New putative insights into neprilysin (NEP)-dependent pharmacotherapeutic role of roflumilast in treating COVID-19

Abstract

Nowadays, coronavirus disease 2019 (COVID-19) represents the most serious inflammatory respiratory disease worldwide. Despite many proposed therapies, no effective medication has yet been approved. Neutrophils appear to be the key mediator for COVID-19-associated inflammatory immunopathologic, thromboembolic and fibrotic complications. Thus, for any therapeutic agent to be effective, it should greatly block the neutrophilic component of COVID-19. One of the effective therapeutic approaches investigated to reduce neutrophil-associated inflammatory lung diseases with few adverse effects was roflumilast. Being a highly selective phosphodiesterase-4 inhibitors (PDE4i), roflumilast acts by enhancing the level of cyclic adenosine monophosphate (cAMP), that probably potentiates its anti-inflammatory action via increasing neprilysin (NEP) activity. Because activating NEP was previously reported to mitigate several airway inflammatory ailments; this review thoroughly discusses the proposed NEP-based therapeutic properties of roflumilast, which may be of great importance in curing COVID-19. However, further clinical studies are required to confirm this strategy and to evaluate its in vivo preventive and therapeutic efficacy against COVID-19.

Generation and Effect Testing of a SARS-CoV-2 RBD-Targeted Polyclonal Therapeutic Antibody Based on a 2-D Airway Organoid Screening System

“…Based on RNA-seq analysis, we found that chemokine ligand 20 (CCL20), chemokine (C-X-C motif) ligand 8 (CXCL8), interleukin 33 (IL-33), signal transducer and activator of transcription 6 (STAT6), and transforming growth factor beta 1 (TGF-β1) were upregulated in both the presence and absence of the anti-RBD pAbs in the infected HBECs ( Figure 5D ). Several key immune markers have been identified in clinical studies of COVID-19, including IL-8, TGF-β1, IL-33, CXCL8, and CXCL10 ( 30 – 33 ). The chemokine CXCL8 has been induced by viral infection, contributing to lung injury ( 31 ).…”

Phosphodiesterase Inhibitors in Acute Lung Injury: What Are the Perspectives?

“…ACE2 is highly expressed in the lung alveolar and bronchial membranes, in pneumocytes type II, and possibly on vascular endothelial cells as well as in oral and nasal mucosa, gastrointestinal tract, heart, liver, kidney, skin, brain, etc., which can explain common respiratory and extra-pulmonary symptoms in COVID-19 [ 197 , 198 ]. However, binding of SARS-CoV2 with ACE2 receptor downregulates the ACE2 expression, which increases the levels of angiotensin II exerting the above mentioned deleterious effects to the lung [ 199 ]. In addition, binding of SARS-CoV virus on the ACE2 receptors triggers an activation of innate immune reaction to combat an infection, with an activation of various immune cells and a production of enormous concentrations of cytokines, so-called cytokine storm [ 194 ].…”

“…In addition, binding of SARS-CoV virus on the ACE2 receptors triggers an activation of innate immune reaction to combat an infection, with an activation of various immune cells and a production of enormous concentrations of cytokines, so-called cytokine storm [ 194 ]. In the pathophysiology of the SARS-CoV2-induced ARDS, IL-6 is of a particular importance; it promotes a clearance of the virus by neutrophils, triggers an accumulation of fluid and immune cells including neutrophils in the lung, causes a serious endothelial dysfunction, and induces an intestinal, olfactory, ocular inflammation causing diarrhea, anosmia, and conjunctivitis, the extra-pulmonary signs of COVID-19 [ 199 , 200 ]. SARS-CoV2 itself induces an endothelial dysfunction, which results in a platelet activation and aggregation, and finally leads to a pulmonary intravascular coagulopathy and a deep vein thrombosis.…”

“…The structural and functional changes of endothelium and activated coagulation further stimulate a leukocyte trafficking. In the SARS-CoV infection, the inflammation is mediated mainly by neutrophils representing the first line of defense of innate immune system [ 199 ]. The activated neutrophils exert phagocytosis, degranulation, and release of proteases (elastase, cathepsin G etc.…”

“…Simultaneously, endothelin-1 as a product of injured endothelium exaggerates the inflammation by decreasing cAMP [ 204 ] and stimulates a pulmonary fibrosis by increasing the release of TGF-β1 [ 205 ]. The multiple effects of dysregulated inflammation, endothelial dysfunction, and hypercoagulopathy may finally lead to the multiorgan damage and failure, with a higher mortality risk in elderly people and in patients with chronic diseases [ 199 ]. Extent of the injury to the lung and other organs (heart, liver, muscles, kidneys, etc.)…”