PDE4抑制剂作为肺纤维化的治疗靶点

PDE4 inhibitors serve as therapeutic targets for pulmonary fibrosis

特发性肺纤维化(IPF)是一种进行性并最终致命的慢性间质性肺病,其特征是肺功能进行性下降,且目前治疗选择有限。cAMP是最重要的第二信使之一,在松弛气道平滑肌细胞和减少炎症方面起着关键作用。磷酸二酯酶(PDE)是一种酶超家族,PDE4酶在11种PDE超家族酶中占主导地位,并具有4种同工型——PDE4A、PDE4B、PDE4C和PDE4D,可选择性地水解cAMP,而PDE4抑制剂通过阻止cAMP分解来提高cAMP水平,从而发挥抗炎、抗重塑作用,为治疗IPF提供了一个有吸引力的药物靶点。本综述总结了肺纤维化与PKE4相互关联的知识,以及有关PDE4抑制剂的新出现的临床前研究和临床试验。

Idiopathic pulmonary fibrosis(IPF)is a progressive and ultimately fatal chronic interstitial lung disease characterized by a progressive decline in lung function,and current treatment options are limited.cAMP is one of the most important second messengers and plays a key role in relaxing airway smooth muscle cells and reducing inflammation.Phosphodiesterase(PDE)is a superfamily of enzymes,and PDE4 enzymes dominate 11 PDE superfamily enzymes,available in four isoforms-PDE4A,PDE4B,PDE4C and PDE4D,which selectively decompose cAMP,while PDE4 inhibitors increase cAMP levels by preventing cAMP from breaking down,thereby exerting anti-inflammatory,anti-remodeling effects and providing an attractive drug target for the treatment of IPF.This review summarizes knowledge about the association of pulmonary fibrosis with PKE4,as well as emerging preclinical studies and clinical trials regarding PDE4 inhibitors.