Project 2 :Specialized Pro-Resolving Lipid Mediators

项目2中的拟议实验将检验以下假设：在健康情况下，有害刺激引起的粘膜上皮损伤启动气道形成促进急性炎症消退和气道稳态恢复的特化促消退介质。已发表的报告和与项目1、3和4正在进行的合作的初步数据已经确定了气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， 在吸入时，胃酸对气道上皮完整性的破坏导致组织损伤和对感染的易感性增加，这可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），在气道炎症过程中存在，并转化为生物活性脂质介质。这些介质中的一些，即protectins，D-系列resolvins和maresins显示抗炎和促消退作用，包括调节白细胞运输以防止嗜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衍生的protectin、D-系列resolvins和maresins在气道损伤中的产生及其阻断炎症和促进气道消退的能力尚未得到评价。除了产生这些专门的促消退介质外，它们在粘膜表面的器官保护作用将是项目2的重点。 为了验证我们的假设，我们提出了三个具体目标： * 确定气道后特异性促消退介质形成的时程 损伤 专门的促消退介质对气道上皮功能反应的作用， 和 * 建立专业化救治急性肺损伤的规程 调解员 项目2的气道解决药理学的具体目标将大大促进协同作用和独特的资源，将提供拟议的研究计划项目和核心，并将使我们能够（i）发现新的分子见解脂质衍生的信号通路参与粘膜损伤下呼吸道;和（ii）设计新的治疗策略，减轻严重程度和后果 急性肺损伤和危重病的发病率。 .

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. .