NADPH OXIDASE REGULATION OF THE MACROPHAGE INFLAMMATORY PHENOTYPE IN SEPSIS

NADPH 氧化酶对脓毒症巨噬细胞炎症表型的调节

基本信息

批准号：
8078053
负责人：
John W Christman
金额：
$ 39.25万
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：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8078053
关键词：
Acute Acute Lung Injury Address Adoptive Transfer Alveolar Macrophages Animals Anti-Inflammatory Agents Anti-inflammatory Attenuated Binding Bone Marrow Bone Marrow Cells Cells Chest Chimera organism Cues Data Edema Endotoxemia Endotoxins Ensure Event Exhibits Exposure to Family member Generations Genetic Transcription Goals Inflammation Inflammatory Inflammatory Response Injection of therapeutic agent Injury Interleukin-10 Knockout Mice Lead Link Lipopolysaccharides Liposomes Lung Lung Inflammation Macrophage Activation Measures Mediating Mediator of activation protein Methods Modeling Molecular Morbidity - disease rate Mus Myelogenous Myeloid Cells NADP NADPH Oxidase NF-kappa B Neutrophil Activation Oxidants Oxidases Oxidation-Reduction Oxygen Pathogenesis Pathway interactions Phenotype Phosphatidylinositols Phosphoric Monoester Hydrolases Phosphotransferases Production Pulmonary Edema Reactive Oxygen Species Regulation Relative (related person)Resolution Respiratory physiology Role Sepsis Signal Pathway Signal Transduction Supportive care Syndrome TNF gene Testing Time Transgenic Mice Vascular Permeabilities Wild Type Mouse base cytokine improved in vivo lung injury macrophage mortality mouse model myo-inositol-1 (or 4)-monophosphatase neutrophil novel novel therapeutic intervention pathogen phosphoinositide-3,4-bisphosphate public health relevance research study response septic src-Family Kinases surfactant toll-like receptor 4 uptake

项目摘要

DESCRIPTION (provided by applicant): Acute lung injury (ALI) associated with Gram-negative sepsis is characterized by neutrophil- mediated inflammation that exhibits excessive morbidity and mortality. In spite of improved supportive care, there are currently no specific treatments for ALI that are based on the molecular pathogenesis of the syndrome. Our overall goal is to identify signaling mechanisms in pulmonary macrophages that regulate the activation of neutrophils that are crucial in mediating lung inflammatory injury. We have shown that inhibition of NADPH oxidase activity results in dampening of the transcription nuclear factor kappa B (NF-kB) activation in lungs that are treated with endotoxin without a reduction in cytokine generation or inflammation mediated by neutrophils. The mechanisms of increased inflammation seen in NADPH oxidase-deficient mice relative to wt have not been defined. Using reciprocal bone marrow chimera p47phox-/- wt mice, we observed that p47phox-/- bone marrow in wt mice resulted in enhanced NF-kB activation and neutrophilic inflammation in lungs LPS challenge. Our central hypothesis based on these data is that NADPH oxidase-generated ROS signaling converts macrophages from a pro- to anti- inflammatory phenotype during endotoxemia. We will address the postulate that this phenotype switch occurs via NADPH oxidase-generated ROS activation of a redox-sensitive Src, Lyn kinase, which in turn activate the SH2-containing phosphatidyl inositol phosphatase-1 (SHIP-1). In this model, Lyn kinase and SHIP-1 represent a critical signaling node that enhances PIP3 degradation to PI (3, 4) P2, which attenuates activation of Akt and thereby of NF-kB. This model will be interrogated in Aim 1 in which we will determine the role of NADPH oxidase-generated ROS signaling in the mechanism of the anti-inflammatory phenotype switch in macrophages. Further in Aim 2, we will identify the redox-activated signaling mechanisms downstream of NADPH oxidase generation of ROS in mediating the conversion in macrophage function and thereby identify the potentially important role of macrophages in mitigating lung inflammatory injury. By systematically delineating the role of NADPH oxidase in regulating the function of lung macrophages in modulating lung inflammation, we should identify novel signaling pathways that could provide novel therapeutic approaches to limit the injury. PUBLIC HEALTH RELEVANCE: Our supporting data suggests that reactive oxygen species (ROS) have an important role in modulating an anti-inflammatory macrophage phenotype through negative regulation of the NF-kB activation pathway. We will dissect the involved mechanisms that link ROS to a role for macrophages in the resolution of lung inflammation which should lead to new treatments for acute lung inflammation.

描述（由申请人提供）：与革兰氏阴性脓毒症相关的急性肺损伤（ALI）的特征是中性粒细胞介导的炎症，其表现出过高的发病率和死亡率。尽管支持治疗有所改善，但目前还没有基于该综合征分子发病机制的 ALI 特异性治疗方法。我们的总体目标是确定肺巨噬细胞中调节中性粒细胞激活的信号机制，这对于介导肺部炎症损伤至关重要。我们已经证明，抑制 NADPH 氧化酶活性会抑制用内毒素处理的肺中转录核因子 kappa B (NF-kB) 的激活，但不会减少细胞因子的产生或中性粒细胞介导的炎症。与野生型相比，NADPH 氧化酶缺陷型小鼠炎症增加的机制尚未明确。使用互惠骨髓嵌合体 p47phox-/- wt 小鼠，我们观察到 wt 小鼠中的 p47phox-/- 骨髓导致 LPS 攻击中 NF-kB 激活增强和肺部中性粒细胞炎症。我们基于这些数据的中心假设是，在内毒素血症期间，NADPH 氧化酶产生的 ROS 信号将巨噬细胞从促炎表型转变为抗炎表型。我们将假设这种表型转换是通过 NADPH 氧化酶产生的 ROS 激活氧化还原敏感的 Src、Lyn 激酶而发生的，而后者又激活含有 SH2 的磷脂酰肌醇磷酸酶-1 (SHIP-1)。在此模型中，Lyn 激酶和 SHIP-1 代表关键信号传导节点，可增强 PIP3 降解为 PI (3, 4) P2，从而减弱 Akt 的激活，从而减弱 NF-kB 的激活。该模型将在目标 1 中得到检验，其中我们将确定 NADPH 氧化酶产生的 ROS 信号在巨噬细胞抗炎表型转换机制中的作用。此外，在目标 2 中，我们将确定 NADPH 氧化酶生成 ROS 下游介导巨噬细胞功能转换的氧化还原激活信号传导机制，从而确定巨噬细胞在减轻肺部炎症损伤中的潜在重要作用。通过系统地描述 NADPH 氧化酶在调节肺巨噬细胞功能以调节肺部炎症中的作用，我们应该确定新的信号传导途径，从而提供新的治疗方法来限制损伤。公共健康相关性：我们的支持数据表明，活性氧 (ROS) 通过负向调节 NF-kB 激活途径，在调节抗炎巨噬细胞表型方面发挥着重要作用。我们将剖析将 ROS 与巨噬细胞在解决肺部炎症中的作用联系起来的相关机制，这应该会导致急性肺部炎症的新治疗方法。