Specialized Pro-Resolving Mediators in Asthma

描述（由申请人提供）：拟定的实验将检验过敏性气道炎症导致产生专门的促消退介质的假设，该介质参与先天免疫效应机制，包括先天淋巴细胞，以限制适应性炎症-一种在哮喘急性发作的情况下被病毒感染破坏的调节机制。 尽管我们习惯于将哮喘急性发作期间气道炎症和高反应性的增加视为过度丰富的促炎刺激的结果，但哮喘急性发作的严重程度和持续时间也可能是由于内源性抗炎效应物不足。半胱氨酰白三烯在哮喘中发挥促炎作用，但并非所有脂质介质都能引发炎症。现在有几个家族的专门的促消退介质（SPM），已被确定和表征急性炎症。这些保护性介质是酶促衍生自必需脂肪酸，并作为特定受体的激动剂，对哮喘细胞类型的特异性功能反应，包括许多相关的哮喘。由于已经开发了几种药物来阻断白三烯的形成或作用，产生选择内源性脂质衍生介质以促进哮喘气道反应消退的概念将改变传统思维，并将这些天然促消退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的目标：建立SPM生物合成在室内尘螨驱动的过敏性气道反应的时间过程;确定先天免疫机制SPM生物作用于先天淋巴细胞;和检查SPM的形成和行动的破坏病毒感染。该提案的具体目标是揭示控制健康和疾病中过敏性气道反应的基本机制。

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.