Mechanisms by Which <i>S</i>-Albuterol Induces Human Bronchial Smooth Muscle Cell Proliferation

Abstract

Background: Racemic albuterol is a 50:50 mixture of the R-isomer, levalbuterol, and the S-isomer, S-albuterol. S-Albuterol increases airway hyperresponsiveness to spasmogens, exacerbates asthmatic conditions and stimulates cell growth, whereas levalbuterol attenuates cell growth in culture. The mechanisms of S-albuterol-induced cell proliferation are not well understood. We studied the role of albuterol isomers and intracellular cell cycle regulators on proliferation of human bronchial smooth muscle cells. Methods: Serum-starved cells (72 h) were fed test agents for 24 h and cell proliferation was measured. The expression of nuclear factor-ĸB inhibitory protein IĸBα, nuclear factor-ĸB, cyclin-dependent kinases 2 and 4, interleukin (IL)-6, and retinoblastoma and platelet-activating factor (PAF) receptor protein were measured by Western blotting. Results:S-Albuterol, PAF and platelet-derived growth factor stimulated cell proliferation, but levalbuterol and the racemic mixture inhibited cell proliferation compared with the effect of 5% fetal bovine serum alone. The proliferative effect of platelet-derived growth factor on S-albuterol was not additive, suggesting that the 2 mediators act by different mechanisms. S-Albuterol induced greater expression of all the measured proteins than either levalbuterol, the racemic mixture or 5% fetal bovine serum. S-Albuterol stimulated IL-6 secretion and abolished the ability of levalbuterol to inhibit IL-6 secretion. Conclusion: Our data show that S-albuterol stimulates cell proliferation by activating expression and phosphorylation of several intracellular mitogenic proteins and may exacerbate asthma by stimulating the release of IL-6. Induction of PAF receptor protein expression by S-albuterol strongly suggests that S-albuterol may exert its adverse effects by binding to a G protein-coupled receptor such as the PAF receptor.

Albuterol Isomers Modulate Platelet-Activating Factor Synthesis and Receptor Signaling in Human Bronchial Smooth Muscle Cells

“…In a previous study, Tomlinson et al [24] showed that salbutamol, the racemic mixture of levalbuterol and (S)-albuterol, inhibited proliferation of human airway smooth muscle cells in culture. Later reports with HBSMC and racemic mixture of albuterol isomers [9,10] corroborated this report by Tomlinson et al [24] and further showed that treatment of the cells with levalbuterol alone resulted in inhibition of cell proliferation, while (S)-albuterol treatment stimulated cell growth. The present report is also in agreement with the previous reports cited above and further lends some insight into the biochemical pathways of (S)-albuterol-induced HBSMC proliferation in culture.…”

“…However, recent pieces of evidence suggest that (S)-albuterol is not a true β 2 -adrenergic agonist [9,10,28,29,30]. Prolonged administration of racemic albuterol leads to increased airway responsiveness to spasmogens and may result in loss of asthma control [7,8,31].…”

“…Furthermore, the mechanism by which (S)-albuterol induces increased airway hyperresponsiveness is not well understood, but may involve activation of other inflammatory cell signaling pathways. We can speculate that one mechanism by which (S)-albuterol present in racemic albuterol induces the proliferation of HBSMCs in culture may be by inhibiting the ability of levalbuterol to stimulate cyclic adenosine monophosphate (cAMP) production, by activation of PAF receptor-mediated pathway as well as by activation of some other intracellular mitogenic proteins [9,10]. In the present study, we provide further evidence to show that (S)-albuterol induces the proliferation of HBSMCs in culture and that if it occurs in vivo, may exacerbate asthmatic conditions via some yet undefined mode of interaction with PAF receptor-linked signaling.…”

“…Levalbuterol was reported to inhibit proliferation of human bronchial smooth muscle cells (HBSMCs) in vitro, by increasing cAMP production and augmenting activity of cAMP-dependent protein kinase A (PKA). On the other hand, (S)-albuterol induces cell proliferation by inhibiting levalbuterol-induced elevation of cAMP levels, by activating some intracellular mitogenic signaling pathways such as mitogen activated protein kinases (MAPK), nuclear factor-ĸB (NF-kB), p65 and retinoblastoma (Rb) proteins, among others [9,10]. (S)-albuterol has also been reported to induce bronchial smooth muscle cell proliferation in culture via a pathway linked to platelet-activating factor (PAF) receptor activation.…”

β2-agonists promote host defense against bacterial infection in primary human bronchial epithelial cells

“…Future studies are warranted to: (1) further explore the mechanisms by which albuterol or formoterol exerts host defense functions. These include, but are not limited to, studies aimed at dissecting the involvement of β2-adrenergic receptor vs. other receptors such as platelet-activating factor (PAF) receptor and β1-adrenergic receptor[37]; and (2) determine if β2-agonists are able to reduce lung bacterial load in COPD patients, especially those with acute exacerbations.…”