The Phosphodiesterase Inhibitor Ensifentrine Reduces Production of Proinflammatory Mediators in Well Differentiated Bronchial Epithelial Cells by Inhibiting PDE4

Abstract

Cystic fibrosis (CF) is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) anion channel that impair airway salt and fluid secretion. Excessive release of pro-inflammatory cytokines and chemokines by CF bronchial epithelium during airway infection leads to chronic inflammation and a slow decline in lung function, thus there is much interest in finding safe and effective treatments that reduce inflammation in CF. We showed previously that the cyclic nucleotide phosphodiesterase (PDE) inhibitor ensifentrine (RPL554; Verona Pharma) stimulates the channel function of CFTR mutants with abnormal gating and also those with defective trafficking that are partially rescued using a clinically approved corrector drug. PDE inhibitors also have known anti-inflammatory effects, therefore we examined whether ensifentrine alters the production of pro-inflammatory cytokines in CF bronchial epithelial cells. Ensifentrine reduced the production of monocyte chemoattractant protein-1 (MCP-1) and granulocyte monocyte colony stimulating factor (GM-CSF) during challenge with Interleukin-1β. Comparing the effect of ensifentrine with milrinone and roflumilast, selective PDE3 and PDE4 inhibitors respectively, demonstrated that the anti-inflammatory effect of ensifentrine was mainly due to inhibition of PDE4. Beneficial modulation of GM-CSF was further enhanced when ensifentrine was combined with low concentrations of the β 2adrenergic agonist isoproterenol or the corticosteroid dexamethasone. The results indicate ensifentrine may have beneficial anti-inflammatory effects in CF airways particularly when used in combination with β 2-adrenergic agonists or corticosteroids.

An Analysis of Cardiac Disorders Associated With Chimeric Antigen Receptor T Cell Therapy in 126 Patients: A Single-Centre Retrospective Study

“…Its pharmacological mechanisms involve reducing inflammatory cytokines production, leukocyte infiltration and phagocytosis at the onset of inflammation (29,30). Besides, the corticosteroid can interfere with the interaction between proinflammatory factors (31,32). Although corticosteroids may cause injury to the infused CAR-T cell and reduce the curative effect, previous studies and our results show that corticosteroids are still very important for the treatment of cytokine storm-related diseases as hemophagocytic syndrome and CRS (33)(34)(35).…”

Clinical Implication of Phosphodiesterase-4-Inhibition

“…Thus, ensifentrine (PDE4 and 3 inhibitor) reduced their secretion in bronchial epithelial cells. This mechanism is exclusively driven by PDE4 [125]. In human alveolar epithelial cells (A549; stimulated with cigarette smoke and LPS), roflumilast and its active metabolite roflumilast N-oxide reduced IL-8 and MCP-1 release and the secretion of CXCL1 [126].…”

Inhaled Dual Phosphodiesterase 3/4 Inhibitors for the Treatment of Patients with COPD: A Short Review

“…They demonstrated that dual inhibition of PDE3 and 4 by ensifentrine diminished the release of proinflammatory mediators, and that this effect was enhanced when ensifentrine was associated to a beta-2 agonist or a glucocorticosteroid. 56 …”

“…59,60 A recent study confirmed cAMPmediated CFTR up-regulation by dual PDE3/4 inhibitors in human bronchial epithelial cells expressing wild-type CFTR or F508del CFTR. 56 Previously, Lambert et al had described restoration of CFTR function with a PDE4 inhibitor alone in human bronchial epithelial cells exposed to cigarette smoke; this effect was greater when the PDE4 inhibitor was associated to a CFTR potentiator (Ivacaftor). 61,62 Finally, PDE 4 inhibitors can enhance ciliary function, possibly through effects on CFTR activity.…”