Anti-inflammatory effects of PGE2 in the lung: role of the EP4 receptor subtype.
Anti-inflammatory effects of PGE2 in the lung: role of the EP4 receptor subtype.
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DOI：
10.1136/thoraxjnl-2014-206592
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发表时间：
2015-08
期刊：
影响因子：
10
通讯作者：
Belvisi MG
中科院分区：
文献类型：
--
作者：
Birrell MA;Maher SA;Dekkak B;Jones V;Wong S;Brook P;Belvisi MG
哮喘和慢性阻塞性肺疾病（COPD）是气道的慢性炎症性疾病。目前的治疗选择（长效β-肾上腺素受体激动剂和糖皮质激素）不是最佳的，因为它们仅在某些患者组中有效，并且两种化合物类别都存在安全性问题。因此，正在寻求新的支气管扩张剂和抗炎策略。前列腺素E2（PGE 2）是由肺产生的花生四烯酸衍生的类二十烷酸，其作用于四种不同的G蛋白偶联受体（EP 1 -4）以引起一系列有益和有害的作用。本研究的目的是使用一系列基于细胞的测定和体内模型来鉴定介导PGE 2在肺中的抗炎作用的EP受体。在三种不同的模型系统（先天刺激，脂多糖（LPS）;过敏反应，卵清蛋白（OVA）;吸入污染物，香烟烟雾）中证明，缺失功能性EP 4（Ptger 4 −/−）受体的小鼠具有更高水平的气道炎症，表明内源性PGE 2通过EP 4受体激活抑制炎症。基于细胞的测定系统（鼠和人单核细胞/肺泡巨噬细胞）证明PGE 2抑制LPS刺激的细胞的细胞因子释放，并且这被EP 4（但不是EP 1 -3）受体激动剂模拟并被EP 4受体拮抗剂抑制。抗炎作用发生在转录水平，并通过腺苷酸环化酶/cAMP/cAMP依赖性蛋白激酶（PKA）轴。这项研究表明，EP 4受体激活是负责PGE 2的抗炎活性在一系列疾病相关的模型，因此，可以代表一个新的治疗目标慢性气道炎症条件。
Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases of the airway. Current treatment options (long acting β-adrenoceptor agonists and glucocorticosteroids) are not optimal as they are only effective in certain patient groups and safety concerns exist regarding both compound classes. Therefore, novel bronchodilator and anti-inflammatory strategies are being pursued. Prostaglandin E2 (PGE2) is an arachidonic acid-derived eicosanoid produced by the lung which acts on four different G-protein coupled receptors (EP1–4) to cause an array of beneficial and deleterious effects. The aim of this study was to identify the EP receptor mediating the anti-inflammatory actions of PGE2 in the lung using a range of cell-based assays and in vivo models. It was demonstrated in three distinct model systems (innate stimulus, lipopolysaccharide (LPS); allergic response, ovalbumin (OVA); inhaled pollutant, cigarette smoke) that mice missing functional EP4 (Ptger4−/−) receptors had higher levels of airway inflammation, suggesting that endogenous PGE2 was suppressing inflammation via EP4 receptor activation. Cell-based assay systems (murine and human monocytes/alveolar macrophages) demonstrated that PGE2 inhibited cytokine release from LPS-stimulated cells and that this was mimicked by an EP4 (but not EP1–3) receptor agonist and inhibited by an EP4 receptor antagonist. The anti-inflammatory effect occurred at the transcriptional level and was via the adenylyl cyclase/cAMP/ cAMP-dependent protein kinase (PKA) axis. This study demonstrates that EP4 receptor activation is responsible for the anti-inflammatory activity of PGE2 in a range of disease relevant models and, as such, could represent a novel therapeutic target for chronic airway inflammatory conditions.