Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia.
Airways Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
J Allergy Clin Immunol. 2017 Feb;139(2):519-532. doi: 10.1016/j.jaci.2016.04.038. Epub 2016 Jun 10.
Severe steroid-insensitive asthma is a substantial clinical problem. Effective treatments are urgently required, however, their development is hampered by a lack of understanding of the mechanisms of disease pathogenesis. Steroid-insensitive asthma is associated with respiratory tract infections and noneosinophilic endotypes, including neutrophilic forms of disease. However, steroid-insensitive patients with eosinophil-enriched inflammation have also been described. The mechanisms that underpin infection-induced, severe steroid-insensitive asthma can be elucidated by using mouse models of disease.
We sought to develop representative mouse models of severe, steroid-insensitive asthma and to use them to identify pathogenic mechanisms and investigate new treatment approaches.
Novel mouse models of Chlamydia, Haemophilus influenzae, influenza, and respiratory syncytial virus respiratory tract infections and ovalbumin-induced, severe, steroid-insensitive allergic airway disease (SSIAAD) in BALB/c mice were developed and interrogated.
Infection induced increases in the levels of microRNA (miRNA)-21 (miR-21) expression in the lung during SSIAAD, whereas expression of the miR-21 target phosphatase and tensin homolog was reduced. This was associated with an increase in levels of phosphorylated Akt, an indicator of phosphoinositide 3-kinase (PI3K) activity, and decreased nuclear histone deacetylase (HDAC)2 levels. Treatment with an miR-21-specific antagomir (Ant-21) increased phosphatase and tensin homolog levels. Treatment with Ant-21, or the pan-PI3K inhibitor LY294002, reduced PI3K activity and restored HDAC2 levels. This led to suppression of airway hyperresponsiveness and restored steroid sensitivity to allergic airway disease. These observations were replicated with SSIAAD associated with 4 different pathogens.
We identify a previously unrecognized role for an miR-21/PI3K/HDAC2 axis in SSIAAD. Our data highlight miR-21 as a novel therapeutic target for the treatment of this form of asthma.
严重的激素不敏感型哮喘是一个重大的临床问题。然而，有效的治疗方法迫切需要，但其发展受到对疾病发病机制缺乏了解的阻碍。激素不敏感型哮喘与呼吸道感染和非嗜酸性表型有关，包括疾病的中性粒细胞形式。然而，也描述了激素不敏感型哮喘伴嗜酸性粒细胞增多炎症的患者。通过使用疾病的小鼠模型，可以阐明感染诱导的严重激素不敏感型哮喘的潜在机制。
我们试图开发具有代表性的严重激素不敏感型哮喘小鼠模型，并利用它们来确定发病机制和研究新的治疗方法。
在 BALB/c 小鼠中开发并研究了新型肺炎衣原体、流感嗜血杆菌、流感病毒和呼吸道合胞病毒呼吸道感染以及卵清蛋白诱导的严重激素不敏感型过敏性气道疾病（SSIAAD）的小鼠模型。
在 SSIAAD 期间，感染诱导肺中 microRNA（miRNA）-21（miR-21）表达水平增加，而 miR-21 靶标磷酸酶和张力蛋白同源物的表达减少。这与磷酸化 Akt 水平的升高有关，磷酸化 Akt 是磷脂酰肌醇 3-激酶（PI3K）活性的指标，以及核组蛋白去乙酰化酶（HDAC）2 水平的降低有关。用 miR-21 特异性拮抗剂（Ant-21）治疗可增加磷酸酶和张力蛋白同源物的水平。用 Ant-21 或泛 PI3K 抑制剂 LY294002 治疗可降低 PI3K 活性并恢复 HDAC2 水平。这导致气道高反应性的抑制和过敏性气道疾病对类固醇的敏感性恢复。这些观察结果在与 4 种不同病原体相关的 SSIAAD 中得到了复制。
我们发现了以前未被认识的 miR-21/PI3K/HDAC2 轴在 SSIAAD 中的作用。我们的数据突出了 miR-21 作为治疗这种形式哮喘的新的治疗靶点。
