ABSTRACT

Context: Allergic asthma is a multifactorial airway disease characterised by chronic lung inflammation and airway remodelling. The histamine H4 receptor involved in the chemotaxis of leukocytes and mast cells to the site of inflammation is suggested to be a potential drug target for allergy and asthma. In this study we examined the effect of Compound A, N-(2-Aminoethyl)-5-chloro-1H-indol-2-carboxamide a H4 receptor antagonist in allergic asthma mice model. Objective: To investigate the anti-asthmatic effect of compound A in in vivo, airway inflammation in ovalbumin (OVA) induced allergic asthma mouse model was used.

Methodology: Allergic asthma was induced in Balb/c mice using ovalbumin. BAL fluid was examined for the level of IgE, IL-4, IL-5, IL-13 and IL-17 using ELISA. Furthermore, infiltration of leucocytes by histopathology and effect of compound A on signalling molecules were examined in lung tissue.

Results: In mice pre-treatment with compound A (10 mg/kg, 20 mg/kg, 30 mg/kg) at different concentrations markedly reduced the levels of IgE, Th2 cytokine IL-4, IL-5, IL-13 and Th17 cytokine IL-17 in BAL fluid. Histopathological examination of lung tissue showed that compound A was able to reduce the level of inflammatory infiltrates. Furthermore, lung tissue from Compound A treated group shown to down-regulate the levels of signalling molecules such as ERK1/2, Akt, SAPK/JNK and NF-κB compared to OVA treated group.

Discussion and conclusion: Taken together our data demonstrates that compound A has shown to block the H4R-mediated allergic inflammation in this allergic asthma mice model and may be used as a molecule to study the function of H4R.

Abbreviations: Compound A, N-(2-Aminoethyl)-5-chloro-1H-indol-2-carboxamide; JNJ7777120, 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine; H₄R: Histamine 4 Receptor; AHR: Airway hyper responsiveness

摘要

背景：过敏性哮喘是一种多因素气道疾病，其特征是慢性肺部炎症和气道重塑。参与白细胞和肥大细胞向炎症部位趋化的组胺 H4 受体被认为是过敏和哮喘的潜在药物靶点。在这项研究中，我们检查了化合物 A，N -(2-Aminoethyl)-5-chloro-1 H -indol-2-carboxamide 是一种 H4 受体拮抗剂在过敏性哮喘小鼠模型中的作用。目的：研究化合物A的体内抗哮喘作用，采用卵清蛋白（OVA）诱导的过敏性哮喘小鼠模型气道炎症。

方法： 使用卵清蛋白在 Balb/c 小鼠中诱导过敏性哮喘。使用ELISA检查BAL液的IgE、IL-4、IL-5、IL-13和IL-17的水平。此外，在肺组织中检查了组织病理学对白细胞的浸润和化合物 A 对信号分子的影响。

结果：在用不同浓度的化合物 A（10 mg/kg、20 mg/kg、30 mg/kg）预处理的小鼠中，IgE、Th2 细胞因子 IL-4、IL-5、IL-13 和BAL液中的Th17细胞因子IL-17。肺组织的组织病理学检查表明，化合物 A 能够降低炎症浸润的水平。此外，与OVA治疗组相比，来自化合物A治疗组的肺组织显示出下调信号分子例如ERK1/2、Akt、SAPK/JNK和NF-κB的水平。

讨论和结论： 综合我们的数据，我们的数据表明化合物 A 已显示在这种过敏性哮喘小鼠模型中阻断 H4R 介导的过敏性炎症，并可用作研究 H4R 功能的分子。

缩写：化合物A，N- (2-氨基乙基)-5-氯-1H-吲哚-2-甲酰胺；JNJ7777120，1-[(5-氯-1H-吲哚-2-基)羰基]-4-甲基哌嗪；H ₄ R：组胺 4 受体；AHR：气道高反应性