Effect of beta-agonists on LAM progression and treatment

作者：Kang Le, Wendy K. Steagall, Mario Stylianou, Gustavo Pacheco–Rodriguez, Thomas N. Darling, Martha Vaughan, Joel Moss · 发表于：Proceedings of the National Academy of Sciences · 年份：2018 · DOI：10.1073/pnas.1719960115 · 被引用次数：19 · 研究领域：Tuberous Sclerosis Complex Research、Mast cells and histamine、Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis

fibroblasts or LAM lung cells incubated short-term with isoproterenol (beta-agonist) showed a sirolimus-independent increase in phosphorylation of S6, a downstream effector of the mTOR pathway, and increased cell growth. Cells incubated long-term with isoproterenol, which may lead to beta-adrenergic receptor desensitization, did not show increased S6 phosphorylation. Inhibition of PKA blocked the isoproterenol effect on S6 phosphorylation. Thus, activation of PKA by beta-agonists increased phospho-S6 independent of mTOR, an effect abrogated by beta-agonist-driven receptor desensitization. In agreement, retrospective clinical data from patients with LAM suggested that a combination of bronchodilators in conjunction with sirolimus may be preferable to sirolimus alone for stabilization of pulmonary function.