Department of Biological Chemistry, School of Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece.
Department of Biological Chemistry, School of Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece; Second Department of Critical Care, Attikon General University Hospital, Medical School, National and Kapodistrian University of Athens, Chaidari, Greece.
Metabolism. 2020 Aug;109:154282. doi: 10.1016/j.metabol.2020.154282. Epub 2020 Jun 1.
The most severe presentation of COVID-19 is characterized by a hyperinflammatory state attributed to the massive pro-inflammatory cytokine release, called "cytokine storm". Several specific anti-inflammatory/immunosuppressive agents are being evaluated by ongoing clinical trials; however, there is currently insufficient evidence for their efficacy and safety in COVID-19 treatment. Given the role of phosphodiesterase 4 (PDE) 4 and cyclic adenosine monophosphate in the inflammatory response, we hypothesize that selective PDE4 inhibition may attenuate the cytokine storm in COVID-19, through the upstream inhibition of pro-inflammatory molecules, particularly TNF-α, and the regulation of the pro-inflammatory/anti-inflammatory balance. Conversely, other anti-cytokine agents lead to the downstream inhibition of specific targets, such as IL-1, IL-6 or TNF-α, and may not be efficient in blocking the cytokine storm, once it has been triggered. Due to their mechanism of action targeting an early stage of the inflammatory response and ameliorating lung inflammation, we believe that selective PDE4 inhibitors may represent a promising treatment option for the early phase of COVID-19 pneumonia before the cytokine storm and severe multiorgan dysfunction take place. Furthermore, PDE4 inhibitors present several advantages including an excellent safety profile; the oral route of administration; the convenient dosing; and beneficial metabolic properties. Interestingly, obesity and diabetes mellitus type 2 have been reported to be risk factors for the severity of COVID-19. Therefore, randomized clinical trials of PDE4 inhibitors are necessary to explore their potential therapeutic effect as an adjunct to supportive measures and other therapeutic regiments.
COVID-19 最严重的表现特征是一种由大量促炎细胞因子释放引起的过度炎症状态，被称为“细胞因子风暴”。目前正在进行的临床试验正在评估几种特定的抗炎/免疫抑制药物；然而，这些药物在 COVID-19 治疗中的疗效和安全性目前还没有足够的证据。鉴于磷酸二酯酶 4（PDE）4 和环磷酸腺苷在炎症反应中的作用，我们假设选择性 PDE4 抑制可能通过上游抑制促炎分子（特别是 TNF-α）和调节促炎/抗炎平衡来减轻 COVID-19 中的细胞因子风暴。相反，其他抗细胞因子药物会导致下游特定靶点（如 IL-1、IL-6 或 TNF-α）的抑制，并且一旦触发细胞因子风暴，可能无法有效地阻断其发生。由于其作用机制针对炎症反应的早期阶段，并改善肺部炎症，我们认为选择性 PDE4 抑制剂可能是 COVID-19 肺炎早期阶段的一种有前途的治疗选择，即在细胞因子风暴和严重多器官功能障碍发生之前。此外，PDE4 抑制剂具有许多优点，包括出色的安全性、口服给药途径、方便的剂量和有益的代谢特性。有趣的是，肥胖和 2 型糖尿病已被报道是 COVID-19 严重程度的危险因素。因此，需要进行 PDE4 抑制剂的随机临床试验，以探索其作为支持性措施和其他治疗方案的辅助治疗的潜在治疗效果。
