Phosphodiesterase 4 Inhibitors Attenuate the Asthma Phenotype Produced by β2-Adrenoceptor Agonists in Phenylethanolamine N-Methyltransferase–Knockout Mice
| Autor: | Tonio Pera, Patricia Gonnella, Radhika Joshi, Gloria S. Forkuo, Brian J. Knoll, Sergio Parra, Hosu Kim, Vaidehi J. Thanawala, Raymond B. Penn, Daniel Valdez, Nour A. Al-Sawalha, Richard A. Bond, Julia K. L. Walker |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Agonist Cyclopropanes medicine.medical_specialty medicine.drug_class Clinical Biochemistry Aminopyridines Biology Pharmacology 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Internal medicine Formoterol Fumarate medicine Animals Molecular Biology Adrenergic beta-2 Receptor Agonists Lung Roflumilast Rolipram Original Research Inflammation Mice Knockout Phenylethanolamine N-Methyltransferase Cell Biology respiratory system Phenylethanolamine N-methyltransferase Asthma respiratory tract diseases Phenylethanolamine Eosinophils Mucus 030104 developmental biology Endocrinology Phenotype 030228 respiratory system chemistry Knockout mouse Benzamides Drug Therapy Combination Formoterol Phosphodiesterase 4 Inhibitors Bronchial Hyperreactivity medicine.drug |
| Popis: | Mice lacking the endogenous β2-adrenoceptor (β2AR) 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 β2AR agonists to PNMT-KO mice restores the phenotype. Based on these and other studies showing differential effects of various β2AR ligands on the asthma phenotype, we have speculated that the permissive effect of endogenous epinephrine and exogenous β2AR agonists on allergic lung inflammation can be explained by qualitative β2AR signaling. The β2AR can signal through at least two pathways: the canonical Gαs-cAMP pathway and a β-arrestin-dependent pathway. Previous studies suggest that β-arrestin-2 is required for allergic lung inflammation. On the other hand, cell-based assays suggest antiinflammatory effects of Gαs-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 β2AR agonists formoterol and salmeterol in vivo in PNMT-KO mice, based on the hypothesis that skewing β2AR signaling toward Gαs-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 β2AR-mediated cAMP by phosphodiesterase 4 inhibitors attenuates the asthma-like phenotype promoted by β-agonists. |
| Databáze: | OpenAIRE |
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