Carbon Monoxide and Specialized Pro-Resolving Mediators

一氧化碳和专门的促分解介质

• 批准号: 8225581
• 负责人: Charles Nicholas Serhan
• 金额: $ 45.54万
• 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/8225581
• 关键词: Action Potentials; Acute; Acute Lung Injury; Address; Affect; Anabolism; Animal Disease Models; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Back; Breathing; CD59 Antigen; Carbon Monoxide; Cells; Coupled; Dose; Eicosanoids; Endothelial Cells; Exudate; Family; Gases; Goals; Histology; Homeostasis; Human; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Instruction; Ischemia; Knowledge; Laboratories; Leukotrienes; Libraries; Ligation; Limb structure; Link; Lipoxins; Lung; Mediator of activation protein; Microbe; Mus; Organ; Pathway interactions; Patient Care; Patients; Peritonitis; Phagocytes; Phase; Pre-Clinical Model; Process; Production; Prostaglandins; Puncture procedure; Reperfusion Injury; Reperfusion Therapy; Resolution; Sepsis; Severity of illness; Signal Transduction; Stem cells; Testing; Tissues; antimicrobial; clinical practice; heme oxygenase-1; improved; in vivo; indexing; killings; lipid mediator; lipoxin A4; lung injury; macrophage; microbial; neutrophil; novel; novel strategies; novel therapeutic intervention; programs; response; tissue processing; uptake

PROJECT SUMMARY (See instructions): Tissue injury and microbial invasion evoke acute inflammation that is usually protective and ideally should be "self-limited". The resolution phase of acute inflammation was believed to be passive and defined earlier by histology of tissue processes leading from acute inflammation back to homeostasis. In this Project 4 leader's laboratory and now others worldwide, evidence has emerged indicating that resolution is an active process with the Identification and synthesis of a novel genus of specialized pro-resolving mediators (SPM). These local-acting, distinct families of molecules are non-redundant and include resolvins, lipoxins and protectins. These SPM are potent anti-inflammatory and pro-resolving signals. With new flndings from animal disease models including sepsis from cecal ligation and puncture, it has become evident that the resolution program of acute inflammation is largely uncharted and is needed to improve patient care. The focus of Project 4 within the Translational P01 is the systematic elucidation of low-dose inhaled carbon monoxide (CO) on activating resolution components using unbiased lipid mediator (LM)-lipidomics with resolution indices, an approach developed in the Serhan lab with inflammatory exudates. Because phagocytes, e.g. neutrophils and macrophages, are key in the release of pro-inflammatory lipid mediators including leukotrienes and prostaglandins that can affect organ function, this project will focus on CO activation of novel SPM metabolome and related mediators that down-regulate excessive PMN accumulation and stimulate clearance of both microbes and cellular debris. Project 4 will test the following hypothesis: Local activation of tissue resolution programs by inhaled CO involves production of novel anti-inflammatory and pro-resolving lipid mediators that enhance the clearance of apoptotic cells and microbes. CO activates the production of the new genus of SPM including resolvins and lipoxins and reduces biosynthesis of proinflammatory lipid mediators. SPM and CO act together to govern responses required for limiting inflammation and enhancing microbial killing and resolution. To test this. Project 4 will address 4 specific aims: 1.Determine the impact of CO on biosynthesis of lipid mediators and SPM during acute inflammation. 2. SPM activation of hemeoxygenase- 1 (HO-1). 3. Impact of CO and SPM In resolution of sepsis and second organ l/R acute lung injury; and 4. LM-lipidomic profiling with sepsis vs. ALI patient library/bank. Project 4 will provide the groundwork to harness uncontrolled Inflammatory responses and lung injury to Impact clinical practice by providing direct evidence for novel interactions between CO and SPM activation of resolution programs.

项目总结(见说明)： 组织损伤和微生物入侵引起的急性炎症通常是保护性的，理想情况下应该是“自我限制的”。急性炎症的消退阶段被认为是被动的，早期由组织学定义，导致从急性炎症回到稳态。在这个项目4负责人的实验室中，以及现在世界各地的其他实验室，已经出现了证据表明，随着一类新的专门的促拆分介体(SPM)的鉴定和合成，拆分是一个活跃的过程。这些局部作用的、不同的分子家族是非多余的，包括溶血素、脂蛋白和保护素。 这些SPM是有效的抗炎和促进分解的信号。随着动物疾病模型的新发现，包括盲肠结扎和穿孔引起的脓毒症，很明显，急性炎症的解决方案在很大程度上是未知的，需要改善患者的护理。翻译P01中项目4的重点是系统地阐明低剂量吸入一氧化碳(CO)使用无偏倚脂类介体(LM)激活拆分成分-具有拆分指数的脂质组学，这是Serhan实验室针对炎性渗出物开发的一种方法。由于吞噬细胞，如中性粒细胞和巨噬细胞，在包括白三烯和前列腺素在内的影响器官功能的促炎脂质介质的释放中起关键作用，本项目将集中在新的SPM代谢体和相关介质的CO激活上，这些介质下调PMN的过量积累并刺激清除 微生物和细胞碎片。项目4将检验以下假设：吸入CO对组织分解程序的局部激活涉及产生新的抗炎和促进分解的脂质介质，以增强对凋亡细胞和微生物的清除。CO可激活包括解毒素和脂氧素在内的新型SPM的产生，并减少促炎脂质介质的生物合成。SPM和CO共同作用，控制限制炎症和增强微生物杀灭和分解所需的反应。来测试这一点。项目4将解决4个具体目标：1.确定急性炎症期间CO对脂质介质和SPM生物合成的影响。2.SPM激活血红素加氧酶- 1(HO-1)。3.CO和SPM在解决脓毒症和第二器官L/R急性肺损伤中的作用；4.脓毒症与ALI患者文库/库的光镜下脂质组学分析。项目4将通过提供CO和SPM之间新的相互作用的直接证据，为控制不受控制的炎症反应和肺损伤影响临床实践提供基础。