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

• 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
• 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

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）以中性粒细胞介导的炎症为特征，表现出过高的发病率和死亡率。尽管支持治疗得到了改善，但目前还没有针对ALI的基于该综合征分子发病机制的特异性治疗方法。我们的总体目标是确定在肺巨噬细胞中调节中性粒细胞激活的信号机制，中性粒细胞在介导肺炎症损伤中至关重要。我们已经证明，抑制NADPH氧化酶活性导致内毒素处理肺中转录核因子κ B （NF-kB）活化的抑制，而不减少细胞因子的产生或中性粒细胞介导的炎症。与wt相比，NADPH氧化酶缺陷小鼠炎症增加的机制尚未明确。在互惠骨髓嵌合体p47phox-/- wt小鼠中，我们观察到p47phox-/-骨髓在LPS刺激下导致NF-kB活化增强和中性粒细胞炎症。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化为抗炎表型。我们将提出这样的假设，即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，进而激活含有sh2的磷脂酰肌醇磷酸酶-1 （SHIP-1）发生的。在这个模型中，Lyn激酶和SHIP-1是一个关键的信号节点，它促进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Aim 1中进行研究，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。在Aim 2中，我们将进一步确定NADPH氧化酶生成ROS下游的氧化还原激活信号机制，介导巨噬细胞功能的转化，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调节肺部炎症功能中的作用，我们应该发现新的信号通路，可以提供新的治疗方法来限制损伤。