced by LPS, and to explore the possibility that p120-catenin interferes with the TLR4-activated signaling pathway to mitigate lung inflammatory injury. The proposal will address the following Specific Aims: 1. To determine the mechanisms of regulation of pulmonary endothelial p120-catenin expression in response to LPS-induced lung injury. Here we will dissect the signaling pathways that cause the loss of p120 in the pulmonary microvasculature following LPS challenge. 2. To define the role of endothelial p120-catenin expression in the regulation of LPS-induced lung inflammatory injury. 3. To identify the signaling pathways by which endothelial p120 regulates TLR4 signaling-mediated lung inflammation. The identification of p120-catenin-activated pathways modulating LPS-induced sepsis will be of great interest in the design of therapeutic strategies for the treatment or prevention of acute lung injury. PUBLIC HEALTH RELEVANCE: Acute lung injury caused by widespread bacterial infection is a severe and life threatening condition that requires a mechanical breathing machine and other supportive care in hospital intensive care units. We have shown that protein p120-catenin in the lung plays an essential role in preventing severe lung inflammation that causes acute lung injury. The purpose of this research is to define the basic molecular mechanisms by which p120-catenin regulates lung inflammation in order to design new and effective strategies for the treatment or prevention of acute lung injury.