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

• 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
• 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

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脓毒症致死亡的主要原因。最初存活的患者可能随后死于免疫瘫痪，其特征是不清楚的机制涉及抑制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。脓毒症诱导血红素加氧酶-1 （HO-1; Hmox1）产生特异性抗炎作用，例如通过一氧化碳（CO）介导的IL-10产生，并对线粒体生物发生的转录网络施加强大的控制