Carbon Monoxide and Specialized Pro-Resolving Mediators

一氧化碳和专门的促分解介质

基本信息

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
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/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

项目摘要

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.

项目摘要（参见说明）：组织损伤和微生物入侵会引起急性炎症，这种炎症通常是保护性的，理想情况下应该是“自限性”的。急性炎症的消退阶段被认为是被动的，并且较早地通过从急性炎症回到稳态的组织过程的组织学来定义。在这个项目 4 领导者的实验室以及现在世界各地的其他实验室中，已经出现的证据表明，消解是一个活跃的过程，需要识别和合成一类新的专门的促消解介质 (SPM)。这些局部作用的独特分子家族是非冗余的，包括分解素、脂氧素和保护素。这些 SPM 是有效的抗炎和促消退信号。随着动物疾病模型的新发现，包括盲肠结扎和穿刺引起的脓毒症，很明显，急性炎症的解决方案在很大程度上是未知的，需要改善患者护理。转化 P01 项目 4 的重点是使用具有分辨率指数的无偏脂质介质 (LM)-脂质组学系统地阐明低剂量吸入一氧化碳 (CO) 对激活分辨率成分的作用，该方法是 Serhan 实验室针对炎症渗出物开发的方法。因为吞噬细胞，例如中性粒细胞和巨噬细胞是释放促炎脂质介质（包括白三烯和前列腺素）的关键，这些介质可以影响器官功能，该项目将重点关注新型 SPM 代谢组和相关介质的 CO 激活，从而下调过度的 PMN 积累并刺激清除微生物和细胞碎片。项目 4 将测试以下假设：吸入 CO 局部激活组织分解程序涉及产生新型抗炎和促分解脂质介质，从而增强凋亡细胞和微生物的清除。 CO 激活新属 SPM 的产生，包括分解素和脂氧素，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消退所需的反应。为了测试这个。项目 4 将解决 4 个具体目标： 1.确定 CO 对急性炎症期间脂质介质和 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对解决脓毒症和第二器官l/R急性肺损伤的影响； 4.脓毒症与 ALI 患者库/库的 LM 脂质组学分析。项目 4 将为 CO 和 SPM 激活消解程序之间的新型相互作用提供直接证据，为利用不受控制的炎症反应和肺损伤影响临床实践奠定基础。