Phosphodiesterase 4 Inhibitors Attenuate the Asthma Phenotype Produced by ?2-Adrenoceptor Agonists in Phenylethanolamine N-Methyltransferase-Knockout Mice.

ABSTRACT: Mice lacking the endogenous ?2-adrenoceptor (?2AR) 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 ?2AR agonists to PNMT-KO mice restores the phenotype. Based on these and other studies showing differential effects of various ?2AR ligands on the asthma phenotype, we have speculated that the permissive effect of endogenous epinephrine and exogenous ?2AR agonists on allergic lung inflammation can be explained by qualitative ?2AR signaling. The ?2AR can signal through at least two pathways: the canonical G?s-cAMP pathway and a ?-arrestin-dependent pathway. Previous studies suggest that ?-arrestin-2 is required for allergic lung inflammation. On the other hand, cell-based assays suggest antiinflammatory effects of G?s-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 ?2AR agonists formoterol and salmeterol in vivo in PNMT-KO mice, based on the hypothesis that skewing ?2AR signaling toward G?s-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 ?2AR-mediated cAMP by phosphodiesterase 4 inhibitors attenuates the asthma-like phenotype promoted by ?-agonists.

SUBMITTER: Forkuo GS 

PROVIDER: S-EPMC4979368 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature