PGE2 in the Pathogenesis of Allergic Airway Disease

描述（申请人提供）：前列腺素E2是气道生理的重要调节剂。在哮喘等变应性炎症发作期间，PGE2可能通过两种不同的途径影响疾病的发病机制：直接影响气道张力和调节炎症反应的强度。PGE2的这些作用由4种不同的受体介导（EP1-4）。在之前的资助期内，我们发现PGE2激活EP1和EP3受体可导致气道阻塞，而EP2受体的激活可防止甲基苯丙胺诱导的支气管收缩。此外，EP1和EP3受体具有促炎作用，而EP2和EP4受体抑制炎症和免疫反应。PGE2作为一种半衰期短的脂质介质，在特定的肺微环境中调节PGE2水平可以提供一种机制来控制这些明显不同的行为。花生四烯酸通过磷脂酶、环加氧酶和PGE合成酶的连续作用合成PGE2。迄今为止，已经确定了3种推测的PGE2合成酶，可以从内过氧化物中生成PGE2。至少有一种酶负责PGE2的体内代谢，15-前列腺素脱氢酶（PGDH），已被确定。然而，这些合成和代谢PGE2的不同途径在控制其在气道中的作用中的作用尚不清楚。我们的中心假设是PGE2主要在过敏性气道中发挥保护作用。我们认为这种作用的机制是：抑制炎症，防止高反应性气道的发展，减弱气道重塑。这些保护作用依赖于PGE2、EP2和EP4受体的表达。我们将使用小鼠模型来验证这一假设，其中一些是在之前的资助期间开发的。我们的初步研究表明，PGE2的保护作用可能随着年龄的增长而减弱，这是由于与年龄相关的促炎PGE2途径的增加。我们假设PGE2在老年动物中作用的这种转变的机制反映了肥大细胞对促进气道炎症的更突出贡献。明确PGE2控制气道炎症的机制，并制定增强其抗炎作用的策略，将为减轻哮喘的发展提供新的途径。

DESCRIPTION (provided by applicant): Prostaglandin E2 is an important modulator of airway physiology. During episodes of allergic inflammation such as in asthma, PGE2 may affect disease pathogenesis through 2 distinct pathways: by direct effects on airway tone and by modulating the intensity of the inflammatory response. These actions of PGE2 are mediated by 4 different receptors (EP1-4). In the previous funding period, we showed that activation of the EP1 and EP3 receptors by PGE2 leads to airway obstruction, while activation of the EP2 receptor protected against methacholine-induced bronchoconstriction. Moreover, EP1 and EP3 receptors are pro-inflammatory while the EP2 and EP4 receptors constrain inflammatory and immune responses. As a lipid mediator with a short half-life, regulation of PGE2 levels within specific pulmonary microenvironments could provide a mechanism to control these apparently disparate actions. PGE2 is synthesized from arachidonic acid by the sequential actions of phospholipases, cyclo-oxygenases, and PGE synthases. To date, 3 putative PGE synthases have been identified that generate PGE2 from endoperoxides. At least 1 enzyme responsible for in vivo metabolism of PGE2, 15-prostaglandin dehydrogenase (PGDH), has been identified. However, the roles of these various pathways for synthesis and metabolism of PGE2 in controlling its actions in the airways are not known. Our central hypothesis is that PGE2 primarily exerts a protective effect in allergic airway. We posit that the mechanism of this effect is: constraint of inflammation, protection against development of hyper reactive airways, and attenuation of airway remodeling. These protective effects are dependent on expression of the PGE2 EP2 and EP4 receptors. We will test this hypothesis using mouse models, some of which were developed in the previous funding period. Our preliminary studies suggest that the protective actions of PGE2 may diminish with age due to age-related increase in the pro-inflammatory PGE2 pathways. We hypothesize that the mechanism for this shift in the actions of PGE2 in older animals reflects a more prominent contribution of mast cells to promote airway inflammation. Defining the mechanisms used by PGE2 to control inflammation in the airways and developing strategies to enhance its anti-inflammatory effects should provide new approaches for attenuating the development of asthma.