Department of Physiology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia.
Department of Pharmacology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia.
Int J Mol Sci. 2021 Feb 16;22(4):1929. doi: 10.3390/ijms22041929.
Despite progress in understanding the pathophysiology of acute lung damage, currently approved treatment possibilities are limited to lung-protective ventilation, prone positioning, and supportive interventions. Various pharmacological approaches have also been tested, with neuromuscular blockers and corticosteroids considered as the most promising. However, inhibitors of phosphodiesterases (PDEs) also exert a broad spectrum of favorable effects potentially beneficial in acute lung damage. This article reviews pharmacological action and therapeutical potential of nonselective and selective PDE inhibitors and summarizes the results from available studies focused on the use of PDE inhibitors in animal models and clinical studies, including their adverse effects. The data suggest that xanthines as representatives of nonselective PDE inhibitors may reduce acute lung damage, and decrease mortality and length of hospital stay. Various (selective) PDE3, PDE4, and PDE5 inhibitors have also demonstrated stabilization of the pulmonary epithelial-endothelial barrier and reduction the sepsis- and inflammation-increased microvascular permeability, and suppression of the production of inflammatory mediators, which finally resulted in improved oxygenation and ventilatory parameters. However, the current lack of sufficient clinical evidence limits their recommendation for a broader use. A separate chapter focuses on involvement of cyclic adenosine monophosphate (cAMP) and PDE-related changes in its metabolism in association with coronavirus disease 2019 (COVID-19). The chapter illuminates perspectives of the use of PDE inhibitors as an add-on treatment based on actual experimental and clinical trials with preliminary data suggesting their potential benefit.
尽管人们对急性肺损伤的病理生理学有了一定的了解，但目前批准的治疗方法仅限于肺保护性通气、俯卧位和支持性干预。各种药物治疗方法也已经过测试，神经肌肉阻滞剂和皮质类固醇被认为是最有希望的方法。然而，磷酸二酯酶（PDE）抑制剂也具有广泛的有利作用，可能对急性肺损伤有益。本文综述了非选择性和选择性 PDE 抑制剂的药理作用和治疗潜力，并总结了目前关于 PDE 抑制剂在动物模型和临床研究中应用的研究结果，包括其不良反应。数据表明，黄嘌呤作为非选择性 PDE 抑制剂的代表，可能减轻急性肺损伤，降低死亡率和住院时间。各种（选择性）PDE3、PDE4 和 PDE5 抑制剂也已被证明能够稳定肺上皮-内皮屏障，降低脓毒症和炎症引起的微血管通透性，抑制炎症介质的产生，最终改善氧合和通气参数。然而，目前缺乏足够的临床证据限制了它们的广泛应用。一个单独的章节侧重于环磷酸腺苷（cAMP）的参与及其代谢与 2019 冠状病毒病（COVID-19）的相关性以及 PDE 相关变化。该章节阐述了基于实际的实验和临床试验数据，将 PDE 抑制剂作为附加治疗的使用前景，这些数据初步表明了它们的潜在益处。
