Levalbuterol Inhibits Human Airway Smooth Muscle Cell Proliferation: Therapeutic Implications in the Management of Asthma

Background: Racemic albuterol is a mixture of (R)- and (S)-enantiomers of albuterol. Its pharmacological activity and clinical efficacy reside in the (R)-enantiomer (levalbuterol), but the (S)-enantiomer exacerbates airway reactivity in nonclinical models. The role of albuterols in airway smooth muscle cell (SMC) proliferation is not well understood. Methods: The effect of levalbuterol on human bronchial SMC growth was compared with the effects of racemic albuterol and (S)-albuterol. Cells were fed albuterols and 3 H-thymidine in 5% FBS and incubated for 24 h. The effect of (S)-albuterol on levalbuterol actions was also studied and so were the effects of cAMP/PKA, PI-3 kinase, NK-ĸB, and retinoblastoma (Rb) proteins on albuterols and human bronchial SMC proliferation. Results: Levalbuterol inhibited cell proliferation at low concentrations. The growth-inhibitory effect of levalbuterol occurs via activation of the cAMP/PKA pathway. Addition of (S)-albuterol to levalbuterol decreased the growth-inhibitory effect of levalbuterol, and (S)-albuterol attenuated levalbuterol-induced cAMP release by 65%. Levalbuterol inhibited NF-ĸB and Rb protein expressions. ICI-118551 abrogated the inhibitory properties of levalbuterol. The PAF receptor antagonist CV-3988 inhibited (S)-albuterol-induced cell growth, with no effect on levalbuterol. Conclusions: Levalbuterol inhibits cell growth by activating the cAMP/PKA pathway and inhibiting PI-3 kinase, NF-ĸB and Rb protein expression, and (S)-albuterol induces cell growth by activating PAF-receptor-mediated cell signaling.