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

• 批准号: 8370970
• 负责人: CLAUDE A PIANTADOSI
• 金额: $ 39.25万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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/8370970
• 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

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. PUBLIC HEALTH RELEVANCE: This is a proposal to study the regulation and the role of mitochondrial turnover in 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 acute respiratory distress syndrome (ARDS) with multiple organ dysfunction syndrome (MODS), but often die with so-called "immune paralysis" and recurrent infections. One important pro-resolution mechanism discovered by our group is the powerful control over inflammation by the 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 also promotes the clearance of damaged organelles (mitophagy) and limits further inflammatory damage in MODS. We have preliminary evidence that the process of mitochondrial biogenesis may integrate the clearance of damaged mitochondria, anti-inflammation, and anti-oxidant defenses into a coherent injury resolution network at the major sites of lung damage in ARDS. We would like to understand how the genetic program of mitochondrial biogenesis mediates lung protection through anti-inflammatory gene expression, suppression of inflammatory interleukin-1b (IL-1¿) production, and activates mitophagy leading to resolution of lung capillary leak in ARDS patients.

描述（由申请人提供）：这是一份修订后的申请，旨在研究线粒体生物发生和线粒体自噬在由S.金黄色。它与ICU患者相关，这些患者在严重脓毒症和ARDS/多器官功能障碍综合征（MODS）的初始发作中存活，但死于以效应细胞凋亡、抗炎细胞因子过表达、促炎细胞因子合成抑制和复发性感染为特征的所谓的“免疫麻痹”。我们小组发现的一个重要的促消退机制是通过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有力控制，其通过血红素加氧酶-1/一氧化碳系统（HO-1/CO）的诱导而被强烈激活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的清除（线粒体自噬）并限制MODS中进一步的炎症损伤。已发表的和初步的数据提出了新的可能性，即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中的连贯损伤解决网络中，肺泡上皮是ALI中肺损伤的主要部位。我们认为线粒体生物发生的程序通过HO-1/CO激活Nfe 2l 2和NRF-1介导肺保护，导致1）抗炎Socs 3和IL-10基因表达，2）抑制炎性小体介导的IL-1产生，3）通过Bnip 3和Atg 5激活线粒体自噬，促进肺泡上皮细胞存活和屏障功能障碍的解决。使用live S.在小鼠金黄色葡萄球菌败血症和肺炎的研究和补充肺细胞研究中，我们将研究线粒体生物发生的整合遗传网络如何影响肺部炎症和ALI的解决。概念验证意味着脓毒症/肺炎中的肺具有反调节保护措施，涉及诱导线粒体生物发生以防止全身炎症反应引起的进一步线粒体损伤，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（AT 2）细胞，我们提出了转化研究来测试人肺中弥漫性肺泡损伤（DAD）的概念，如果成功，将为改善线粒体功能和解决ALI/ARDS开辟治疗途径。我们的具体目的是：目的1：确定Nfe 212和NRF 1是否诱导小鼠S.金黄色葡萄球菌脓毒症和肺炎上调Socs 3和Il 10抗炎基因表达，抑制caspase 1裂解和IL-1？产生，减轻肺部炎症和ALI。目标二：使用功能获得和丧失研究来确定Nfe 2l 2和NRF 1是否诱导线粒体生物发生的肺a）调节自噬基因Bnip 3和Atg 5和B）在鼠S中通过HO-1/CO相关的线粒体ROS产生激活促存活线粒体自噬。金黄色肺炎目标三：评估与健康人肺相比，ALI/ARDS患者肺泡上皮线粒体生物发生的程度、位置和与线粒体自噬的关系。这些目标的完成将把线粒体生物发生的转录调节与线粒体自噬和免疫反调节、抗氧化防御和细胞存活联系起来。在人类ALI/ARDS中的阳性预测研究将对我们理解脓毒症和MODS的解决方案产生很大影响。 公共卫生相关性：本研究拟探讨线粒体更新在脓毒症及急性肺损伤中的调控及作用。金黄色。值得一 重症监护病房的患者在严重脓毒症和急性呼吸窘迫综合征（ARDS）伴多器官功能障碍综合征（MODS）的首次发作中幸存下来，但往往死于所谓的“免疫麻痹”和复发性感染。我们小组发现的一个重要的促消退机制是通过线粒体生物发生网络对炎症的有力控制，该网络通过诱导血红素加氧酶-1/一氧化碳系统（HO-1/CO）来强烈激活，以保护能量代谢和线粒体质量，但我们认为这也促进了受损细胞器（线粒体自噬）的清除，并限制了MODS中的进一步炎症损伤。我们有初步证据表明，线粒体生物发生的过程可能整合了受损线粒体的清除，抗炎和抗氧化防御，在ARDS肺损伤的主要部位形成了一个连贯的损伤解决网络。我们希望了解线粒体生物发生的遗传程序如何通过抗炎基因表达、抑制炎性白细胞介素-1b（IL-1）的产生以及激活线粒体自噬来介导肺保护，从而导致ARDS患者肺毛细血管渗漏的解决。