Mechanisms by which S-albuterol induces human bronchial smooth muscle cell proliferation.
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-kappaB inhibitory protein IkappaBalpha, nuclear factor-kappaB, 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.


CONCLUSIONS
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.
Ibe
Basil O
BO
Department of Pediatrics, Los Angeles Biomedical Institute, Harbor-UCLA Medical Center, Torrance, CA 90502, USA. ibe@labiomed.org
Abdallah
May F
MF
Raj
J Usha
JU
D000420:Albuterol / Q000009:adverse effects / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D001993:Bronchodilator Agents / Q000009:adverse effects / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000096:biosynthesis; D051358:Cyclin-Dependent Kinase 4 / Q000096:biosynthesis; D004357:Drug Synergism; D006801:Humans; D051550:I-kappa B Kinase / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000096:biosynthesis; D010766:Phosphorylation / Q000187:drug effects; D010972:Platelet Activating Factor / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000096:biosynthesis; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis; D016160:Retinoblastoma Protein / Q000096:biosynthesis
D001993:Bronchodilator Agents; D015850:Interleukin-6; D016328:NF-kappa B; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D010982:Platelet-Derived Growth Factor; D043562:Receptors, G-Protein-Coupled; D016160:Retinoblastoma Protein; C039351:platelet activating factor receptor; C075278:platelet-derived growth factor A; D051550:I-kappa B Kinase; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D000420:Albuterol