Albuterol isomers modulate platelet-activating factor synthesis and receptor signaling in human bronchial smooth muscle cells.
BACKGROUND
Racemic albuterol is a 50:50 mixture of the (R)- and (S)-enantiomers of albuterol. Its clinical efficacy resides in the (R)-enantiomer (levalbuterol). Studies have shown that (S)-albuterol induces human bronchial smooth muscle cell (HBSMC) proliferation via a pathway linked to platelet-activating factor (PAF), but the underlying mechanism by which (S)-albuterol augments PAF effects is not clear. In this study, we compared effect of levalbuterol and (S)-albuterol on PAF receptor (PAFr)-mediated signaling and PAF metabolism by HBSMCs after incubation with the albuterol isomers.


METHODS
PAF binding and inositol phosphate (IP(3)) release were studied on adherent cultured cells. PAFr protein expression was measured by Western blotting, PAF synthesis and catabolism were measured in membrane and cytosolic proteins of cells incubated with albuterol isomers.


RESULTS
Compared to control conditions, (S)-albuterol increased PAF binding by 70% after 30 min of preincubation and by 150% after 24 h of preincubation. Levalbuterol had no effect on PAF binding under both conditions. (S)-albuterol also augmented PAF stimulation of IP(3) release, while levalbuterol and the racemic mixture had no effect. WEB 2170, a PAFr antagonist, inhibited the ability of (S)-albuterol to increase PAF binding or stimulate IP(3) release. (S)-albuterol stimulated PAFr protein expression. With PAF metabolism, (S)-albuterol treatment augmented PAF synthesis, but significantly inhibited PAF catabolism.


CONCLUSIONS
Our data suggest that one mechanism by which (S)-albuterol stimulates HBSMC proliferation involves upregulation of PAFr-mediated effects including increased PAF synthesis and decreased PAF catabolism.
Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Rena
R
Bae
Alba
A
Arteaga
J Usha
JU
Raj
Basil O
BO
Ibe
D000420:Albuterol / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism; D001993:Bronchodilator Agents / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D010972:Platelet Activating Factor / Q000096:biosynthesis*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology
D001381:Azepines; D001993:Bronchodilator Agents; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; C039351:platelet activating factor receptor; D015544:Inositol 1,4,5-Trisphosphate; C063964:bepafant; D000420:Albuterol