A prostacyclin agonist with thromboxane inhibitory activity for airway allergic inflammation in mice
A prostacyclin agonist with thromboxane inhibitory activity for airway allergic inflammation in mice
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DOI：
10.1111/j.1365-2222.2009.03418.x
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发表时间：
2010-02-01
影响因子：
6.1
通讯作者：
Gejyo, F.
中科院分区：
文献类型：
--
作者：
Hayashi, M.;Koya, T.;Gejyo, F.
背景ONO-1301是一种新型的前列环素激动剂，具有血栓素A(2)(TXA(2))合酶抑制活性。方法用ONO-1301、OKY-046(TXA(2)合成酶抑制剂)、前列环素受体(IP)激动剂贝拉前列素、ONO-1301加CAY10449(选择性IP拮抗剂)或赋形剂致敏激发OVA小鼠。在OVA激发后24小时，评估气道对乙酰胆碱的高反应性(AHR)，并进行支气管肺泡灌洗。取肺标本进行杯状细胞染色和肺树突状细胞(DC)分析。结果ONO-1301组小鼠的AHR、气道嗜酸性粒细胞、T辅助细胞2型细胞因子水平、黏液产量和肺DC数均显著低于赋形剂组。ONO-1301的上述作用可被CAY10449逆转。ONO-1301单独处理的BMDCs具有较低的DC功能，如协同刺激因子的表达或对脾T细胞的刺激作用。结论ONO-1301可能通过对DC的调节而抑制AHR和气道变态反应性炎症，主要通过IP受体介导。引用如下：M.Hayashi，T.Koya，H.Kawakami，T.Sakagami，T.Hasegawa，H.Kagamu，T.Takada，Y.Sakai，E.Suzuki，E.W.Gelfand and F.Gejyo，临床与实验过敏，2010(40)317-326。
P>BackgroundONO-1301 is a novel drug that acts as a prostacyclin agonist with thromboxane A(2) (TxA(2)) synthase inhibitory activity. We investigated the effect of ONO-1301 on development of airway allergic inflammation.MethodsMice sensitized and challenged to ovalbumin (OVA) received ONO-1301, OKY-046 (TxA(2) synthase inhibitor), beraprost, a prostacyclin receptor (IP) agonist, ONO-1301 plus CAY10449 (selective IP antagonist) or vehicle during the challenge period. Twenty-four hours after the OVA challenge, airway hyperresponsiveness (AHR) to methacholine was assessed and bronchoalveolar lavage was performed. Lung specimens were excised for goblet cell staining and analysis of lung dendritic cells (DCs). Bone marrow-derived dendritic cells (BMDCs) were generated, in the presence or absence of drugs, for analysis of DC function.ResultsMice that received ONO-1301 showed significantly lower AHR, airway eosinophilia, T-helper type 2 cytokine levels, mucus production and lung DCs numbers than vehicle-treated mice. These effects of ONO-1301 were mostly reversed by CAY10449. BMDCs treated with ONO-1301 alone showed lower DC functions, such as expression of costimulatory factors or stimulation to spleen T cells.ConclusionsThese data suggest that ONO-1301 may suppress AHR and airway allergic inflammation through modulation of DCs, mainly mediated through the IP receptor. This agent may be effective as an anti-inflammatory drug in the treatment of asthma.Cite this as: M. Hayashi, T. Koya, H. Kawakami, T. Sakagami, T. Hasegawa, H. Kagamu, T. Takada, Y. Sakai, E. Suzuki, E. W. Gelfand and F. Gejyo, Clinical & Experimental Allergy, 2010 (40) 317- 326.