Carbon Monoxide and Specialized Pro-Resolving Mediators

项目总结（见说明）： 组织损伤和微生物入侵引起急性炎症，通常是保护性的，理想情况下应该是“自限性的”。急性炎症的消退期被认为是被动的，并且通过组织过程的组织学较早地定义，导致从急性炎症回到稳态。在这个项目4领导者的实验室和现在世界各地的其他实验室中，已经出现的证据表明，解决是一个积极的过程，鉴定和合成一种新的专门的促解决介质（SPM）。这些局部作用的不同分子家族是非冗余的，包括消退素、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，需要改善患者护理。转化P01中项目4的重点是系统阐明低剂量吸入一氧化碳（CO）对使用无偏脂质介质（LM）-脂质组学和分辨率指数激活分辨率组分的影响，这是Serhan实验室开发的一种炎症渗出物方法。由于吞噬细胞，如中性粒细胞和巨噬细胞，是释放促炎脂质介质的关键，包括可影响器官功能的白三烯和白藜芦醇，因此本项目将重点关注新型SPM代谢组和相关介质的CO激活，这些介质下调过多的PMN积聚并刺激清除 微生物和细胞碎片项目4将检验以下假设：吸入CO对组织消退程序的局部激活涉及产生新型抗炎和促消退脂质介质，其增强凋亡细胞和微生物的清除。一氧化碳激活新属SPM的产生，包括消退素和脂氧素，并减少促炎脂质介质的生物合成。SPM和CO共同作用以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将涉及4个具体目标：1.确定急性炎症过程中CO对脂质介质和SPM生物合成的影响。2.血红素加氧酶的SPM活化- 1（HO-1）。3. CO和SPM在脓毒症和第二器官I/R急性肺损伤的消退中的影响;以及4.败血症LM-脂质组学分析与ALI患者库/库。项目4将提供基础，通过提供CO和SPM激活解决方案之间的新型相互作用的直接证据，利用不受控制的炎症反应和肺损伤影响临床实践。

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.