@article {Joshimol.118.115311, author = {Radhika Joshi and Dong Yan and Omar Hamed and Mahmoud M Mostafa and Taruna Joshi and Robert Newton and Mark A Giembycz}, title = {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}, elocation-id = {mol.118.115311}, year = {2019}, doi = {10.1124/mol.118.115311}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, 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, GSK 256066 after 1, 2, 6 or 18h of exposure. However, real-time PCR 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 anti-viral, anti-inflammatory and anti-bacterial activities that could contribute to the clinical efficacy of roflumilast in COPD. RNA-Seq 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-on 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.SIGNIFICANCE STATEMENT The ability of the PDE4 inhibitor, roflumilast, to potentiate gene expression changes in human airway epithelial cells by the long-acting Beta2-adrenoceptor agonist, indacaterol, may contribute to its clinical efficacy in COPD.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/early/2019/04/29/mol.118.115311}, eprint = {https://molpharm.aspetjournals.org/content/early/2019/04/29/mol.118.115311.full.pdf}, journal = {Molecular Pharmacology} }