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首页> 外文期刊>Journal of aerosol medicine and pulmonary drug delivery >New pharmacotherapy for airway mucus hypersecretion in asthma and COPD: Targeting intracellular signaling pathways
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New pharmacotherapy for airway mucus hypersecretion in asthma and COPD: Targeting intracellular signaling pathways

机译：哮喘和COPD中气道黏液分泌过多的新药物疗法：靶向细胞内信号通路

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Airway mucus hypersecretion is a pathophysiological feature of asthma and chronic obstructive pulmonary disease (COPD). The hypersecretion is associated with phenotypic changes in the airways, notably, increases in the number of surface epithelial goblet cells (hyperplasia) and in the size of the submucosal glands (hypertrophy). The hyperplasia and hypertrophy are associated with increased production of mucin, the gel-forming component of mucus. The excess mucus production contributes to morbidity and mortality in many patients, particularly in those with more severe disease. Although current pharmacotherapy is effective in clinical management of patients with stable asthma, severe asthma is poorly treated and there is no current drug treatment for COPD. In neither disease is there specific, effective pharmacotherapy for the hypersecretion. Consequently, identification of potential drug targets for treatment of hypersecretion in asthma and COPD is warranted. The inflammatory mediators and the associated intracellular signaling pathways underlying upregulation of mucin synthesis and development of goblet cell hyperplasia are gradually being elucidated. These include Th2 cytokines (predominantly IL-9 and IL-13), and IL-1β, tumor necrosis factor-alpha (TNF-α) and cyclooxygenase (COX)-2. IL-9 may act predominantly via calcium-activated chloride channels (CLCA), IL-13 via STAT-6 and FOXA2, TNF-α via NF-κB, and IL-1β via COX-2. Epidermal growth factor receptor (EGF-R) signaling and FOXA2 appear to be convergent intracellular pathways for a number of inflammatory mediators, with EGF-R upregulated in the airways of asthmatic and COPD patients. Thus, preclinical studies have clearly identified a number of intracellular signaling pathways as possible targets for pharmacotherapy of airway mucus hypersecretion in asthma and COPD. Of these, the EGF-R and Th2 cytokine pathways may have the greatest potential for inhibition of excessive mucus production. However, because these targets are so often intimately involved with different aspects of airway (and systemic) homeostasis, there is potential for development of unwanted side effects with drug intervention. Thus, translation of the promising preclinical studies to the clinic will depend on development of drug moieties with low off-target activity. This may be accomplished by maximizing airway selectivity, which may be facilitated by appropriate delivery device design.
机译：气道粘液分泌过多是哮喘和慢性阻塞性肺疾病（COPD）的病理生理特征。过度分泌与气道的表型改变有关，尤其是表面上皮杯状细胞的数量增加（增生）和粘膜下腺的大小（肥大）。增生和肥大与粘蛋白（粘液的凝胶形成成分）的产生增加有关。过多的粘液产生会导致许多患者的发病率和死亡率，特别是在那些病情较严重的患者中。尽管当前的药物疗法在稳定哮喘患者的临床治疗中是有效的，但严重的哮喘治疗效果较差，目前尚无针对COPD的药物治疗方法。在这两种疾病中，都没有针对分泌过多的特异性有效药物治疗。因此，有必要确定治疗哮喘和COPD过度分泌的潜在药物靶标。逐渐阐明了粘蛋白合成的上调和杯状细胞增生发生的炎症介质和相关的细胞内信号通路。这些包括Th2细胞因子（主要是IL-9和IL-13）和IL-1β，肿瘤坏死因子-α（TNF-α）和环氧合酶（COX）-2。 IL-9可能主要通过钙激活的氯离子通道（CLCA）起作用，IL-13可以通过STAT-6和FOXA2起作用，TNF-α可以通过NF-κB起作用，IL-1β可以通过COX-2起作用。表皮生长因子受体（EGF-R）信号和FOXA2似乎是许多炎性介质的会聚细胞内途径，哮喘和COPD患者的气道中EGF-R上调。因此，临床前研究清楚地确定了许多细胞内信号传导途径作为哮喘和COPD气道粘液分泌过多药物治疗的可能靶标。其中，EGF-R和Th2细胞因子途径可能具有最大的抑制过量粘液产生的潜力。但是，由于这些靶标经常与气道（和全身）动态平衡的不同方面密切相关，因此通过药物干预可能会产生不良副作用。因此，有希望的临床前研究向临床的转化将取决于具有低脱靶活性的药物部分的发展。这可以通过最大化气道选择性来实现，这可以通过适当的输送装置设计来促进。

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