Lipid Mediators in the Resolution of Asthma Exacerbations

描述（由申请人提供）： 所提出的实验将检验以下假设：响应于哮喘加重，在气道中建立生物合成回路，用于产生促进气道炎症和高反应性消退的特定脂质介质。 虽然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，但哮喘急性发作也可能是由于内源性抗炎效应物不足所致。 脂质介质，如半胱氨酰白三烯，在哮喘中发挥重要作用，但不是所有的脂质介质都能引发炎症。 例如，脂氧素（LX）是一类独特的花生四烯酸衍生的脂质介质，其调节白细胞运输并抑制过敏性气道炎症和高反应性。因此，LX是抗炎和消退的脂质介质不断增长的家族中的初始成员。在肺外组织，有趣的组织保护作用最近被分配给新发现的脂质介质来自二十碳五烯酸和二十二碳六烯酸。除了引发炎症和支气管收缩之外，还产生选择内源性脂质介质以促进这些气道反应的解决的概念将改变传统思维，并将这些天然抗炎化合物确定为合理药物设计的新模板。 为了验证我们的假设，我们提出了四个具体的目标，以确定：形成新的脂质介质在体内的小鼠实验模型的哮喘急性发作和决议;选择脂质介质对人类气道上皮功能的影响;调节小鼠实验性哮喘的具体，亲解决的脂质;和产生候选人亲解决的脂质介质在人类哮喘急性发作和决议。 该提案的具体目标是揭示哮喘急性发作的病理生物学基本机制。

DESCRIPTION (provided by applicant): The proposed experiments will test the hypothesis that in response to an asthma exacerbation, biosynthetic circuits are established in the airway for production of specific lipid mediators that promote resolution of airway inflammation and hyper-responsiveness. 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, an asthma exacerbation could also result from insufficient endogenous anti-inflammatory effectors. Lipid mediators, such as cysteinyl leukotrienes, are well appreciated to play important roles in asthma, but not all lipid mediators initiate inflammation. For example, lipoxins (LXs) are a distinct class of arachidonic acid-derived lipid mediators that regulate leukocyte trafficking and inhibit allergic airway inflammation and hyper-responsiveness. Thus, LXs are the initial members in a growing family of lipid mediators of anti-inflammation and resolution. In extrapulmonary tissues, intriguing tissue-protective actions have recently been assigned to newly identified lipid mediators derived from eicosapentaenoic acid and docosahexaenoic acid. In addition to triggering inflammation and bronchoconstriction, the notion that select endogenous lipid mediators are also generated to promote resolution of these airway responses would turn conventional thinking on its head, and identify these natural anti-inflammatory compounds as novel templates for rational drug design. To test our hypothesis, we propose four specific aims to determine: formation of novel lipid mediators in vivo during a murine experimental model of asthma exacerbation and resolution; the influence of select lipid mediators on human airway epithelial function; regulation of murine experimental asthma by specific, pro-resolving lipids; and generation of candidate pro-resolving lipid mediators during asthma exacerbation and resolution in humans. This proposal's specific aims are directed towards uncovering basic mechanisms in the pathobiology of resolution from asthma exacerbation.