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Safer approaches to therapeutic modulation of TGF-β signaling for respiratory disease
Pharmacology & Therapeutics ( IF 13.5 ) Pub Date : 2018-02-17 , DOI: 10.1016/j.pharmthera.2018.02.010
Philippe Lachapelle , Meina Li , Jo Douglass , Alastair Stewart

The transforming growth factor (TGF)-β cytokines play a central role in development and progression of chronic respiratory diseases. TGF-β overexpression in chronic inflammation, remodeling, fibrotic process and susceptibility to viral infection is established in the most prevalent chronic respiratory diseases including asthma, COPD, lung cancer and idiopathic pulmonary fibrosis. Despite the overwhelming burden of respiratory diseases in the world, new pharmacological therapies have been limited in impact. Although TGF-β inhibition as a therapeutic strategy carries great expectations, the constraints in avoiding compromising the beneficial pleiotropic effects of TGF-β, including the anti-proliferative and immune suppressive effects, have limited the development of effective pharmacological modulators. In this review, we focus on the pathways subserving deleterious and beneficial TGF-β effects to identify strategies for selective modulation of more distal signaling pathways that may result in agents with improved safety/efficacy profiles. Adverse effects of TGF-β inhibitors in respiratory clinical trials are comprehensively reviewed, including those of the marketed TGF-β modulators, pirfenidone and nintedanib. Precise modulation of TGF-β signaling may result in new safer therapies for chronic respiratory diseases.



中文翻译:

治疗性调节TGF-β信号转导呼吸道疾病的更安全方法

转化生长因子(TGF)-β细胞因子在慢性呼吸系统疾病的发生和发展中起着核心作用。在最常见的慢性呼吸道疾病(包括哮喘,COPD,肺癌和特发性肺纤维化)中,已确定TGF-β在慢性炎症,重塑,纤维化过程和对病毒感染的易感性中过表达。尽管世界上呼吸道疾病负担沉重,但新药理疗法的影响仍然有限。尽管将TGF-β抑制作为一种治疗策略具有很高的期望,但在避免损害TGF-β的有益多效性(包括抗增殖和免疫抑制作用)方面的制约因素限制了有效药理调节剂的开发。在这篇评论中,我们专注于保留有害和有益的TGF-β效应的途径,以鉴定选择性调控更多远端信号通路的策略,这些策略可能会导致药物的安全性/有效性得到改善。对TGF-β抑制剂在呼吸道临床试验中的不良反应进行了全面的综述,包括市售的TGF-β调节剂,吡非尼酮和nintedanib。精确调节TGF-β信号传导可能会导致针对慢性呼吸道疾病的新的更安全的疗法。吡非尼酮和nintedanib。精确调节TGF-β信号传导可能会为慢性呼吸道疾病带来新的更安全的疗法。吡非尼酮和nintedanib。精确调节TGF-β信号传导可能会导致针对慢性呼吸道疾病的新的更安全的疗法。

更新日期:2018-02-17
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