Effects of a selection of histone deacetylase inhibitors on mast cell activation and airway and colonic smooth muscle contraction
Effects of a selection of histone deacetylase inhibitors on mast cell activation and airway and colonic smooth muscle contraction
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DOI：
10.1016/j.intimp.2008.08.017
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发表时间：
2008-12-20
影响因子：
5.6
通讯作者：
Marson, Charles M.
中科院分区：
文献类型：
--
作者：
Assem, El-Sayed K.;Peh, Kheng H.;Marson, Charles M.
组蛋白脱乙酰酶(HDAC)抑制剂是一种新型抗癌药物，在自身免疫性疾病、哮喘和炎症性肠病模型中的研究表明，HDAC抑制剂也可能具有有用的抗炎作用。因此，使用一些HDAC抑制剂进行了与哮喘和炎症性肠病有关的体外研究：Suberoylanilde异羟肟酸(SAHA，Vorinostat(TM))，以及相关的分支异羟肟酸、联胺(1)、MGCD0103和两种短链脂肪酸衍生物：丁酸钠(用于炎症性肠病)和丙戊酸钠。检测了这些HDAC抑制剂对抗原或激动剂诱导的豚鼠离体气管环和结肠收缩、激动剂诱导的大鼠结肠收缩以及大鼠腹膜肥大细胞组胺释放的调节能力。SAHA、联胺(1)或MGCD0103与10-40 mU M的SAHA、联胺(1)或MGCD0103预孵育6 h可显著抑制抗原诱导的豚鼠气管环的收缩，并能抑制G蛋白偶联受体激动剂组胺、5-羟色胺和氨基甲胆碱引起的收缩，丁酸钠(1 MM)和丙戊酸钠(100 MM)是较弱的抑制剂。MGCD0103可阻断氟化钠(NaF，一种非选择性G蛋白激活剂)、KCl和过氧化自由基生成物对气管环的收缩作用。此外，MGCD0103显著抑制IgE抗体敏感的大鼠腹膜肥大细胞抗原诱导的组胺释放，以及NaF诱导的组胺释放，以及NaF诱导的结肠收缩。这些不同的作用似乎涉及细胞信号的调节，可能涉及G蛋白偶联通路，并进一步支持HDAC抑制剂作为抗炎剂的发展。(C)2008爱思唯尔B.V.保留所有权利。
Studies of histone deacetylase (HDAC) inhibitors, novel anticancer drugs, in models of autoimmune diseases, asthma, and inflammatory bowel disease suggest that HDAC inhibitors may also have useful anti-inflammatory effects. Accordingly, in vitro studies relevant to asthma and inflammatory bowel disease were conducted using a selection of HDAC inhibitors: suberoylanilide hydroxamic acid (SAHA, Vorinostat(TM)), and a related branched hydroxamic acid, diamide (1), MGCD0103 and two short chain fatty acid derivatives: sodium butyrate (of use in inflammatory bowel disease) and sodium valproate. The ability of those HDAC inhibitors to modulate antigen- or agonist-induced contraction of isolated guinea pig tracheal rings and colon, agonist-induced contraction of rat colon, and histamine release from rat peritoneal mast cells was examined. Pre-incubation (up to 6 h) with 10-40 mu M of SAHA, diamide (1), or MGCD0103 caused significant inhibition of the antigen-induced contraction of sensitised guinea pig tracheal rings as well as inhibition of the contraction induced by histamine, 5-hydroxytryptamine and carbachol (G-protein coupled receptor agonists), while sodium butyrate (1 mM) and sodium valproate (100 mu M) were weak inhibitors. Contraction of tracheal rings by sodium fluoride (NaF, a non-selective G-protein activator), KCl and a peroxyl radical generator was blocked by MGCD0103. Additionally, MGCD0103 significantly inhibited antigen-induced histamine release from IgE antibody-sensitised rat peritoneal mast cells, and NaF-induced histamine release, as well as inhibiting NaF-induced colon contraction. Those various effects appear to involve modulation of cell signaling, probably involving G-protein coupled pathways, and further support the development of HDAC inhibitors as anti-inflammatory agents. (C) 2008 Elsevier B.V. All rights reserved.