Project 2 :Specialized Pro-Resolving Lipid Mediators

项目2中提议的实验将检验这一假设，即在健康情况下，伤害性刺激造成的粘膜上皮损伤会启动专门的促分解介质的气道形成，从而促进急性炎症的缓解和呼吸道内稳态的恢复。已发表的报告和正在进行的与项目1、3和4的合作的初步数据已经确定了呼吸道上皮细胞和白细胞在调节急性炎症、损伤和宿主防御中的关键作用。在常见的临床环境中 吸入、胃酸破坏呼吸道上皮完整性会导致组织损伤，增加对感染的易感性，从而导致急性呼吸窘迫综合征。多不饱和脂肪酸，包括二十二碳六烯酸(C22：6)，存在于呼吸道炎症中，并转化为生物活性脂质介质。其中一些介质，即保护素、D系列溶血素和松脂，显示出抗炎和促消解作用，包括调节白细胞的运输以防止中性粒细胞介导的组织损伤，增加微生物清除和增强粘膜上皮宿主防御。C22：6衍生保护素、D系列分解素和松脂在呼吸道损伤中的生成以及它们在呼吸道中阻断炎症和促进分解的能力尚未得到评估。除了产生这些专门的促分解介质外，它们在粘膜表面对器官保护的作用将是项目2的重点。 为了验证我们的假设，我们提出了三个具体目标： *确定气道后专门的促分解介质形成的时间进程 伤害 ？专门化促分解介质对呼吸道上皮功能反应的作用， 和 *建立专门化预解肺规范急性肺损伤消解 调解员 项目2‘S在呼吸道分解药理学方面的具体目标将大大促进拟议的研究计划项目和核心所提供的协同和独特的资源，并将使我们能够(I)发现下呼吸道粘膜损伤期间参与的脂质衍生信号通路的新的分子见解；(Ii)设计新的治疗策略，以减轻严重程度和由此而来的 急性肺损伤和危重疾病的发病率。 。

The proposed experiments in Project 2 will test the hypothesis that in health, mucosal epithelial injury by noxious stimuli initiates airway formation of specialized pro-resolving mediators that promote resolution of acute inflammation and restitution of airway homeostasis. Published reports and preliminary data from ongoing collaborations with Projects 1, 3 and 4 have identified pivotal roles for airway epithelia and leukocytes in regulating acute inflammation, injury and host defense. In the common clinical setting of aspiration, disruption of airway epithelial integrity by gastric acid leads to tissue injury and an increased susceptibility to infection that can result in the acute respiratory distress syndrome. Polyunsaturated fatty acids, including docosahexaenoic acid (C22:6), are present during airway inflammation and converted to bioactive lipid mediators. Some ofthese mediators, namely protectins, D-series resolvins, and maresins display anti-inflammatory and pro-resolving actions, including regulation of leukocyte trafficking to protect against neutrophil-mediated tissue injury, increased microbial clearance and enhanced mucosal epithelial host defense. Generation ofthe C22:6-derived protectins, D-series resolvins and maresins in airway injury and their capacity to block inflammation and promote resolution in the airway has not been evaluated. In addition to generation ofthese specialized pro-resolving mediators, their roles for organ protection at mucosal surfaces will be the focus of Project 2. To test our hypothesis, we propose three specific aims: * Determine the time course for specialized pro-resolving mediator formation after airway injury ¿ Actions of specialized pro-resolving mediators on airway epithelial functional responses, and * Establish the regulation of acute lung injury resolution by specialized pro-resolving mediators Project 2's specific aims on airway resolution pharmacology will be greatly facilitated by the synergy and unique resources to be provided by the proposed research program Projects and Cores and will enable us to (i) uncover new molecular insights into lipid-derived signaling pathways engaged during mucosal injury to the lower respiratory tract; and (ii) design novel therapeutic strategies that lessen the severity and consequent morbidity of acute lung injury and critical illnesses. .