<p>Glucocorticoid Receptor α Mediates Roflumilast’s Ability to Restore Dexamethasone Sensitivity in COPD</p>

Abstract

Background: Glucocorticoids are commonly prescribed to treat inflammation of the respiratory system; however, they are mostly ineffective for controlling chronic obstructive pulmonary disease (COPD)-associated inflammation. This study aimed to elucidate the molecular mechanisms responsible for such glucocorticoid inefficacy in COPD, which may be instrumental to providing better patient outcomes. Roflumilast is a selective phosphodiesterase-4 (PDE4) inhibitor with antiinflammatory properties in severe COPD patients who have a history of exacerbations. Roflumilast has a suggested ability to mitigate glucocorticoid resistance, but the mechanism is unknown. Methods: To understand the mechanism that mediates roflumilast-induced restoration of glucocorticoid sensitivity in COPD, we tested the role of glucocorticoid receptor α (GRα). Roflumilast's effects on GRα expression and transcriptional activity were assessed in bronchial epithelial cells from COPD patients. Results: We found that both GRα expression and activity are downregulated in bronchial epithelial cells from COPD patients and that roflumilast stimulates both GRα mRNA synthesis and GRα's transcriptional activity in COPD bronchial epithelial cells. We also demonstrate that roflumilast enhances dexamethasone's ability to suppress pro-inflammatory mediator production, in a GRα-dependent manner. Discussion: Our findings highlight the significance of roflumilast-induced GRα upregulation for COPD therapeutic strategies by revealing that roflumilast restores glucocorticoid sensitivity by sustaining GRα expression.

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

“…The mechanism of the interaction between corticosteroids and cAMP-elevating agonists remains uncertain (Taylor and Hancox, 2000). In neurons, synergism between forskolin and dexamethasone has been ascribed to cAMP upregulation of glucocorticoid receptor (GR) expression (Scarceriaux et al, 1995) while roflumilast enhances the expression of GRα in COPD pHBE cells after 6 h treatment (Reddy et al, 2020). However, we did not observe an effect of ensifentrine on GR mRNA expression, perhaps due to our analysis of GR expression occurring later (24 h) than in previous studies.…”

“…The effects were mirrored in welldifferentiated pHBE cells, indicating that using drugs in combination has more potent anti-inflammatory effects than either drug alone. PDE4 inhibition has previously been shown to enhance corticosteroid-induced activation of the GRE in BEAS-2B and pHBE cells and potentiate dexamethasone-induced downregulation of IL-8 and TNFα in pHBE cells from COPD patients (Moodley et al, 2013;BinMahfouz et al, 2015;Reddy et al, 2020). Furthermore, in human airway epithelia, TNF-α-stimulated GM-CSF production is significantly reduced in cells treated with both the glucocorticoid budesonide and the cAMP-elevating formoterol (Korn et al, 2001) with these effects of budesonide and formoterol further enhanced when MRP4-dependent cAMP efflux is also blocked (Huff et al, 2018).…”

“…We next explored whether the anti-inflammatory effects of ensifentrine could be enhanced by combination therapies. Several studies have demonstrated that PDE inhibition can enhance the ability of corticosteroids and/or β 2 -adrenergic agonists to modulate the expression of genes under the regulation of the glucocorticoid response element (GRE) and cAMP response element (CRE) (Moodley et al, 2013;BinMahfouz et al, 2015;Reddy et al, 2020). We therefore tested the effects of combining ensifentrine with low concentrations of dexamethasone and/or isoproterenol on IL-1β-stimulated GM-CSF production in CFBE41o -F508del cells.…”

New putative insights into Neprilysin (NEP)-dependent pharmacotherapeutic role of Roflumilast in treating COVID-19

“…At the same time, roflumilast was reported to reverse the corticosteroid-associated insensitivity towards neutrophils in COPD patients (Milara et al, 2015b). As well, other study revealed the great value of roflumilast in restoring the glucocorticoid sensitivity in glucocorticoid-resistant patients through blocking the downregulation of glucocorticoid receptor alpha (GRα), which was known to be responsible for glucocorticoid resistance (Reddy et al, 2020).…”

New putative insights into neprilysin (NEP)-dependent pharmacotherapeutic role of roflumilast in treating COVID-19

“…At the same time, roflumilast was reported to reverse the corticosteroid-associated insensitivity towards neutrophils in COPD patients ( Milara et al, 2015b ). As well, other study revealed the great value of roflumilast in restoring the glucocorticoid sensitivity in glucocorticoid-resistant patients through blocking the downregulation of glucocorticoid receptor (GRα) alpha, which was known to be responsible for glucocorticoid resistance ( Reddy et al, 2020 ).…”