Phosphodiesterase 4 Inhibitors Attenuate the Asthma Phenotype Produced by β₂-Adrenoceptor Agonists in Phenylethanolamine N-Methyltransferase–Knockout Mice

Abstract

Mice lacking the endogenous b 2 -adrenoceptor (b 2 AR) agonist epinephrine (phenylethanolamine N-methyltransferase [PNMT]-knockout mice) are resistant to developing an "asthma-like" phenotype in an ovalbumin sensitization and challenge (Ova S/C) model, and chronic administration of b 2 AR agonists to PNMT-KO mice restores the phenotype. Based on these and other studies showing differential effects of various b 2 AR ligands on the asthma phenotype, we have speculated that the permissive effect of endogenous epinephrine and exogenous b 2 AR agonists on allergic lung inflammation can be explained by qualitative b 2 AR signaling. The b 2 AR can signal through at least two pathways: the canonical Gas-cAMP pathway and a b-arrestin-dependent pathway. Previous studies suggest that b-arrestin-2 is required for allergic lung inflammation. On the other hand, cell-based assays suggest antiinflammatory effects of Gas-cAMP signaling. This study was designed to test whether the in vitro antiinflammatory effects of phosphodiesterase 4 inhibitors, known to increase intracellular cAMP in multiple airway cell types, attenuate the asthma-like phenotype produced by the b 2 AR agonists formoterol and salmeterol in vivo in PNMT-KO mice, based on the hypothesis that skewing b 2 AR signaling toward Gas-cAMP pathway is beneficial. Airway inflammatory cells, epithelial mucus production, and airway hyperresponsiveness were quantified. In Ova S/C PNMT-KO mice, formoterol and salmeterol restored the asthma-like phenotype comparable to Ova S/C wild-type mice. However, coadministration of either roflumilast or rolipram attenuated this formoterol-or salmeterol-driven phenotype in Ova S/C PNMT-KO. These findings suggest that amplification of b 2 AR-mediated cAMP by phosphodiesterase 4 inhibitors attenuates the asthma-like phenotype promoted by b-agonists.

Protease-activated receptor-2 signaling through β-arrestin-2 mediates Alternaria alkaline serine protease-induced airway inflammation

“…While PAR 2 Ϫ/Ϫ mouse models have been used to evaluate the role for house dust mite- (15) or cockroach-induced asthma (16,45), examination of ␤-arrestin-2 signaling arm for PAR 2 activation has provided further clues in understanding the mechanisms that underlie allergic asthma. That GPCR/␤-arrestin signaling pathways are important mediators of inflamma-tion, and airway hyperresponsiveness is corroborated by other studies in ovalbumin-induced and cigarette smoke-induced allergic asthma animal models (11,68) and by studies showing that some of the adverse effects associated with ␤ 2 -adrenergic receptor activation are ␤-arrestin dependent (20,64). Our studies suggested that PAR 2 -stimulated, ␤-arrestin-dependent cell migration is a major contributing factor to the cellular inflammation observed during asthma.…”

Alleviation of Multiple Asthmatic Pathologic Features with Orally Available and Subtype Selective GABAA Receptor Modulators

“…Eosinophils were determined as a percentage of the total cells in each field and expressed as percent eosinophil. 23, 47 …”

Understanding how long‐acting β2‐adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids in asthma – an update

“…If confirmed, this highlights the need to understand the structural elements in these ligands that preferentially stabilize the β 2 ‐adrenoceptor in this unwanted conformation. One means to compensate for adverse‐effects mediated by β‐arrestin‐dependent ERK activation is to offset bias by enhancing LABA‐induced, cAMP signalling with a PDE4 inhibitor (Forkuo et al , ; Pera and Penn, ). Indeed, in sensitized and challenged PNMT ‐deficient mice, roflumilast and rolipram prevented formoterol and salmeterol from restoring the asthma‐like phenotype when compared with wild‐type animals.…”

“…This effect may not only protect against MAPK‐dependent desensitization (Nino et al , ) but should also reduce unwanted signalling due to biased agonism from the β 2 ‐adrenoceptor. Thus, reducing the effect of β 2 ‐adrenoceptor‐mediated, β‐arrestin signalling with a PDE4 inhibitor and/or a glucocorticoid could tip the balance away from ‘pro‐asthma’ effects towards more favourable ‘therapeutic’ outcomes (Forkuo et al , ; Pera and Penn, ).…”