Regulation of Neutrophilic Lung Inflammation

中性粒细胞性肺部炎症的调节

• 批准号: 8391106
• 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 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391106
• 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.

描述（由申请人提供）： 摘要：急性呼吸窘迫综合征（ARDS）是一种严重脓毒症相关的嗜酸性炎症性肺病（NLI），具有较高的发病率和死亡率。尽管支持性治疗的改善导致了更好的生存率，但仍没有基于分子发病机制的有效的ARDS特异性治疗。我们建议调查导致细胞因子和趋化因子介导的炎症在肺巨噬细胞的转录前事件。在前几年的资助中，我们重点关注NADPH氧化酶的早期作用，这些作用导致NF-：B活化途径的减弱。我们现在建议研究NADPH氧化酶在肺巨噬细胞嗜酸性肺炎症消退中的作用。我们将考虑NADPH氧化酶对环氧化酶-2（考克斯-2）和脂质运载蛋白-前列腺素D合酶（L-PgDS）基因表达的基因调节（导致前列腺素D2（PgD 2）相对增加）以及对核因子E2 p45相关因子2（Nrf 2）激活的影响。PgD 2的降解产物，称为环戊酮，具有有效的抗炎特性，Nrf 2在抗氧化和解毒蛋白的基因调控中具有保护作用。我们的实验室已经确定了一种新的途径，通过这种途径，氧化还原敏感激酶NF-：B诱导激酶（NIK）通过磷酸化巨噬细胞特异性转录因子PU. 1来调节基因表达L-PgDS和PgD 2的产生。在本提案中，我们假设肺巨噬细胞中的NADPH氧化酶产生的活性氧在介导嗜中性粒细胞肺部炎症中具有双重作用。在早期嗜肺细胞性肺炎中，ROS有助于NF-：B的活化以及细胞因子、趋化因子和环氧合酶-2（考克斯-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通过影响抗炎性前列腺素类和抗氧化剂以及由Nrf 2调节的解毒蛋白的产生来介导嗜中性粒细胞肺部炎症的消退。我们提出两个具体目标：一曰：确定巨噬细胞NADPH氧化酶产生的ROS对中性粒细胞肺部炎症消退的必要性，以响应内毒素治疗; 2：确定巨噬细胞NADPH氧化酶产生的ROS在NIK和Nrf 2活化的氧化还原调节中的需求，并确定NIK和Nrf 2活化对NLI消退的影响。通过检查NADPH氧化酶在解决中性粒细胞肺部炎症中的生理作用，我们希望找到新的机制，为限制肺损伤并恢复患有ARDS和其他炎症性肺部疾病的患者的健康的有效治疗方法提供证据。