Regulation of Neutrophilic Lung Inflammation

中性粒细胞性肺部炎症的调节

• 批准号: 8195567
• 负责人: John W Christman
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195567
• 关键词: Address; Adult Respiratory Distress Syndrome; Alveolar Macrophages; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Attenuated; B-Lymphocytes; Binding; Bone Marrow; Breathing; Cells; Chimera organism; Data; Distal; Endotoxins; Enzymes; Event; Funding; Gene Expression; Gene Expression Regulation; Generations; Health; In Vitro; Inflammation; Inflammatory; Intensive Care Units; Isomerase; Laboratories; Lead; Life; Lung; Lung Inflammation; Lung diseases; MAP Kinase Kinase Kinase; Mechanics; Mediating; Molecular; Morbidity - disease rate; Mus; NADPH Oxidase; NF-kappa B; NF-kappaB-inducing kinase; Nuclear; Oxidation-Reduction; Pathogenesis; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Phosphorylation; Phosphotransferases; Physiological; Play; Production; Property; Prostaglandin D2; Prostaglandins; Proteins; Regulation; Relative (related person); Research; Resolution; Role; Sepsis; Serine; Stimulus; Supportive care; Survival Rate; Therapeutic; Time; Work; abstracting; attenuation; base; chemokine; cyclooxygenase 2; cyclopentanone; cytokine; design; effective therapy; lipocalin 1; lung injury; macrophage; mortality; neutrophil; novel; novel strategies; prostaglandin R2 D-isomerase; public health relevance; response; transcription factor

DESCRIPTION (provided by applicant): Abstract: The acute respiratory distress syndrome (ARDS) associated with severe sepsis is a neutrophilic inflammatory lung disease (NLI) with excessive morbidity and mortality. In spite of improvements in supportive care that have resulted in better survival rates, there are no effective specific treatments of ARDS that are based on the molecular pathogenesis. We propose to investigate the pre-transcriptional events in pulmonary macrophages that lead to cytokine- and chemokine-mediated inflammation in the lung. In previous years of funding, we have focused on the early effects of NADPH oxidase that result in attenuation of the NF-:B activation pathway. We now propose to investigate the role of NADPH oxidase in the resolution of neutrophilic lung inflammation in pulmonary macrophages. We will consider the effects of NADPH oxidase on gene regulation of cyclooxygenase-2 (COX-2) and lipocalin-prostaglandin D synthase (L-PgDS) gene expression which results in relative increase in prostaglandin D2 (PgD2) and on activation of nuclear factor E2 p45-related factor 2 (Nrf2). Degradation products of PgD2, called cyclopentanones, have potent anti-inflammatory properties and Nrf2 has a role in gene regulation of anti-oxidant and detoxifying proteins that are protective. Our laboratory has identified a novel pathway by which a redox sensitive kinase, NF-:B inducing kinase (NIK), regulates gene expression L-PgDS and production of PgD2 through phosphorylation of PU.1, a macrophage specific transcription factor. In this proposal, we hypothesize that NADPH oxidase generated ROS in pulmonary macrophages has a dual role in mediating neutrophiilc lung inflammation. In early neutrophilc lung inflammation, ROS contributes to activation of NF-:B and generation of cytokine, chemokine, and cyclooxygenase-2 (COX-2) gene expression. However, at later time points, which will be the focus of this proposal, NADPH oxidase- generated ROS mediates resolution of neutrophilc lung inflammation through effects on the production of anti-inflammatory prostanoids and anti-oxidants and detoxifying proteins regulated by Nrf2. We propose two specific aim: 1: To determine the necessity of macrophage NADPH oxidase generated ROS on resolution of neutrophil lung inflammation in response to treatment with endotoxin and 2: To determine the requirement of macrophage NADPH oxidase generated ROS in redox regulation of NIK and Nrf2 activation and to determine the consequences of NIK and Nrf2 activation on the resolution of NLI. By examining the physiological role of NADPH oxidase on the resolution of neutrophilc lung inflammation, we expect to identify novel mechanisms that could provide evidence for effective therapeutic approaches to limit lung injury and restore health in patients suffering from ARDS and other inflammation lung diseases. PUBLIC HEALTH RELEVANCE: Project Narrative: The acute respiratory distress syndrome (ARDS) is a severe and life threatening condition that requires a mechanical breathing machine and other supportive care in an intensive care unit. We have shown that macrophages in the lung have an essential role in initiating the severe lung inflammation that causes ARDS. The purpose of this research is to define the basic molecular mechanisms that regulate macrophage involvement in ARDS in order to design new and effective treatments.

描述(由申请人提供)： 摘要：严重脓毒症并发的急性呼吸窘迫综合征(ARDS)是一种发病率和死亡率均较高的中性粒细胞炎症性肺部疾病。尽管支持性治疗的改进带来了更高的存活率，但目前还没有基于分子发病机制的有效的ARDS特效治疗方法。我们建议研究肺巨噬细胞中导致细胞因子和趋化因子介导的炎症的转录前事件。在前几年的资助中，我们将重点放在NADPH氧化酶导致NF-：B激活途径减弱的早期影响上。我们现在建议研究NADPH氧化酶在肺巨噬细胞中性粒细胞肺部炎症消退中的作用。我们将考虑NADPH氧化酶对环氧合酶-2(COX-2)和脂钙素-前列腺素D合成酶(L-PGDS)基因表达的调控，从而导致前列腺素D2(PGD2)的相对增加和核因子E2 P45相关因子2(NRF2)的激活。PGD2的降解产物，称为环戊酮，具有强大的抗炎特性，而Nrf2在抗氧化和解毒蛋白的基因调控中具有保护作用。我们的实验室已经发现了一条新的途径，通过巨噬细胞特异性转录因子PU.1的磷酸化，氧化还原敏感的激酶-核因子：B诱导激酶(NIK)调节L-PGDS的基因表达和PGD2的产生。在这项建议中，我们假设NADPH氧化酶在肺巨噬细胞中产生的ROS在介导中性粒细胞肺部炎症方面具有双重作用。在早期中性粒细胞肺部炎症中，ROS参与了核因子-B的激活和细胞因子、趋化因子以及环氧合酶-2(COX-2)基因表达的产生。然而，在稍后的时间点，这将是本提案的重点，NADPH氧化酶产生的ROS通过影响Nrf2调节的抗炎前列腺素和抗氧化剂以及解毒蛋白的产生来介导中性粒细胞肺部炎症的缓解。我们提出了两个特定的目标：1：确定巨噬细胞NADPH氧化酶产生的ROS在内毒素治疗后对中性粒细胞肺部炎症的消退作用的必要性；2：确定巨噬细胞NADPH氧化酶产生的ROS在NIK和Nrf2激活的氧化还原调节中的需求，并确定NIk和Nrf2激活对NLI分解的影响。通过研究NADPH氧化酶在中性粒细胞肺部炎症消退中的生理作用，我们期望确定新的机制，为限制ARDS和其他炎症性肺部疾病患者的肺损伤和恢复健康的有效治疗方法提供证据。 公共卫生相关性： 项目简介：急性呼吸窘迫综合征(ARDS)是一种严重的危及生命的疾病，需要在重症监护病房使用机械呼吸机和其他支持性护理。我们已经证明，肺中的巨噬细胞在引发引起ARDS的严重肺部炎症中起着至关重要的作用。本研究的目的是明确巨噬细胞参与ARDS的基本分子机制，以设计新的有效的治疗方法。