The -agonist isoproterenol attenuates EGF-stimulated wound closure in human airway epithelial cells

Schnackenberg, Bradley J., Stacie M. Jones, Crystal Pate, Brian Shank, Laura Sessions, Laura M. Pittman, Lawrence E. Cornett, and Richard C. Kurten. The -agonist isoproterenol attenuates EGF-stimulated wound closure in human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 290: L485–L491, 2006. First published October 14, 2005; doi:10.1152/ajplung.00233.2005.— 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 -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 -agonists can alter the signaling of epidermal growth factor (EGF) receptors, which are important in timely wound healing. Therefore, we hypothesized that the -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 2-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.