title: The beta-agonist isoproterenol attenuates EGF-stimulated wound closure in human airway epithelial cells.
abstract: Asthma is a disease characterized by reversible airway obstruction. An additional hallmark of chronic asthma is altered wound healing that leads to airway remodeling. Although beta-agonists are effective in treating the bronchospasm associated with asthma, their effects on airway wound healing, which are related to airway remodeling, are unknown. It has been demonstrated that beta-agonists can alter the signaling of epidermal growth factor (EGF) receptors, which are important in timely wound healing. Therefore, we hypothesized that the beta-agonist isoproterenol would affect wound healing. Using an in vitro scrape wound assay, we demonstrated that isoproterenol attenuates EGF-stimulated wound healing in 16HBE airway epithelial cell cultures. Through experiments with forskolin and cells overexpressing beta2-adrenergic receptor-yellow fluorescent protein, we show that attenuation is due to the accumulation of cAMP and the involvement of at least one additional pathway. Furthermore, attenuation is not due to a direct effect on the EGF receptor or to an alteration of the ERK/MAPK signaling cascade. Based on these results, we propose that isoproterenol may exert its effects through other MAPK signaling pathways (JNK and/or p38) or through parallel mechanisms. These results also demonstrate a problem of potential therapeutic relevance in which a commonly prescribed medication may alter wound healing and contribute to the remodeling of asthmatic airways.
authors.affiliation: Dept. of Pediatrics, Univ. of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, 1120 Marshall St., Slot 512-13, Little Rock, AR 72202, USA. SchnackenbergBradley@uams.edu
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Schnackenberg
authors.forename: Stacie M
authors.initials: SM
authors.lastname: Jones
authors.forename: Crystal
authors.initials: C
authors.lastname: Pate
authors.forename: Brian
authors.initials: B
authors.lastname: Shank
authors.forename: Laura
authors.initials: L
authors.lastname: Sessions
authors.forename: Laura M
authors.initials: LM
authors.lastname: Pittman
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Cornett
authors.forename: Richard C
authors.initials: RC
authors.lastname: Kurten
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004338:Drug Combinations; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D000318:Adrenergic beta-Agonists; D001426:Bacterial Proteins; D004338:Drug Combinations; D008164:Luminescent Proteins; D018343:Receptors, Adrenergic, beta-2; D011993:Recombinant Fusion Proteins; C054562:yellow fluorescent protein, Bacteria; D005576:Colforsin; D004815:Epidermal Growth Factor; D000242:Cyclic AMP; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D007545:Isoproterenol