PDE4 inhibition as a therapeutic strategy for improvement of pulmonary dysfunctions in Covid-19 and cigarette smoking

Abstract

Angiotensin-converting enzyme 2 (ACE2) is the binding-site and entry-point for SARS-CoV-2 in human and highly expressed in the lung. Cigarette smoking (CS) is the leading cause of pulmonary and cardiovascular diseases. Chronic CS leads to upregulation of bronchial ACE2 inducing a high vulnerability in COVID-19 smoker patients. Interestingly, CS-induced dysregulation of pulmonary renin-angiotensin system (RAS) in part contributing into the potential pathogenesis COVID-19 pneumonia and acute respiratory distress syndrome (ARDS). Since, CS-mediated ACE2 activations is not the main pathway for increasing the risk of COVID-19, it appeared that AngII/AT₁R might induce an inflammatory-burst in COVID-19 response by up-regulating cyclic nucleotide phosphodiesterase type 4 (PDE4), which hydrolyses specifically the second intracellular messenger 3', 5'-cyclic AMP (cAMP). It must be pointed out that CS might induce PDE4 up-regulation similarly to the COVID-19 inflammation, and therefore could potentiate COVID-19 inflammation opening the potential therapeutic effects of PDE4 inhibitor in both COVID-19-inflammation and CS.

Keywords: Angiotensin-converting enzyme 2 (ACE2); COVID-19; Cigarette smoking (CS); Inflammation; PDE4; Respiratory epithelial cells.

Graphical abstract

Fig. 1

Effect of nicotine smoking on the renin-angiotensin system (RAS). Angiotensinogen is hydrolyzed by renin to produce angiotensin (ANG) I, which is then converted by angiotensin-converting enzyme (ACE) into the biologically active ANG II. More recently, renin- and ACE-independent formation of ANG II have also been reported. By cleaving ANG II into ANG-(1–7), ACE2 plays a pivotal role in the compensatory ACE2/ ANG-(1–7)/MasR axis of the RAS by counterbalancing the deleterious actions of the ACE/ANG II/AT₁R arm. ACE: Angiotensin converting enzyme; ACE2: Angiotensin converting enzyme type 2; MLDAD: mononuclear leukocyte-derived aspartate decarboxylase; MasR: Mass receptor; AT₁R: Angiotensin II type 1 receptor; AT₂R: Angiotensin II type 2 receptor; APA: Aminopeptidase A; APN: Aminopeptidase N; MrgD: Mas-related G protein-coupled receptor D. Adapted from¹¹.

Fig. 2

Cross-talk between COV-19 and PDE4 mediated by AT₁R and its potentiation by CS. On one hand, PDE4 inhibitor overcomes HIV-1 infection and infection, and might also inhibit SARS-COV-2 replication and infection. On the other hand, SARS-COV-2 spikes by inhibiting ACE2 regulates ANG-II production, which induces PDE4 up-regulation. Cigarette smoking might up-regulate AT₁R and therefore increases PDE4. The up-regulated PDE4 might produce an increase of 5′-AMP, as well as of H⁺, inducing lung injury and acute lung inflammation. These de-regulations might be related to PDE4B and PDE4C up-regulations, inducing increases in ROS production, as well in TNF-α, IL-1 β, IL-6, IL-8, NFκB and p-p38 MAPK. Interestingly, PDE4 is also up-regulated by CS, opening a commune therapeutic approach in COVID-19 and CS. Altogether, the use of specific PDE4 inhibitor or microRNA-124-3p to act on SARS-COV-2 and on PDE4 up-regulation, represents innovative approaches for treating Covid-19 CS.

Fig. 3

Short- and long-term effect of rolipram and PDE4-inhibitor pre-treatment in HUVEC. Agonist induces [Ca²⁺]_I and may stimulate adenylyl cyclase (AC) activity. After 2 min pretreatment with cAMP elevating agents (rolipram, PDE4-I) enhances local increases of cAMP, reduces agonist stimulated [Ca²⁺]_I, by inhibiting Ca²⁺mobilization from internal stores. A sustained elevation of cAMP after 8 h pre-treatment with cAMP elevating agents, increases the expression and activity of PDE4 subtypes, which would speed up cAMP degradation.