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: 8776499
• 负责人: John W Christman
• 金额: $ 36.99万
• 依托单位: OHIO STATE UNIVERSITY
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8776499
• 关键词: NADPH; OXIDASE; REGULATION; MACROPHAGE; INFLAMMATORY

ABSTRACT 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-¿B) 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-¿B 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-¿B. 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.

抽象的 与革兰氏阴性败血症相关的急性肺损伤（ALI）的特征是中性粒细胞 介导的炎症表现出多余的发病率和死亡率。尽管有改善 支持护理，目前尚无基于分子的ALI治疗 综合征的发病机理。我们的总体目标是确定肺部信号传导机制 调节中性粒细胞激活的巨噬细胞在介导肺中至关重要 炎症伤害。我们已经表明，抑制NADPH氧化物活性导致 转录核因子Kappa B（NF-€）激活的肺部受损 内毒素无需降低细胞因子产生或注射。 中性粒细胞。在NADPH氧化物缺陷小鼠中看到的感染增加的机制 相对于WT尚未定义。使用相互的骨髓嵌合体P47phox - / - WT小鼠， 我们观察到WT小鼠中的P47phox - / - 骨髓导致NF-®B激活增强和 肺LPS挑战中的嗜中性炎症。我们基于这些数据的中心假设是 NADPH氧化酶生成的ROS信号传导将巨噬细胞从促巨噬细胞转化为抗抗 内毒素血症期间的炎症表型。我们将解决此表型的假设 开关是通过氧化物氧化物生成的氧化还原敏感SRC的NADPH氧化物的ROS激活发生的 激酶，进而激活含SH2的磷脂酰肌醇磷酸酶-1（Ship-1）。 在此模型中，Lyn激酶和Ship-1代表一个临界信号节点，可增强PIP3 降解对Pi（3，4）P2，它减弱了Akt的激活，因此NF-¿B的激活。此模型 将在AIM 1中进行审问，其中我们将确定NADPH氧化物生成的作用 巨噬细胞中抗炎表型转换机理中的ROS信号传导。 在AIM 2中，我们将确定下游的氧化还原激活的信号传导机制 NADPH氧化物的产生ROS在介导巨噬细胞功能的转化和 从而确定巨噬细胞在缓解肺部炎症中的潜在重要作用 受伤。通过系统地描述NADPH氧化物在确定功能中的作用 调节肺注射时的肺巨噬细胞，我们应该确定新的信号通路 这可以提供新颖的治疗方法来限制伤害。

项目成果

Protective Effect of the Fruit Hull of Gleditsia sinensis on LPS-Induced Acute Lung Injury Is Associated with Nrf2 Activation.

• DOI: 10.1155/2012/974713
• 发表时间: 2012
• 期刊: Evidence-based complementary and alternative medicine : eCAM
• 作者: Choi JY;Kwun MJ;Kim KH;Lyu JH;Han CW;Jeong HS;Ha KT;Jung HJ;Lee BJ;Sadikot RT;Christman JW;Jung SK;Joo M
• 通讯作者: Joo M