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宿主抵抗微生物感染的重要防御机制。然而，相同的氧化剂生成机制也会导致组织损伤，例如由于吞噬细胞激活不受控制而导致的急性肺损伤（ALI）。虽然对吞噬细胞 NADPH 氧化酶的研究已经产生了大量有关其激活机制的信息，但人们对限制吞噬细胞氧化剂产生的负调节机制知之甚少。项目 2 的目标是定义此类负调节机制并探索抑制肺部炎症反应的潜力。提出的研究有两个具体目标，重点是我们最近发现的 MAP 激酶磷酸酶 5 (MKPS) 的调节机制，该机制抑制多形核中性粒细胞产生氧化剂，从而减少 LPS 诱导的炎症血管损伤。在目标 1 中，我们将确定 MKP5 如何调节 PMN 氧化剂的产生，这对于 ALI 至关重要。 MKP5 的深刻负调节作用表明，MKP5 的靶标 p38 MAPK 对于 PMN NADPH 氧化酶激活至关重要。提出的研究旨在检验以下假设：p38 MAPK 对于多种蛋白激酶对 p47[phox] 的顺序磷酸化至关重要，从而导致 p47[phox] 构象变化和 NADPH 氧化酶的完全激活。我们还将测试 p38 MAPK 信号通过 MK2 进一步放大的假设，MK2 是一种下游效应器和蛋白激酶，有助于 p47[phox] 磷酸化。将使用 MK2 -/- 和 MKP5 -/- 小鼠来研究 MK2 在 ALI 中的体内功能及其受 MKP5 的调节。在目标 2 中，我们将定义 MKP5 通过调节 PMN 和内皮激活来预防 ALI 的核心作用。使用小鼠肺部炎症模型，我们将检验以下假设：MKP5 是一种重要的调节因子，可减少促炎症细胞因子和趋化因子的表达，限制 PMN 浸润，并抑制 PMN 氧化剂的产生和氧化剂介导的肺损伤。我们还将质疑内皮 MKP5 在限制 ICAM-1 表达方面发挥重要作用，从而防止 PMN 粘附以及氧化剂介导的损伤的可能性。这些研究旨在阐明 LPS 引发 PMN 氧化剂产生的潜在机制，并探索其在控制 ALI 方面的治疗潜力的新型负调节机制。