Regulation of Neutrophilic Lung Inflammation
中性粒细胞性肺部炎症的调节
基本信息
- 批准号:8391106
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAdult Respiratory Distress SyndromeAlveolar MacrophagesAnti-Inflammatory AgentsAnti-inflammatoryAntioxidantsAttenuatedB-LymphocytesBindingBone MarrowBreathingCellsChimera organismDataDistalEndotoxinsEnzymesEventFundingGene ExpressionGene Expression RegulationGenerationsHealthIn VitroInflammationInflammatoryIntensive Care UnitsIsomeraseLaboratoriesLeadLifeLungLung InflammationLung diseasesMAP Kinase Kinase KinaseMechanicsMediatingMolecularMorbidity - disease rateMusNADPH OxidaseNF-kappa BNF-kappaB-inducing kinaseNuclearOxidation-ReductionPathogenesisPathway interactionsPatientsPeroxisome Proliferator-Activated ReceptorsPhosphorylationPhosphotransferasesPhysiologicalPlayProductionPropertyProstaglandin D2ProstaglandinsProteinsRegulationRelative (related person)ResearchResolutionRoleSepsisSerineStimulusSupportive careSurvival RateTherapeuticTimeWorkabstractingattenuationbasechemokinecyclooxygenase 2cyclopentanonecytokinedesigneffective therapylipocalin 1lung injurymacrophagemortalityneutrophilnovelnovel strategiesprostaglandin R2 D-isomerasepublic health relevanceresponsetranscription factor
项目摘要
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: 与严重脓毒症相关的急性呼吸窘迫综合征(ARDS)是一种中性粒细胞性炎症性肺病(NLI),具有极高的发病率和死亡率。尽管支持治疗的改进导致了更高的生存率,但目前还没有基于分子发病机制的 ARDS 的有效特异性治疗方法。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肺部炎症的转录前事件。在前几年的资助中,我们重点关注 NADPH 氧化酶导致 NF-:B 激活途径减弱的早期影响。我们现在建议研究 NADPH 氧化酶在解决肺巨噬细胞中性粒细胞性肺部炎症中的作用。我们将考虑 NADPH 氧化酶对环氧合酶-2 (COX-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的影响,从而导致前列腺素 D2 (PgD2) 相对增加和核因子激活E2 p45 相关因子 2 (Nrf2)。 PgD2 的降解产物(称为环戊酮)具有有效的抗炎特性,而 Nrf2 在保护性抗氧化和解毒蛋白的基因调控中发挥作用。我们的实验室已经确定了一种新的途径,氧化还原敏感激酶 NF-:B 诱导激酶 (NIK) 通过巨噬细胞特异性转录因子 PU.1 的磷酸化来调节基因表达 L-PgDS 和 PgD2 的产生。在这个提议中,我们假设 NADPH 氧化酶在肺巨噬细胞中产生的 ROS 在介导中性粒细胞性肺部炎症中具有双重作用。在早期中性粒细胞肺部炎症中,ROS 有助于激活 NF-:B 以及细胞因子、趋化因子和环氧合酶-2 (COX-2) 基因表达的产生。然而,在稍后的时间点,即本提案的重点,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和解毒蛋白的产生,介导中性粒细胞肺部炎症的解决。我们提出两个具体目标:1:确定巨噬细胞 NADPH 氧化酶产生的 ROS 对解决内毒素治疗引起的中性粒细胞肺部炎症的必要性;2:确定巨噬细胞 NADPH 氧化酶产生的 ROS 在 NIK 和 Nrf2 氧化还原调节中的需求激活并确定 NIK 和 Nrf2 激活对 NLI 分辨率的影响。通过检查 NADPH 氧化酶对解决中性粒细胞肺部炎症的生理作用,我们期望找到新的机制,为有效的治疗方法提供证据,以限制 ARDS 和其他炎症性肺部疾病患者的肺损伤并恢复健康。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
John W Christman其他文献
John W Christman的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('John W Christman', 18)}}的其他基金
REGULATION OF THE MACROPHAGE INFLAMMATORY PHENOTYPE IN ARDS
ARDS 中巨噬细胞炎症表型的调节
- 批准号:
10650813 - 财政年份:2018
- 资助金额:
-- - 项目类别:
REGULATION OF THE MACROPHAGE INFLAMMATORY PHENOTYPE IN ARDS
ARDS 中巨噬细胞炎症表型的调节
- 批准号:
10094230 - 财政年份:2018
- 资助金额:
-- - 项目类别:
REGULATION OF THE MACROPHAGE INFLAMMATORY PHENOTYPE IN ARDS
ARDS 中巨噬细胞炎症表型的调节
- 批准号:
10455872 - 财政年份:2018
- 资助金额:
-- - 项目类别:
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 - 财政年份:2010
- 资助金额:
-- - 项目类别:
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:
8252156 - 财政年份:2010
- 资助金额:
-- - 项目类别:
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:
7944664 - 财政年份:2010
- 资助金额:
-- - 项目类别:
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 - 财政年份:2010
- 资助金额:
-- - 项目类别:
相似国自然基金
肺撞击伤的生物力学机理及其并发ARDS的病理机制研究
- 批准号:39370670
- 批准年份:1993
- 资助金额:5.3 万元
- 项目类别:面上项目
刺激性气体致成人呼吸窘迫综合征的机理及诊断防治研究
- 批准号:39270582
- 批准年份:1992
- 资助金额:4.0 万元
- 项目类别:面上项目
相似海外基金
Treatment of Inflammatory Complications of Viral Pneumonia
病毒性肺炎炎症并发症的治疗
- 批准号:
10383991 - 财政年份:2022
- 资助金额:
-- - 项目类别:
CREB Instruction of Macrophage Fate and Lung fluid homeostasis
CREB对巨噬细胞命运和肺液稳态的指导
- 批准号:
10305990 - 财政年份:2021
- 资助金额:
-- - 项目类别:
A critical role for macrophage ferroptosis in promoting fungal invasion in lung transplant recipients
巨噬细胞铁死亡在促进肺移植受者真菌侵袭中的关键作用
- 批准号:
10186399 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Impact of chronic ethanol consumption on lung functional and immunological landscape and implication for susceptibility to SARSCoV2 infection
慢性乙醇消耗对肺功能和免疫状况的影响以及对 SARSCoV2 感染易感性的影响
- 批准号:
10288563 - 财政年份:2020
- 资助金额:
-- - 项目类别: