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Impact of Phosphodiesterase 4 Inhibition on the Operational Efficacy, Response Maxima, and Kinetics of Indacaterol-Induced Gene Expression Changes in BEAS-2B Airway Epithelial Cells: A Global Transcriptomic Analysis
- Source :
- Molecular pharmacology. 96(1)
- Publication Year :
- 2018
-
Abstract
- The effects of phosphodiesterase (PDE) 4 inhibitors on gene expression changes in BEAS-2B human airway epithelial cells are reported and discussed in relation to the mechanism(s) of action of roflumilast in chronic obstructive pulmonary disease (COPD). Microarray-based gene expression profiling failed to identify mRNA transcripts that were differentially regulated by the PDE4 inhibitor 6-[3-(dimethylcarbamoyl)benzenesulphonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide (GSK 256066) after 1, 2, 6, or 18 hours of exposure. However, real-time polymerase chain reaction analysis revealed that GSK 256066 was a weak stimulus, and the negative microarray results reflected low statistical power due to small sample sizes. Furthermore, GSK 256066, roflumilast, and its biologically active metabolite roflumilast N-oxide generally potentiated gene expression changes produced by the long-acting β2-adrenoceptor agonists (LABAs) salmeterol, indacaterol, and formoterol. Many of these genes encode proteins with antiviral, anti-inflammatory, and antibacterial activities that could contribute to the clinical efficacy of roflumilast in COPD. RNA-sequencing experiments established that the sensitivity of genes to salmeterol varied by ∼7.5-fold. Consequently, the degree to which a PDE4 inhibitor potentiated the effect of a given concentration of LABA was gene-dependent. Operational model fitting of concentration-response curve data from cells subjected to fractional, β2-adrenoceptor inactivation determined that PDE4 inhibition increased the potency and doubled the efficacy of LABAs. Thus, adding roflumilast to standard triple therapy, as COPD guidelines recommend, may have clinical relevance, especially in target tissues where LABAs behave as partial agonists. Collectively, these results suggest that the genomic impact of roflumilast, including its ability to augment LABA-induced gene expression changes, may contribute to its therapeutic activity in COPD.
- Subjects :
- 0301 basic medicine
Cyclopropanes
Aminopyridines
Pharmacology
Quinolones
Cell Line
03 medical and health sciences
0302 clinical medicine
Gene expression
medicine
Humans
Sulfones
Adrenergic beta-2 Receptor Agonists
Lung
Salmeterol Xinafoate
Roflumilast
Oligonucleotide Array Sequence Analysis
COPD
Chemistry
Gene Expression Profiling
Phosphodiesterase
Drug Synergism
Epithelial Cells
medicine.disease
Gene expression profiling
030104 developmental biology
Gene Expression Regulation
Benzamides
Indans
Aminoquinolines
Molecular Medicine
Indacaterol
Formoterol
Salmeterol
Phosphodiesterase 4 Inhibitors
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 15210111
- Volume :
- 96
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Molecular pharmacology
- Accession number :
- edsair.doi.dedup.....e5254b8164e82a542c4f7cf50ce0e3bf