The parasitic worm-derived immunomodulator, ES-62 and its drug-like small molecule analogues exhibit therapeutic potential in a model of chronic asthma.
The parasitic worm-derived immunomodulator, ES-62 and its drug-like small molecule analogues exhibit therapeutic potential in a model of chronic asthma.
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DOI：
10.1038/srep19224
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发表时间：
2016-01-14
影响因子：
4.6
通讯作者：
Harnett MM
中科院分区：
文献类型：
--
作者：
Coltherd JC;Rodgers DT;Lawrie RE;Al-Riyami L;Suckling CJ;Harnett W;Harnett MM
慢性哮喘与持续的肺部炎症和气道的长期重塑有关，这些气道重塑已被证明对常规治疗（如类固醇）是难治的，尽管它们在控制急性气道收缩和支气管炎症方面有效。由于其最近在工业化国家的急剧增加并没有反映在发展中地区，因此有人认为蠕虫感染可能会保护人类免受哮喘的发展。与此一致，ES-62，一种由寄生蠕虫Acanthocheilonema viteae分泌的免疫调节剂，可以预防实验小鼠模型中与慢性哮喘相关的病理学（肺的细胞浸润，特别是嗜中性粒细胞和肥大细胞，粘液过度产生和气道增厚）。重要的是，ES-62甚至可以在气道重塑已经建立后起作用，阻止发病机制并改善由反复暴露于过敏原引起的炎症发作，这是严重慢性哮喘的衰弱特征。此外，ES-62的两种化学类似物11 a和12 B在恢复调节性B细胞水平和抑制中性粒细胞和肥大细胞反应方面模拟其治疗作用。因此，这些研究为开发基于ES-62的药物提供了一个平台，化合物11 a和12 b代表了开发新型药物的第一步，以对抗迄今为止难治的慢性哮喘疾病。
Chronic asthma is associated with persistent lung inflammation and long-term remodelling of the airways that have proved refractory to conventional treatments such as steroids, despite their efficacy in controlling acute airway contraction and bronchial inflammation. As its recent dramatic increase in industrialised countries has not been mirrored in developing regions, it has been suggested that helminth infection may protect humans against developing asthma. Consistent with this, ES-62, an immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, can prevent pathology associated with chronic asthma (cellular infiltration of the lungs, particularly neutrophils and mast cells, mucus hyper-production and airway thickening) in an experimental mouse model. Importantly, ES-62 can act even after airway remodelling has been established, arresting pathogenesis and ameliorating the inflammatory flares resulting from repeated exposure to allergen that are a debilitating feature of severe chronic asthma. Moreover, two chemical analogues of ES-62, 11a and 12b mimic its therapeutic actions in restoring levels of regulatory B cells and suppressing neutrophil and mast cell responses. These studies therefore provide a platform for developing ES-62-based drugs, with compounds 11a and 12b representing the first step in the development of a novel class of drugs to combat the hitherto intractable disorder of chronic asthma.