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: 8675191
• 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/8675191
• 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.

描述（由应用提供）：这是研究线粒体生物发生和线粒体在实验性败血症和急性肺损伤（ALI）中的调节和作用的修订应用。它与ICU患者有关，这些患者在严重的败血症和ARDS/多器官功能障碍综合征（MOD）中幸存下来，但以所谓的“免疫瘫痪”为特征，其特征是效应细胞凋亡，抗炎细胞因子过表达，抑制促炎性细胞因子的Synthesiss和Recressrents的抑制。我们小组发现的一种重要的促分辨率机制是通过氧化还原调节的双胞胎生物发生的双重基因组转录网络对先天免疫的有力控制，这是通过诱导血红素氧酶-1/碳一氧化碳系统（HO-1/CO）来强烈激活的，从（线粒体）并限制MOD中的进一步炎症损害。发布和初步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，反炎和抗氧化剂防御量整合到肺泡上皮的相干损伤分辨率网络中，肺泡上皮是ALI中肺损伤的主要部位。 We propose that the program of mitochondrial biogenesis mediaates 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功能障碍。使用小鼠和互补的肺细胞研究中的活链球菌sepsi和肺炎，我们将研究这种线粒体生物发生的综合遗传网络如何影响肺部注射和ALI分辨率。概念证明意味着败血症/肺炎中的肺具有反调节性保障措施，涉及诱导线粒体生物发生，以防止全身性炎症反应受到进一步的线粒体损害，并明确损坏了线粒体健康和肺泡上皮修复的能力，例如。尽管2型（AT2）细胞我们提出转化研究，以测试人类肺中弥漫性肺泡损伤（DAD）中的概念，如果成功，该研究将为改善线粒体功能和ALI/ARDS的分辨率开放治疗途径。我们的具体目的是：目标1：确定NFE2L2和NRF1在鼠S. aureus s. s. s. s. s. s. s. s. s. s. s. s.目标2：使用功能研究的增益和丧失来确定线粒体生物发生的NFE2L2和NRF1诱导是否诱导肺a）调节自噬基因BNIP3和ATG5和b）激活鼠肠杆菌孢子菌中的促卵巢线粒体ROS。 AIM 3：与健康的人肺相比，评估线粒体生物发生与人ALI/ARDS患者肺泡上皮的线粒体上皮的程度，位置和关系。这些目标的完成将将线粒体生物发生的转录调节与线粒体和免疫反调节，抗氧化剂防御和细胞存活联系起来。人类ARD/ARD的积极预测研究将对我们对败血症和mod的分辨率的理解产生很大的影响。