Redox Regulation of Lung Mitochondrial Biogenesis in Sepsis/Pneumonia

脓毒症/肺炎中肺线粒体生物发生的氧化还原调节

基本信息

批准号：
8462898
负责人：
CLAUDE A PIANTADOSI
金额：
$ 36.9万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8462898
关键词：
AGTR2 gene Acute Acute Lung Injury Adult Respiratory Distress Syndrome Alveolar Anti-Inflammatory Agents Anti-inflammatory Antioxidants Apoptosis Apoptotic Autophagocytosis Binding Biogenesis Blood capillaries Carbon Monoxide Cell Survival Cells Cytokine Inducible SH2-Containing Protein Data Diffuse Effector Cell Energy Metabolism Epithelial Epithelial Cells Functional disorder Gene Expression Generations Genes Genetic Genetic Programming Genomics Health Heme Human IL10 gene Immune Immunosuppression Infection Inflammation Inflammatory Inflammatory Response Injury Interleukin-1 Interleukin-1 Receptors Interleukin-10 Interleukins Life Link Location Lung Lung Inflammation Mediating Mitochondria Molecular Multiple Organ Failure Mus Natural Immunity Organ Organelles Outcome Oxidation-Reduction Oxidoreductase Paralysed Pathway interactions Patients Pneumonia Process Production Proteins Publishing Pulmonary Edema Quality Control Recurrence Regulation Resolution Response Elements Role Sepsis Site Staphylococcus aureus System TNF gene Testing Therapeutic Transcriptional Regulation Ventilator alveolar epithelium capillary cytokine heme oxygenase-1 human SOD2 protein improved inhibitor/antagonist loss of function novel novel therapeutics nuclear respiratory factor operation prevent programs promoter repaired transcription factor translational study

项目摘要

DESCRIPTION (provided by applicant): This is a revised application to study the regulation and the role of mitochondrial biogenesis and mitophagy in experimental sepsis and acute lung injury (ALI) caused by S. aureus. It is relevant to ICU patients who survive an initial episode of severe sepsis and ARDS/multiple organ dysfunction syndrome (MODS), but die with so- called "immune paralysis" characterized by effector cell apoptosis, anti-inflammatory cytokine over-expression, suppression of pro-inflammatory cytokine synthesis and recurrent infections. One important pro-resolution mechanism discovered by our group is the powerful control over innate immunity by the redox-regulated bi- genomic transcriptional network of mitochondrial biogenesis, which is strongly activated by the induction of the heme oxygenase-1/carbon monoxide system (HO-1/CO) to protect energy metabolism and mitochondrial mass, but which we think may also promote the clearance of damaged organelles (mitophagy) and limit further inflammatory damage in MODS. Published and preliminary data raise the novel possibility that the transcriptional program for mitochondrial biogenesis integrates mitophagy, counter-inflammation, and anti- oxidant defenses into a coherent injury resolution network in alveolar epithelium, the major site of lung damage in ALI. We propose that the program of mitochondrial biogenesis mediates lung protection through HO-1/CO activation of Nfe2l2 and NRF-1 leading to 1) anti-inflammatory Socs3 and IL10 gene expression, 2) suppression of inflammasome-mediated IL-1¿ production, and 3) activation of mitophagy through Bnip3 and Atg5, promoting alveolar epithelial cell survival and resolution of barrier dysfunction. Using live S. aureus sepsi and pneumonia in mice and complementary lung cell studies, we will investigate how this integrated genetic network of mitochondrial biogenesis impacts on lung inflammation and ALI resolution. Proof-of-concept would mean the lung in sepsis/pneumonia has counter-regulatory safeguards involving the induction of mitochondrial biogenesis to prevent further mitochondrial damage from the systemic inflammatory response and clear damaged mitochondria to restore mitochondrial health and capacity for alveolar epithelial repair, e.g. though the type 2 (AT2) cell We propose translational studies to test the concept in diffuse alveolar damage (DAD) in human lung, which if successful, would open up therapeutic avenues for the improvement of mitochondrial function and the resolution of ALI/ARDS. Our Specific Aims are: Aim 1: Determine whether Nfe2l2 and NRF1 induction of lung mitochondrial biogenesis in murine S. aureus sepsis and pneumonia up-regulates Socs3 and Il10 anti-inflammatory gene expression, suppresses caspase1 cleavage and IL-1¿ production and mitigates lung inflammation and ALI. Aim 2: Use gain and loss of function studies to determine whether Nfe2l2 and NRF1 induction of lung of mitochondrial biogenesis a) regulates the autophagy genes Bnip3 and Atg5 and b) activates pro- survival mitophagy through HO-1/CO-related mitochondrial ROS generation in murine S. aureus pneumonia. Aim 3: Assess the extent, location, and relationship of mitochondrial biogenesis to mitophagy in the alveolar epithelium of human ALI/ARDS patients compared with healthy human lung. Completion of these Aims would link transcriptional regulation of mitochondrial biogenesis to mitophagy and to immune counter-regulation, anti-oxidant defenses, and cell survival. Positive predictive studies in human ALI/ARDS would have a high impact on our understanding of the resolution of sepsis and MODS.

描述（由申请人提供）：这是一项修订后的申请，用于研究线粒体生物发生和线粒体自噬在金黄色葡萄球菌引起的实验性脓毒症和急性肺损伤（ALI）中的调节和作用，与最初存活的 ICU 患者相关。严重败血症和 ARDS/多器官功能障碍综合征 (MODS) 发作，但死于所谓的“免疫麻痹”，其特征是效应细胞凋亡、抗炎细胞因子过度表达、促炎细胞因子抑制我们小组发现的一种重要的促解决机制是线粒体生物发生的氧化还原调节的双基因组转录网络对先天免疫的强大控制，该网络通过血红素加氧酶-1/的诱导而被强烈激活。一氧化碳系统 (HO-1/CO) 可以保护能量代谢和线粒体质量，但我们认为这也可能促进受损细胞器（线粒体自噬）的清除，并限制 MODS 中进一步的炎症损伤。线粒体生物发生的转录程序将线粒体自噬、抗炎和抗氧化防御整合到肺泡上皮（ALI 肺损伤的主要部位）的连贯损伤解决网络中，这是一种新的可能性。我们认为线粒体生物发生的程序介导肺。通过 HO-1/CO 激活 Nfe2l2 和 NRF-1 提供保护，从而导致 1) 抗炎 Socs3 和 IL10 基因表达，2) 抑制炎症体介导的IL-1¿ 3) 通过 Bnip3 和 Atg5 激活线粒体自噬，促进肺泡上皮细胞存活并解决功能障碍屏障。利用小鼠活金黄色葡萄球菌脓毒症和肺炎以及补充肺细胞研究，我们将研究线粒体的这种整合遗传网络。生物发生对肺部炎症和 ALI 解决的影响概念验证意味着脓毒症/肺炎中的肺部具有涉及诱导线粒体生物发生以防止进一步发生的反监管保障措施。全身炎症反应引起的线粒体损伤，并清除受损的线粒体，以恢复线粒体健康和肺泡上皮修复能力，例如通过 2 型 (AT2) 细胞。如果成功，将为改善线粒体功能和解决 ALI/ARDS 开辟治疗途径。我们的具体目标是：目标 1：确定 Nfe2l2 和 Nfe2l2 是否存在。 NRF1 诱导小鼠金黄色葡萄球菌败血症和肺炎中肺线粒体生物发生上调 Socs3 和 Il10 抗炎基因表达，抑制 caspase1 裂解和 IL-1¿目标 2：利用功能获得和丧失研究来确定 Nfe2l2 和 NRF1 是否诱导肺部线粒体生物发生 a) 调节自噬基因 Bnip3 和 Atg5，以及 b) 通过 HO- 激活促生存线粒体自噬。鼠金黄色葡萄球菌肺炎中 1/CO 相关的线粒体 ROS 生成目标 3：评估线粒体生物发生的程度、位置及其关系。人类 ALI/ARDS 患者肺泡上皮与健康人肺相比的线粒体自噬完成这些目标将把线粒体生物发生的转录调节与线粒体自噬以及免疫反调节、抗氧化防御和细胞存活联系起来。人类 ALI/ARDS 将对我们对脓毒症和 MODS 解决方案的理解产生重大影响。