Jordan University of Science and Technology

PDE4 Inhibitors Attenuate the Asthma Phenotype Produced by ?2-adrenoceptor Agonists in PNMT-KO Mice.


Authors:  Forkuo GS, Kim H, Thanawala VJ, Al-Sawalha N, Valdez D, Joshi R, Parra S, Pera T, Gonnella PA, Knoll BJ, Walker JK, Penn RB, Bond RA.

Abstract:  
Mice lacking the endogenous ?2-adrenoceptor (?2AR) agonist, epinephrine (PNMT-KO 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 2 pathways: the canonical G?s-cAMP pathway and a ?arrestin-dependent pathway. Previous studies suggest that ?arrestin is required for allergic lung inflammation. On the other hand, cell-based assays suggest anti-inflammatory effects of G?s-cAMP signaling. This study was designed to test whether the in vitro anti-inflammatory effects of phosphodiesterase 4 (PDE4) inhibitors, known to increase intracellular cAMP in multiple airway cells, 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 towards 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 WT mice. However, co-administration 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 PDE4 inhibitors attenuates the 'asthma-like' phenotype promoted by beta-agonists.