The Effect of Phosphodiesterase 4 Inhibition on Gene Expression Changes Produced by Long Acting β <sub>2</sub> ‐adrenoceptor Agonists in BEAS‐2B Airway Epithelial Cells
Bibliographic record
Abstract
Phosphodiesterase 4 (PDE4) inhibitors are prescribed as add‐on therapy to a subset of COPD patients that suffer from exacerbations despite treatment with a combination of long‐acting β 2 ‐adrenoceptor agonists (LABA), long‐acting muscarinic receptor antagonist and inhaled corticosteroids. The molecular mechanisms of their beneficial effects in COPD are ill‐defined. We have previously shown that LABAs, through their effect on the canonical Gs‐cAMP pathway, promote genomic effects in airway epithelial cells. Herein, we hypothesized that PDE4 inhibitors, by inhibiting cAMP degradation, promote similar genomic effects, and further potentiate the effects of LABAs in a human bronchial epithelial cell line. Additionally, we investigated whether this interaction between PDE4 inhibitors and LABAs occurred in an additive or a synergistic manner. Gene expression changes were determined by population‐based RNA‐sequencing in BEAS‐2B cells treated with the PDE4 inhibitor, roflumilast N ‐oxide (RNO), alone and in combination with LABA, salmeterol. RNO showed a weak stimulation of gene expression by itself but showed a strong rank‐order correlation with salmeterol‐induced gene expression changes, suggesting a common mechanism of action. RNO augmented the expression of all salmeterol‐regulated genes, but the magnitude of augmentation varied between genes. This variation can be explained by an estimated 7.5‐fold difference in sensitivities of genes to salmeterol. Deming regression analysis of the gene expression changes produced by the combination of salmeterol and RNO versus the sum of their individual effects showed a deviation away from unity slope that may be explained by a synergistic effect of RNO at some DEGs. Consistent with these results, PDE4 inhibitors, GSK 256066, and roflumilast potentiated the effects of LABAs, indacaterol, and formoterol, on a panel of randomly‐selected genes as measured by RT‐PCR. Collectively, these data suggest that PDE4 inhibition may synergistically augment LABA‐induced gene expression changes in airway epithelial cells. This interaction between LABAs and PDE4 inhibitors may contribute to the therapeutic benefits of their combination in COPD. Support or Funding Information Canadian Institutes for Health Research (PJT 152904) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".