Effect of beta-agonists on LAM progression and treatment

Significance Lymphangioleiomyomatosis (LAM) is a destructive lung disease driven by neoplastic LAM cells with a mutated tumor suppressor gene TSC1 or TSC2, leading to increased activity of the mechanistic target of rapamycin (mTOR), which is inhibited by sirolimus (rapamycin). Beta-agonists may treat asthma-like symptoms due to LAM. We observed stabilization of forced expiratory volume in 1 s in patients receiving sirolimus and long-acting beta-agonists with short-acting rescue inhalers compared with patients receiving only sirolimus. Human TSC2+/− skin fibroblasts and LAM cells from explanted lungs treated with sirolimus and the short-term, but not long-term, beta-agonist isoproterenol showed increased phospho-S6 levels and cell growth due to activation of a cAMP/PKA-dependent pathway. Long-acting beta-agonists affect phospho-S6 content, leading to stabilization of lung function in LAM patients. Lymphangioleiomyomatosis (LAM), a rare disease of women, is associated with cystic lung destruction resulting from the proliferation of abnormal smooth muscle-like LAM cells with mutations in the tuberous sclerosis complex (TSC) genes TSC1 and/or TSC2. The mutant genes and encoded proteins are responsible for activation of the mechanistic target of rapamycin (mTOR), which is inhibited by sirolimus (rapamycin), a drug used to treat LAM. Patients who have LAM may also be treated with bronchodilators for asthma-like symptoms due to LAM. We observed stabilization of forced expiratory volume in 1 s over time in patients receiving sirolimus and long-acting beta-agonists with short-acting rescue inhalers compared with patients receiving only sirolimus. Because beta-agonists increase cAMP and PKA activity, we investigated effects of PKA activation on the mTOR pathway. Human skin TSC2+/− 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.

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