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

Autor: Mark J. Turner, John W. Hanrahan, Larry C. Lands, Nurlan Dauletbaev
Rok vydání: 2020
Předmět:
0301 basic medicine
Intracellular Space
Bronchi
Inflammation
Pyrimidinones
Pharmacology
Cystic fibrosis
Dexamethasone
Cell Line
Proinflammatory cytokine
03 medical and health sciences
0302 clinical medicine
Cyclic AMP
medicine
Humans
Drug Interactions
Phosphodiesterase inhibitor
Chemokine CCL2
Roflumilast
Dose-Response Relationship
Drug
biology
business.industry
Monocyte
Interleukin-8
Granulocyte-Macrophage Colony-Stimulating Factor
Phosphodiesterase
Cell Differentiation
Epithelial Cells
Isoquinolines
medicine.disease
Cystic fibrosis transmembrane conductance regulator
Up-Regulation
030104 developmental biology
medicine.anatomical_structure
biology.protein
Molecular Medicine
Phosphodiesterase 4 Inhibitors
Inflammation Mediators
medicine.symptom
business
030217 neurology & neurosurgery
medicine.drug
Zdroj: Journal of Pharmacology and Experimental Therapeutics. 375:414-429
ISSN: 1521-0103
0022-3565
DOI: 10.1124/jpet.120.000080
Popis: 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 β2-adrenergic 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 β2-adrenergic agonists or corticosteroids. Significance Statement Airways inflammation that is disproportionate to the burden of chronic airway infection causes much of the pathology in the Cystic Fibrosis (CF) lung. We show here that ensifentrine beneficially modulates the release of pro-inflammatory factors in well-differentiated CF bronchial epithelial cells that is further enhanced when combined with β2-adrenergic agonists or low-concentration corticosteroids. The results encourage further clinical testing of ensifentrine, alone and in combination with β2-adrenergic agonists or low-concentration corticosteroids, as a novel anti-inflammatory therapy for CF.
Databáze: OpenAIRE
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