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Levalbuterol inhibits human airway smooth muscle cell proliferation: therapeutic implications in the management of asthma.

International Archives of Allergy and Immunology

immunology, Retinoblastoma Protein, pharmacology, Propanolamines, Platelet Aggregation Inhibitors, Phospholipid Ethers, antagonists & inhibitors, Phosphatidylinositol 3-Kinases, NF-kappa B, drug effects, cytology, Muscle, Smooth, Morpholines, Isoproterenol, Humans, Enzyme Inhibitors, Cyclic AMP, Colforsin, Chromones, Cell Proliferation, Cell Line, Bronchodilator Agents, pathology, drug therapy, Asthma, Albuterol, Adrenergic beta-Antagonists, Adrenergic beta-Agonists

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      Abstract

      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. 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 3H-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-kappaB, and retinoblastoma (Rb) proteins on albuterols and human bronchial SMC proliferation. 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-kappaB 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. Levalbuterol inhibits cell growth by activating the cAMP/PKA pathway and inhibiting PI-3 kinase, NF-kappaB and Rb protein expression, and (S)-albuterol induces cell growth by activating PAF-receptor-mediated cell signaling. Copyright (c) 2006 S. Karger AG, Basel.

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      Journal
      10.1159/000091168
      16446544

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