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The non-antibiotic macrolide EM900 attenuates HDM and poly(I:C)-induced airway inflammation with inhibition of macrophages in a mouse model

非抗生素大环内酯类 EM900 在小鼠模型中通过抑制巨噬细胞减轻 HDM 和 poly (I: C) 诱导的气道炎症

  • 影响因子:2.93
  • DOI:10.1007/s00011-019-01302-3
  • 作者列表:"Sadamatsu, Hironori","Takahashi, Koichiro","Tashiro, Hiroki","Kato, Go","Noguchi, Yoshihiko","Kurata, Keigo","Ōmura, Satoshi","Kimura, Shinya","Sunazuka, Toshiaki","Sueoka-Aragane, Naoko
  • 发表时间:2020-01-01
Abstract

Objective Macrolides have been reported to reduce the exacerbation of severe asthma. The aim of this study was to clarify the effects and mechanisms of EM900, a non-antibiotic macrolide, on allergic airway inflammation. Methods Mice were sensitized and challenged by house dust mite (HDM), then exposed to polyinosinic-polycytidylic acid (poly(I:C)) as a model of asthma complicated with viral infection. Mice were administered with EM900. Airway inflammation was assessed from inflammatory cells in bronchoalveolar lavage fluid (BALF) and cytokines in lung tissues. Lung interstitial macrophages were counted by flow cytometry. Cytokine production, phosphorylation of NF-κB, and p38 in macrophages were examined by ELISA and western blotting. Results Counts of cells in BALF and concentrations of IL-13, IL-5, RANTES, IL-17A, and MIP-2 were significantly decreased by EM900 compared to those without EM900. Percentages of lung interstitial macrophages were significantly decreased with EM900. Concentrations of IL-6, RANTES, and MIP-2 induced by HDM and poly(I:C) were significantly suppressed by EM900 through the suppression of NF-κB and p38 phosphorylation in macrophages. Conclusions HDM and poly(I:C)-induced airway inflammation is attenuated by EM900 with the inhibition of lung interstitial macrophages. Clinical use of EM900 is expected, because EM900 has inhibitory effects against airway inflammation without inducing bacterial drug resistance.

摘要

目的已报道大环内酯类药物可减少严重哮喘的恶化。本研究的目的是阐明非抗生素大环内酯类 EM900 对过敏性气道炎症的作用和机制。方法用屋尘螨 (HDM) 致敏小鼠,然后用聚肌胞-聚胞苷酸 (poly (I: C)) 作为哮喘合并病毒感染的模型。小鼠给予 em900。从支气管肺泡灌洗液 (BALF) 中的炎症细胞和肺组织中的细胞因子评估气道炎症。流式细胞术计数肺间质巨噬细胞。通过 ELISA 和 western blotting 检测巨噬细胞中细胞因子的产生、 NF-κ b 的磷酸化和 p38。结果 EM900 组 BALF 中细胞计数及 IL-13 、 IL-5 、 RANTES 、 IL-17A 、 MIP-2 浓度均显著低于对照组。Em900 使肺间质巨噬细胞百分比显著降低。EM900 通过抑制巨噬细胞中 NF-κ b 和 p38 磷酸化,显著抑制 HDM 和 poly (I: C) 诱导的 IL-6 、 RANTES 和 MIP-2 的浓度。结论 EM900 可通过抑制肺间质巨噬细胞减轻 HDM 和 poly (I: C) 诱导的气道炎症。预计临床使用 EM900,因为 EM900 对气道炎症有抑制作用,而不会诱导细菌耐药。

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