| First Author | Forkuo GS | Year | 2016 |
| Journal | Am J Respir Cell Mol Biol | Volume | 55 |
| Issue | 2 | Pages | 234-42 |
| PubMed ID | 26909542 | Mgi Jnum | J:253798 |
| Mgi Id | MGI:6101243 | Doi | 10.1165/rcmb.2015-0373OC |
| Citation | Forkuo GS, et al. (2016) Phosphodiesterase 4 Inhibitors Attenuate the Asthma Phenotype Produced by beta2-Adrenoceptor Agonists in Phenylethanolamine N-Methyltransferase-Knockout Mice. Am J Respir Cell Mol Biol 55(2):234-42 |
| abstractText | Mice lacking the endogenous beta2-adrenoceptor (beta2AR) 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 beta2AR agonists to PNMT-KO mice restores the phenotype. Based on these and other studies showing differential effects of various beta2AR ligands on the asthma phenotype, we have speculated that the permissive effect of endogenous epinephrine and exogenous beta2AR agonists on allergic lung inflammation can be explained by qualitative beta2AR signaling. The beta2AR can signal through at least two pathways: the canonical Galphas-cAMP pathway and a beta-arrestin-dependent pathway. Previous studies suggest that beta-arrestin-2 is required for allergic lung inflammation. On the other hand, cell-based assays suggest antiinflammatory effects of Galphas-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 beta2AR agonists formoterol and salmeterol in vivo in PNMT-KO mice, based on the hypothesis that skewing beta2AR signaling toward Galphas-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 beta2AR-mediated cAMP by phosphodiesterase 4 inhibitors attenuates the asthma-like phenotype promoted by beta-agonists. |
