Priority Research Centre for Healthy Lungs, Department of Microbiology and Immunology, School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, The University of Newcastle, Hunter Medical Research Institute, Australia.
Pharmacol Res. 2020 Aug;158:104782. doi: 10.1016/j.phrs.2020.104782. Epub 2020 Apr 8.
Asthma is now recognised as a heterogenous inflammatory disease of the lung based on cellular infiltrates and transcriptional profiles of blood and airway cells. Four distinct subgroups have been defined, eosinophilic (T2), neutrophilic (T1), mixed eosinophilic/neutrophilic and paucigranulocytic. Patients can also be stratified at a molecular level into T2-high, T2-low and/or T1 based on their gene signatures. Current treatments for asthma have been centred on administration of steroids and/or bronchodilators for the relief of bronchoconstriction and inflammation. These treatments are not always effective and often have limited efficacy during exacerbations. Eosinophil expansion and homing to tissues, bronchoconstriction, IgE production and mucus hypersecretion (hallmark features of asthma) are regulated by the type 2 cytokines IL-4, IL-5 and IL-13, the latter of which can induce the expression of the eosinophil chemotactic factors CCL11 and CCL24. A number of new generation biologics (monoclonal antibodies) targeting pathways regulated by the T2 cytokines IL-5 and IL-4/13 (IL-4 receptor alpha) have yielded effective therapies for eosinophil induced exacerbations of severe asthma. Despite these advances, difficulties still remain in treating all exacerbations, and this may reflect the contribution of other inflammatory cells such as neutrophils to pathogenesis. This review describes the effectiveness of targeting T2 pathways, emerging approaches and identifies the potential next steps for therapeutic intervention.
哮喘现在被认为是一种基于血液和气道细胞细胞浸润和转录谱的异质炎症性肺病。已经定义了四个不同的亚组，嗜酸性粒细胞（T2）、中性粒细胞（T1）、混合嗜酸性粒细胞/中性粒细胞和少粒细胞。根据基因特征，患者还可以在分子水平上分为 T2 高、T2 低和/或 T1。目前哮喘的治疗方法主要集中在使用类固醇和/或支气管扩张剂来缓解支气管收缩和炎症。这些治疗方法并不总是有效，在发作时往往效果有限。嗜酸性粒细胞扩张和向组织归巢、支气管收缩、IgE 产生和粘液过度分泌（哮喘的标志性特征）受 2 型细胞因子 IL-4、IL-5 和 IL-13 调节，后者可诱导嗜酸性粒细胞趋化因子 CCL11 和 CCL24 的表达。许多针对 2 型细胞因子 IL-5 和 IL-4/13（IL-4 受体 alpha）调节途径的新一代生物制剂（单克隆抗体）已为嗜酸粒细胞诱导的严重哮喘加重提供了有效的治疗方法。尽管取得了这些进展，但治疗所有加重仍然存在困难，这可能反映了其他炎症细胞（如中性粒细胞）对发病机制的贡献。本文描述了靶向 T2 途径的有效性、新兴方法，并确定了治疗干预的潜在下一步。
