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.

摘要

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