Homeostatic Regulation of Neutrophil ROS Production and Lung Injury

中性粒细胞活性氧产生和肺损伤的稳态调节

基本信息

批准号：
8380083
负责人：
RICHARD D YE
金额：
$ 34.66万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-01 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8380083
关键词：
4-ethoxymethylene-2-phenyl-2-oxazoline-5-one Acute Lung Injury Address Adhesions Adult Respiratory Distress Syndrome Bacteria Bacterial Infections Blood Vessels Clinical Treatment Communicable Diseases Complement Complication Edema Endothelial Cells Ensure Family Feedback Goals Homeostasis Host Defense Mechanism In Vitro Infection Inflammation Inflammatory Inflammatory Response Injury Intercellular adhesion molecule 1 Investigation Knowledge Lead Lung Lung Inflammation MAP Kinase Gene MAP kinase phosphatase MKP-5 MAPK14 gene Mammalian Cell Mediating Modeling Mouse Strains Mus NADPH Oxidase Organelles Oxidants Oxidative Stress Pathway interactions Phagocytes Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Production Program Research Project Grants Protein Dephosphorylation Protein Kinase Protein phosphatase Proteins Reactive Oxygen Species Regulation Research Respiratory physiology Role Sepsis Severities Signal Transduction Superoxides Testing Therapeutic Therapeutic Intervention Tissues Vascular Permeabilities bactericide base chemokine cytokine in vivo lung injury microbial mortality mouse model neutrophil novel prevent protective effect

项目摘要

The ability of phagocytes to produce large amounts of oxygen radicals constitutes an important host-defense mechanism against microbial infection. However, the same oxidant-generafing machinery also contributes to tissue injury such as in Acute Lung Injury (ALI) resulting from uncontrolled activation of phagocytes. While research on phagocyte NADPH oxidase has produced a great deal of information regarding its activation mechanisms, little is known about the negative regulatory mechanisms that limit phagocyte oxidant production. The objective of Project 2 is to define such negative regulatory mechanisms and explore the potenfial for dampening lung inflammatory response. Studies are proposed in two substanfial specific aims that focus on our recently identified regulatory mechanism by MAP kinase phosphatase 5 (MKPS), which restrains oxidant production by polymorphnuclear neutrophils, thereby decreasing LPS-induced inflammatory vascular injury. In Aim 1, we will determine how MKP5 regulates PMN oxidant producfion, which is crifical to ALI. The profound negative regulatory effect by MKP5 suggests that p38 MAPK, the target of MKP5, is critical to PMN NADPH oxidase activation. Studies are proposed to test the hypothesis that p38 MAPK is essential for sequential phosphorylation of p47[phox] by a multitude of protein kinases, leading to p47[phox] conformational change and full activation of NADPH oxidase. We will also test the hypothesis that p38 MAPK signaling is further amplified through MK2, a downstream effector and protein kinase that contributes to p47[phox] phosphorylation. The in vivo function of MK2 in ALI and its regulation by MKP5 will be interrogated with the use of MK2 -/- and MKP5 -/- mice. In Aim 2, we will define the central role of MKP5 in preventing ALI through modulation of PMN and endothelial activation. Using mouse models of lung infiammation, we will test the hypothesis that MKP5 is an essential regulator that reduces proinfiammatory cytokine and chemokine expression, limits PMN infiltrafion, and dampens PMN oxidant production and oxidant-mediated lung injury. We will also query the possibility that endothelial MKP5 is important in limifing ICAM-1 expression and thus prevents PMN adhesion as well as oxidant-mediated injury. Together, these studies aims to delineate the underlying mechanism for LPS priming of PMN oxidant producfion, and explore a novel negative regulatory mechanism for its therapeutic potential in controlling ALI.

吞噬细胞产生大量氧自由基的能力构成了针对微生物感染的重要宿主防御机制。然而，相同的氧化剂 - 替代机制也有助于组织损伤，例如由于不受控制的吞噬细胞激活而导致的急性肺损伤（ALI）。虽然对吞噬细胞NADPH氧化酶的研究产生了有关其激活机制的大量信息，但对限制吞噬细胞氧化剂产生的负调控机制知之甚少。项目2的目的是定义这种负面的调节机制，并探索能力减弱肺部炎症反应的力量。提出了在两个分类特定目的中提出的研究，该目标重点是通过MAP激酶磷酸酶5（MKP）鉴定出的最近确定的调节机制，该机制通过多核核中性粒细胞来限制氧化剂的产生，从而降低了LPS诱导的炎性血管损伤。在AIM 1中，我们将确定MKP5如何调节与Ali易碎的PMN氧化剂产生。 MKP5的深刻负调控作用表明，MKP5的靶标p38 MAPK对PMN NADPH氧化酶活性至关重要。提出了研究以检验p38 MAPK对p47 [phox]的顺序磷酸化至关重要的假设，从而导致p47 [phox]构象变化和NADPH氧化酶的充分激活。我们还将检验以下假设：p38 MAPK信号通过MK2进一步扩增，MK2是一种下游效应子和蛋白激酶，有助于P47 [Phox]磷酸化。 MK2在ALI中的体内函数及其对MKP5的调节将通过使用MK2 - / - 和MKP5 - / - 小鼠的质疑。在AIM 2中，我们将定义MKP5通过调节PMN和内皮激活来防止ALI的核心作用。使用肺部输注的小鼠模型，我们将检验以下假设：MKP5是一种必不可少的调节剂，可降低临时细胞因子和趋化因子的表达，限制PMN浸润性，并抑制PMN PMN氧化剂的产生和氧化剂氧化剂介导的肺损伤。我们还将查询内皮MKP5在限制ICAM-1表达的可能性，从而防止PMN粘附以及氧化剂介导的损伤。总之，这些研究旨在描述PMN氧化剂生产的LPS启动的潜在机制，并探索一种用于控制ALI的治疗潜力的新型负调节机制。