Serra-Pages M, Torres R, Plaza J, Herrerias A, Costa-Farré C, Marco A, Jiménez M, Maurer M, Picado C, de Mora F
Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain.
CIBER (Centro de Investigación Biomédica en Red) de Enfermedades Respiratorias, Barcelona, Spain.
Clin Exp Allergy. 2015 Oct;45(10):1590-600. doi: 10.1111/cea.12542.
Prostaglandin E2 (PGE2 ) has been proposed to exert antiasthmatic effects in patients, to prevent antigen-induced airway pathology in murine models, and to inhibit mast cells (MC) activity in vitro.
To assess in a murine model whether the protective effect of PGE2 may be a consequence of its ability to activate the E-prostanoid (EP)2 receptor on airway MC.
Either BALB/c or C57BL/6 mice were exposed intranasally (i.n.) to house dust mite (HDM) aeroallergens. Both strains were given PGE2 locally (0.3 mg/kg), but only BALB/c mice were administered butaprost (EP2 agonist: 0.3 mg/kg), or AH6809 (EP2 antagonist; 2.5 mg/kg) combined with the MC stabilizer sodium cromoglycate (SCG: 25 mg/kg). Airway hyperresponsiveness (AHR) and inflammation, along with lung MC activity, were evaluated. In addition, butaprost's effect was assessed in MC-mediated passive cutaneous anaphylaxis (PCA) in mice challenged with 2,4-dinitrophenol (DNP).
Selective EP2 agonism attenuated aeroallergen-caused AHR and inflammation in HDM-exposed BALB/c mice, and this correlated with a reduced lung MC activity. Accordingly, the blockade of endogenous PGE2 by means of AH6809 worsened airway responsiveness in sensitive BALB/c mice, and such worsening was reversed by SCG. The relevance of MC to PGE2 -EP2 driven protection was further highlighted in MC-dependent PCA, where butaprost fully prevented MC-induced ear swelling. Unlike in BALB/c mice, PGE2 did not protect the airways of HDM-sensitized C57BL/6 animals, a strain in which we showed MC to be irrelevant to aeroallergen-driven AHR and inflammation.
CONCLUSIONS & CLINICAL RELEVANCE: The beneficial effect of both exogenous and endogenous PGE2 in aeroallergen-sensitized mice may be attributable to the activation of the EP2 receptor, which in turn acts as a restrainer of airway MC activity. This opens a path towards the identification of therapeutic targets against asthma along the 'EP2 -MC-airway' axis.
前列腺素E2（PGE2）被认为对患者具有抗哮喘作用，可预防小鼠模型中抗原诱导的气道病变，并在体外抑制肥大细胞（MC）活性。
在小鼠模型中评估PGE2的保护作用是否源于其激活气道MC上E-前列腺素（EP）2受体的能力。
将BALB/c或C57BL/6小鼠经鼻内（i.n.）暴露于屋尘螨（HDM）气传变应原。两种品系小鼠均局部给予PGE2（0.3mg/kg），但仅对BALB/c小鼠给予布他前列素（EP2激动剂：0.3mg/kg），或AH6809（EP2拮抗剂；2.5mg/kg）并联合MC稳定剂色甘酸钠（SCG：25mg/kg）。评估气道高反应性（AHR）、炎症以及肺MC活性。此外，在经2,4-二硝基苯酚（DNP）攻击的小鼠的MC介导的被动皮肤过敏反应（PCA）中评估布他前列素的作用。
选择性EP2激动作用减轻了HDM暴露的BALB/c小鼠中变应原引起的AHR和炎症，这与肺MC活性降低相关。因此，通过AH6809阻断内源性PGE2会使敏感的BALB/c小鼠的气道反应性恶化，而SCG可逆转这种恶化。在MC依赖性PCA中进一步突出了MC对PGE2-EP2驱动的保护作用的相关性，其中布他前列素完全预防了MC诱导的耳部肿胀。与BALB/c小鼠不同，PGE2不能保护HDM致敏的C57BL/6动物的气道，在该品系中我们发现MC与变应原驱动的AHR和炎症无关。
外源性和内源性PGE2在变应原致敏小鼠中的有益作用可能归因于EP2受体的激活，EP2受体进而作为气道MC活性的抑制剂。这为沿着“EP2-MC-气道”轴鉴定抗哮喘治疗靶点开辟了道路。
