title: Phosphodiesterase 4 Inhibitors Attenuate the Asthma Phenotype Produced by β2-Adrenoceptor Agonists in Phenylethanolamine N-Methyltransferase-Knockout Mice.
abstract: 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.
authors.affiliation: 1 Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, Texas.
authors.forename: Gloria S
authors.initials: GS
authors.lastname: Forkuo
authors.affiliation: 1 Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, Texas.
authors.forename: Hosu
authors.initials: H
authors.lastname: Kim
authors.affiliation: 1 Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, Texas.
authors.forename: Vaidehi J
authors.initials: VJ
authors.lastname: Thanawala
authors.affiliation: 1 Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, Texas.
authors.forename: Nour
authors.initials: N
authors.lastname: Al-Sawalha
authors.affiliation: 2 Department of Biology and Biochemistry, University of Houston, Houston, Texas.
authors.forename: Daniel
authors.initials: D
authors.lastname: Valdez
authors.affiliation: 1 Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, Texas.
authors.forename: Radhika
authors.initials: R
authors.lastname: Joshi
authors.affiliation: 3 Vapogenix, Inc., Houston, Texas.
authors.forename: Sergio
authors.initials: S
authors.lastname: Parra
authors.affiliation: 4 Center for Translational Medicine and Jane and Leonard Korman Lung Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania; and.
authors.forename: Tonio
authors.initials: T
authors.lastname: Pera
authors.affiliation: 4 Center for Translational Medicine and Jane and Leonard Korman Lung Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania; and.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Gonnella
authors.affiliation: 1 Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, Texas.|2 Department of Biology and Biochemistry, University of Houston, Houston, Texas.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Knoll
authors.affiliation: 5 Duke University School of Nursing, Duke University Medical Center, Durham, North Carolina.
authors.forename: Julia K L
authors.initials: JK
authors.lastname: Walker
authors.affiliation: 4 Center for Translational Medicine and Jane and Leonard Korman Lung Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania; and.
authors.forename: Raymond B
authors.initials: RB
authors.lastname: Penn
authors.affiliation: 1 Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, Texas.|2 Department of Biology and Biochemistry, University of Houston, Houston, Texas.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Bond
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000009:adverse effects*; D000631:Aminopyridines / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001249:Asthma / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology; D016535:Bronchial Hyperreactivity / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D003521:Cyclopropanes / Q000008:administration & dosage / Q000494:pharmacology; D004359:Drug Therapy, Combination; D004804:Eosinophils / Q000187:drug effects / Q000473:pathology; D000068759:Formoterol Fumarate / Q000008:administration & dosage / Q000494:pharmacology; D007249:Inflammation / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009093:Mucus / Q000378:metabolism; D010641:Phenotype; D010625:Phenylethanolamine N-Methyltransferase / Q000172:deficiency* / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D058988:Phosphodiesterase 4 Inhibitors; C424423:Roflumilast; D010625:Phenylethanolamine N-Methyltransferase; D000068759:Formoterol Fumarate
keywords: asthma model; biased signaling; β2-adrenoceptor