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。这与重症脓毒症和ARDS/多器官功能障碍综合征（MODS）初始发作后存活，但以效应细胞凋亡、抗炎细胞因子过度表达、促炎细胞因子合成抑制和反复感染为特征的所谓“免疫麻痹”死亡的ICU患者有关。我们小组发现的一个重要的促进解决机制是氧化还原调节的线粒体生物发生双基因组转录网络对先天免疫的强大控制，该网络通过诱导血红素氧化酶-1/一氧化碳系统（HO-1/CO）强烈激活来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的进一步炎症损伤。已发表的和初步的数据提出了一种新的可能性，即线粒体生物发生的转录程序将线粒体自噬、抗炎症和抗氧化防御整合到肺泡上皮（ALI肺损伤的主要部位）的一个一致的损伤解决网络中。我们提出，线粒体生物发生程序通过HO-1/CO激活Nfe2l2和NRF-1介导肺保护，导致1)抗炎Socs3和IL10基因表达，2)抑制炎症小体介导的IL-1生成，3)通过Bnip3和Atg5激活线粒体自噬，促进肺泡上皮细胞存活和解决屏障功能障碍。通过小鼠脓毒杆菌和肺炎的活体研究以及互补的肺细胞研究，我们将研究线粒体生物发生的综合遗传网络如何影响肺部炎症和ALI的解决。概念验证将意味着脓毒症/肺炎中的肺具有反调控保障，包括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的能力，例如，通过2型（AT2）细胞，我们建议在人类肺弥漫性肺泡损伤（DAD）中进行转化研究来测试这一概念，如果成功，将为改善线粒体功能和解决ALI/ARDS开辟新的治疗途径。目的1：确定Nfe2l2和NRF1诱导小鼠金黄色葡萄球菌脓毒症和肺炎的肺线粒体生物发生是否上调Socs3和Il10抗炎基因表达，抑制caspase1的裂解和IL-1的产生，减轻肺部炎症和ALI。目的2：通过功能获得和功能丧失研究，确定Nfe2l2和NRF1诱导肺线粒体生物发生是否a)调节自噬基因Bnip3和Atg5， b)通过HO-1/ co相关线粒体ROS生成激活促存活线粒体自噬。目的3：与健康人肺相比，评估人类ALI/ARDS患者肺泡上皮中线粒体生物发生与线粒体自噬的程度、位置和关系。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、免疫反调节、抗氧化防御和细胞存活联系起来。人类ALI/ARDS的阳性预测研究将对我们理解脓毒症和MODS的解决方案产生重大影响。