Lipid Mediators in the Resolution of Asthma Exacerbatio*

描述(由申请人提供)： 拟议的实验将检验这样一种假设，即为了应对哮喘的恶化，在呼吸道中建立了生物合成回路，以产生特定的脂质介质，促进呼吸道炎症的消退和高反应性。虽然我们习惯于将哮喘加重时的气道炎症和高反应性的增加看作是致炎刺激过多的结果，但哮喘加重也可能是内源性抗炎效应物不足所致。脂类介质，如半胱氨酰白三烯，在哮喘中起重要作用，但并不是所有的脂类介质都会引发炎症。例如，脂氧素(LXs)是一类独特的花生四烯酸衍生的脂质介质，调节白细胞的运输，抑制过敏性呼吸道炎症和高反应性。因此，LXs是越来越多的抗炎和消解脂质介体家族中的最初成员。在肺外组织中，最近新发现的二十碳五烯酸和二十二碳六烯酸衍生的脂质介质具有耐人寻味的组织保护作用。除了引发炎症和支气管收缩外，还产生了选择内源性脂质介质来促进这些呼吸道反应的分解的概念，这将颠覆传统的思维，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来确定：在小鼠哮喘加重和缓解的实验模型中体内形成新的脂质介质；选定的脂质介质对人类呼吸道上皮功能的影响；特定的、有利于分解的脂质对小鼠实验性哮喘的调节；以及在人类哮喘加重和缓解过程中候选的有利于分解的脂质介质的生成。这项提案的具体目标是揭示哮喘恶化的病理生物学解决的基本机制。

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.