5-HT2 receptor activation alleviates airway inflammation and structural remodeling in a chronic mouse asthma model
5-HT2 receptor activation alleviates airway inflammation and structural remodeling in a chronic mouse asthma model
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DOI：
10.1016/j.lfs.2019.116790
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发表时间：
2019-11-01
期刊：
影响因子：
6.1
通讯作者：
Nichols, Charles D.
中科院分区：
文献类型：
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作者：
Flanagan, Thomas W.;Sebastian, Melaine N.;Nichols, Charles D.
目的：尽管对血清素 5-HT2A 受体生物学的大量研究都集中在其在中枢神经系统中的作用，但外周组织中这些受体的选择性激活可以产生深远的抗炎作用。我们之前在小鼠卵清蛋白 (OVA) 模型中证明，小分子 5-HT2 受体激动剂 (R)-2,5-二甲氧基-4-碘苯丙胺 [(R)-DOI] 通过 5-HT2A 受体激活抑制 TNF-α 介导的促炎信号级联和炎症，并预防小鼠卵清蛋白 (OVA) 模型中急性过敏性哮喘的发生以及与急性过敏性哮喘相关的炎症。在这里，我们研究了 (R)-DOI 在新开发的慢性哮喘模型中逆转炎症和与已建立的哮喘相关的症状的能力。方法：进行 18 周的卵清蛋白激发期，以在 BALB/c 小鼠中产生持续性慢性哮喘。过敏原停止一周后，进行四次每日一次的 (R)-DOI 鼻内治疗，并通过全身体积描记法 (WBP) 测量呼吸参数。通过定量实时聚合酶链反应 (qRT-PCR) 测量均质肺组织中的细胞因子和趋化因子水平，通过多重测定分析支气管肺泡 (BALF) 液的趋化因子调节，并进行高碘酸-希夫和马森三色染色以确定杯状细胞浸润和肺形态的整体变化。主要发现：通过 (R)-DOI 激活 5-HT2 减弱升高的气道对乙酰甲胆碱的高反应性，减少肺部炎症和粘液产生，并将气道结构重塑和胶原沉积减少近 70%。 意义：总体而言，这些数据为 (R)-DOI 和 5-HT2 受体激活治疗哮喘的治疗潜力提供了支持，并确定 (R)-DOI 作为一种新型的抗肺纤维化治疗化合物。
Aims: Although the bulk of research into the biology of serotonin 5-HT2A receptors has focused on its role in the CNS, selective activation of these receptors in peripheral tissues can produce profound anti-inflammatory effects. We previously demonstrated that the small molecule 5-HT2 receptor agonist (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] inhibits TNF-alpha-mediated proinflammatory signaling cascades and inflammation via 5-HT2A receptor activation and prevents the development of, and inflammation associated with, acute allergic asthma in a mouse ovalbumin (OVA) model. Here, we investigated the ability of (R)-DOI to reverse inflammation and symptoms associated with established asthma in a newly developed model of chronic asthma.Methods: An 18-week ovalbumin challenge period was performed to generate persistent, chronic asthma in BALB/c mice. Four once daily intranasal treatments of ( R)-DOI were administered one week after allergen cessation, with respiratory parameters being measured by whole-body plethysmography (WBP). Cytokine and chemokine levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR) in homogenized lung tissue, bronchoalveolar (BALF) fluid was analyzed for chemokine modulation by multiplex assays, and Periodic Acid-Schiff and Masson's Trichrome staining was performed to determine goblet cell infiltration and overall changes to lung morphology.Key findings: 5-HT2 activation via (R)-DOI attenuates elevated airway hyperresponsiveness to methacholine, reduces pulmonary inflammation and mucus production, and reduces airway structural remodeling and collagen deposition by nearly 70%.Significance: Overall, these data provide support for the therapeutic potential of (R)-DOI and 5-HT2 receptor activation for the treatment of asthma, and identifies (R)-DOI as a novel therapeutic compound against pulmonary fibrosis.