Carbon Monoxide and Mitochondrial Quality Control in Sepsis-induced Lung Injury

脓毒症引起的肺损伤中的一氧化碳和线粒体质量控制

基本信息

批准号：
8225578
负责人：
CLAUDE A PIANTADOSI
金额：
$ 50.32万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-15 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8225578
关键词：
Acute Lung Injury Address Anti-Inflammatory Agents Anti-inflammatory Antioxidants Apoptosis Apoptotic Autophagocytosis BNIP3L gene Binding Biogenesis Biopsy Carbon Monoxide Cause of Death Cell Death Cell model Critical Illness Cytokine Inducible SH2-Containing Protein DNA Damage Data Effector Cell Energy Metabolism Experimental Models Gene Expression Gene Expression Regulation Genes Genomics HOI Heme Hepatic Hepatocyte Human IL8 gene Immune Immune system Immunity Immunosuppression Inflammation Inflammatory Inflammatory Response Instruction Interleukin-1 Interleukin-10 Interleukin-18 Link Liver Lung Lung Inflammation Mediating Mediator of activation protein Mitochondria Modeling Molecular Multiple Organ Failure Mus Organ Organ failure Organelles Oxidation-Reduction Paralysed Patients Peripheral Blood Mononuclear Cell Plasma Pneumonia Process Production Proteins Protocols documentation Quality Control Regulation Resolution Response Elements Sepsis Signal Transduction Skeletal Muscle Stress System TNF gene Testing Therapeutic Translations Up-Regulation Work cytokine heme oxygenase-1 improved inhibitor/antagonist loss of function lung injury mRNA Expression mortality novel novel therapeutics nuclear respiratory factor prevent programs promoter protein phosphatase inhibitor-2 receptor transcription factor

项目摘要

Acute lung injury (ALI) and multiple organ dysfunction syndrome (MODS) is a major cause of sepsis-induced mortality in the ICU. Patients who initially survive may subsequently die with immune paralysis characterized by poorly understood mechanisms involving the over-expression of counter-regulatory cytokines that suppress NF-KB-dependent pro-Inflammatory cytokine synthesis. Sepsis induces heme oxygenase-1 (HO-1; Hmox1), which has specific anti-inflammatory effects, e.g. via carbon monoxide (CO) mediated IL-10 producfion, and exerts powerful control over the transcriptional network of mitochondrial biogenesis, which safeguards energy metabolism by improving mitochondrial mass and promoting clearance of damaged organelles {mitophagy). Our preliminary data demonstrate that HO-1/CO up-regulates the suppressor of cytokine signaling-3 (S0CS3), the inflammasome inhibitor/anti-apoptotic protein BCIXL, DNA damage regulated autophagy modulator protein 1 (Drami), and the mitophagy genes NIX and BNIP3. This information suggests that the H0-1/C0 system links mitochondrial biogenesis, mitophagy, and counter inflammation through mechanisms involving S0CS3, BCIXL and Drami. We hypothesize that the transcriptional network of mitochondrial biogenesis regulates the anti-inflammatory response through HO-1/CO-dependent NFE2I2 and NRF-1 activation, leading to up-regulation of IL10 and S0CS3, activation of mitophagy. and suppression of inflammasome-mediated IL-1 B production and suppression of apoptosis. Using Staphylococcal aureus (S. aureus) sepsis and pneumonia in mice and relevant cell models in two mechanistic molecular Aims, and through a translafional third Aim, we will address how this integrated process of mitochondrial quality control mitigates lung and liver inflammation and hastens the resolution of sepsis. Completion of these Aims and a successful test of this hypothesis would allow a paradigm shift in our understanding and approach to sepsis-induced organ failure both experimentally and clinically, as well as test CO pre-clinically as a way to improve mitochondrial quality control in ALI and MODS.

急性肺损伤（ALI）和多器官功能障碍综合征（MODS）是 ICU 脓毒症所致死亡的主要原因。最初存活的患者随后可能死于免疫麻痹，其特征是免疫麻痹的机制知之甚少，涉及抑制 NF-KB 依赖性促炎细胞因子合成的反调节细胞因子的过度表达。脓毒症会诱导血红素加氧酶-1 (HO-1; Hmox1)，它具有特定的抗炎作用，例如通过一氧化碳 (CO) 介导 IL-10 的产生，并对线粒体生物发生的转录网络发挥强大的控制作用，通过改善线粒体质量和促进受损细胞器（线粒体自噬）的清除来保障能量代谢。我们的初步数据表明，HO-1/CO 上调细胞因子信号传导抑制因子 3 (S0CS3)、炎症小体抑制剂/抗凋亡蛋白 BCIXL、DNA 损伤调节自噬调节蛋白 1 (Drami) 和线粒体自噬基因 NIX和 BNIP3。该信息表明 H0-1/C0 系统通过涉及 S0CS3、BCIXL 和 Drami 的机制将线粒体生物发生、线粒体自噬和抗炎症联系起来。我们假设线粒体生物发生的转录网络通过 HO-1/CO 依赖性 NFE2I2 和 NRF-1 激活调节抗炎反应，导致 IL10 和 S0CS3 上调，激活线粒体自噬。抑制炎症体介导的 IL-1 B 产生和抑制细胞凋亡。在两个机械分子目标中使用金黄色葡萄球菌（S. aureus）脓毒症和肺炎以及相关细胞模型，并通过转化的第三个目标，我们将解决线粒体质量控制的这种综合过程如何减轻肺部和肝脏炎症并加速解决败血症。完成这些目标并成功测试这一假设将使我们在实验和临床上对脓毒症引起的器官衰竭的理解和方法发生范式转变，并在临床前测试 CO 作为改善 ALI 线粒体质量控制的一种方法和模组。