Roflumilast
One of the proposed NEP-dependent mechanisms for blocking the airway inflammation is to cleave the neutrophil-released cathepsin G, that is documented to convert both Angiotensinogen and Ang I into Ang II,Figure 4 (Wintroub et al., 1984; Pham, 2006; Meyer-Hoffert, 2009). In response to severe COVID-19 infection, Ang II is reported to be continuously generated and probably motivates the systemic cytokine storm (Xiong et al., 2020). Among the released cytokines, IL-6 will play a vital role in the progression of numerous inflammatory reactions as well as endothelial dysfunction and platelets activation (Funakoshi et al., 1999; Liu et al., 2020c). Therefore, cleaving cathepsin G by NEP with reducing associated Ang II formation may be a logical commentary for the suppressed IL-6 expression detected following roflumilast treatment (Feng et al., 2017).
Postulating that IL-6 may be a key regulator of COVID-19 pathogenesis (Liu et al., 2020b), decreasing its level by roflumilast will be of great importance. Firstly, roflumilast can stop IL-6-mediated intestinal, olfactory and ocular inflammation and consequently, inhibit the induction of anosmia, diarrhea and conjunctivitis, respectively. Secondly, roflumilast may suppress the endothelial activation and inflammatory thrombocytosis prompted by IL-6 release.
As a result of the endothelial dysfunction, neutrophils trafficking has also been implicated in the pathogenesis of COVID-19, since their activation and accumulation are reported to be associated with tissue damage, exaggerated inflammation and disordered tissue repair (Tay et al., 2020). As such, NEP can degrade the chemoattractant fMLP, which was known to be involved in neutrophils chemotaxis. Hence, NEP may specifically prevent the recruitment of neutrophils across endothelial barrier from the blood circulation into the infected tissues (Sato et al., 2013). In particular, the potential role of roflumilast in inhibiting the adhesion and transmigration of neutrophils and their subsequent inflammatory sepsis may be attributable to increased NEP activity (Sanz et al., 2007; Li et al., 2020a).
Additionally, NEP was recorded to effectively breakdown the endothelium-derived ET-1; preventing the activation and aggregation of platelets as a result of prohibiting the synthesis of PAF (Rao and White, 1982; Mustafa et al., 1995), which was previously demonstrated to be also suppressed by the action of PDE4i (Tenor et al., 1996). Accordingly, this observation may reflect the potential NEP-dependent anti-coagulant role of roflumilast against the thromboembolic events in COVID-19; empowering it to restrain the development of PIC which is the initial step for evolving stroke in COVID-19 patients (Avula et al., 2020).
In line, it was also shown that COVID-19 patients may show pulmonary fibrosis, from which NEP may protect lungs by stopping the ET-1-induced TGF-β1; ensuring the concept that roflumilast may have the potential to attenuate the fibroblast activities and thereby, the ability to function as anti-fibrotic agent via blocking the fibrosis driven by TGF-β1 (Dunkern et al., 2007; Togo et al., 2009).
Because cAMP is underscored to play an important role in improving the immune system of highly risk COVID-19 groups, breaking ET-1 by NEP will also maintain the high level of cAMP which may contribute for long-term anti-inflammatory effect of roflumilast (Graf et al., 1995; Raker et al., 2016).
Accordingly, we recommend that future clinical efforts should be driven towards ensuring the NEP-mediated pharmacotherapeutic mechanisms of roflumilast proposed for counteracting COVID-19 infection.