1. Introduction
Coronavirus disease 2019 (COVID-19) is a global infectious illness that results in a huge number of deaths. For restricting its spread, there is an urgent need to evok the most effective therapy. (Li et al., 2020b). Recently, a study hypothesizes that using the anti-inflammatory phosphodiesterase-4 inhibitor (PDE4i) for modulating COVID-19 may be beneficial (Bridgewood et al., 2020). Among PDE4i, roflumilast exhibits the highest potency for targeting and blunting airway inflammation via enhancing the level of cAMP (Rabe, 2011), which in turn may prolong its anti-inflammatory effect by activating Neprilysin (NEP) (Graf et al., 1995). As NEP is lately supposed to be a new potential target for COVID-19 therapy (El Tabaa and El Tabaa, 2020), roflumilast-enhanced NEP activity may have a prominent significance. Thus, we aim to review the proposed NEP-dependent pharmacological mechanisms by which roflumilast can block COVID-19-associated inflammatory, coagulopathy and fibrotic cascades.