PGE2 in the Pathogenesis of Allergic Airway Disease

PGE2 在过敏性气道疾病发病机制中的作用

• 批准号: 7448475
• 负责人: Beverly H Koller
• 金额: $ 34.46万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-20 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7448475
• 关键词: Acute; Affect; Age; Aging; Allergic; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Arachidonic Acids; Asthma; Attenuated; Bronchoconstriction; Cell Degranulation; Chronic; Complex; Coupling; Cyclic AMP; Data; Development; Dinoprostone; Disease; EP4 receptor; Enzymes; Funding; Half-Life; Immune response; Individual; Inflammation; Inflammatory; Inflammatory Response; Lead; Lung; Mediating; Metabolic Pathway; Metabolism; Modeling; Mus; Oxidoreductase; PTGS2 gene; Pathogenesis; Pathway interactions; Phospholipase; Physiology; Prostaglandin H2; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Prostaglandins E; Regulation; Relative (related person); Research Personnel; Role; Testing; Thromboxane A2; age related; airway hyperresponsiveness; airway inflammation; airway obstruction; airway remodeling; allergic airway disease; attenuation; base; cyclooxygenase 1; cyclooxygenase 2; in vivo; lipid mediator; mast cell; methacholine; mouse membrane-associated prostaglandin E synthase; mouse model; novel strategies; programs; prostaglandin EP2 receptor; prostaglandin EP3 receptor; prostanoid receptor EP1; protective effect; receptor; receptor expression; respiratory smooth muscle; response

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.

描述（由申请人提供）：前列腺素E2是气道生理学的重要调节剂。在过敏性炎症发作期间，如哮喘，PGE 2可能通过2种不同的途径影响疾病的发病机制：通过直接影响气道张力和通过调节炎症反应的强度。PGE 2的这些作用由4种不同的受体（EP 1 -4）介导。在上一个资助期，我们发现PGE 2激活EP 1和EP 3受体导致气道阻塞，而EP 2受体的激活可防止乙酰甲胆碱诱导的支气管收缩。此外，EP 1和EP 3受体是促炎性的，而EP 2和EP 4受体抑制炎症和免疫应答。作为具有短半衰期的脂质介质，在特定的肺微环境中调节PGE 2水平可以提供控制这些明显不同的作用的机制。PGE 2是由花生四烯酸通过磷脂酶、环加氧酶和PGE脱氢酶的顺序作用合成的。迄今为止，已经鉴定了3种推定的PGE脱氢酶，其从内过氧化物产生PGE 2。已经鉴定了至少一种负责PGE 2体内代谢的酶，即15-前列腺素脱氢酶（PGDH）。然而，这些不同的PGE 2合成和代谢途径在控制其在气道中的作用方面的作用尚不清楚。我们的中心假设是PGE 2主要在过敏性气道中发挥保护作用。其作用机制可能是抑制炎症反应，防止气道高反应性的发展，减轻气道重塑。这些保护作用依赖于PGE 2、EP 2和EP 4受体的表达。我们将使用小鼠模型来测试这一假设，其中一些是在上一个资助期开发的。我们的初步研究表明，PGE 2的保护作用可能会随着年龄的增长而减弱，这是由于促炎性PGE 2途径的年龄相关性增加。我们推测，老年动物中PGE 2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的贡献。明确PGE 2控制气道炎症的机制，并开发增强其抗炎作用的策略，应该为减缓哮喘的发展提供新的方法。