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.