Specialized Pro-Resolving Mediators in Asthma

描述（由申请人提供）：拟议的实验将验证过敏性气道炎症导致产生专门的促溶解介质的假设，这些介质参与先天免疫效应机制，包括先天淋巴样细胞，以限制适应性炎症-一种在哮喘加重环境中被病毒感染破坏的调节机制。虽然我们习惯于将哮喘加重期间气道炎症和高反应性的增加视为过度促炎刺激的结果，但哮喘加重的严重程度和持续时间也可能是内源性抗炎效应物不足造成的。半胱氨酸白三烯在哮喘中发挥促炎作用，但并非所有脂质介质都会引发炎症。现在有几个专门的促溶解介质（SPM）家族已被确定并表征为急性炎症。这些保护性介质是从必需脂肪酸中酶促而来的，并作为特定受体的激动剂，转导细胞类型特异性功能反应，包括许多与哮喘相关的功能反应。随着几种阻断白三烯形成或作用的药物已经开发出来，选择内源性脂质衍生介质来促进哮喘气道反应的解决的概念将彻底改变传统的思维，并将这些天然的促解决介质确定为药物设计的新模板。为了验证我们的假设，我们提出了三个具体目标：建立屋尘螨驱动的过敏气道反应中SPM生物合成的时间过程；确定SPM对先天淋巴样细胞生物作用的先天免疫机制并检查病毒感染对SPM形成和作用的破坏。本提案的具体目的是为了揭示在健康和疾病中控制过敏性气道反应解决的基本机制。

DESCRIPTION (provided by applicant): The proposed experiments will test the hypothesis that allergic airway inflammation leads to the generation of specialized pro-resolving mediators that engage innate immune effector mechanisms, including innate lymphoid cells, to limit adaptive inflammation - a regulatory mechanism that is disrupted by viral infection in the setting of asthma exacerbation. Although we are accustomed to viewing the increase in airway inflammation and hyper-responsiveness during asthma exacerbations as the result of an over-abundance of pro-inflammatory stimuli, the severity and duration of an asthma exacerbation could also result from insufficient endogenous anti-inflammatory effectors. Cysteinyl leukotrienes are well appreciated to play pro-phlogistic roles in asthma, but not all lipid mediators initiate inflammation. There are now several families of specialized pro-resolving mediators (SPM) that have been identified and characterized in acute inflammation. These protective mediators are enzymatically derived from essential fatty acids and serve as agonists at specific receptors to transduce cell type specific functional responses, including many that are relevant in asthma. With several drugs already developed to block leukotriene formation or action, the notion that select endogenous lipid-derived mediators are generated to promote resolution of asthmatic airway responses would turn conventional thinking on its head, and identify these natural pro-resolving mediators as novel templates for drug design. To test our hypothesis, we propose three specific aims to: Establish the time course for SPM biosynthesis in house dust mite-driven allergic airways responses; Determine innate immune mechanisms for SPM bioactions on innate lymphoid cells; and Examine the disruption of SPM formation and actions by viral infection. This proposal's specific aims are directed towards uncovering basic mechanisms that govern the resolution of allergic airway responses in health and disease.