Beta-adrenergic receptor-mediated growth of human airway epithelial cell lines.
Abnormal growth of airway epithelium and the resultant thickening of airway walls may produce narrowing of airway calibre, thereby contributing to deterioration of bronchoconstriction in chronic obstructive pulmonary disease (COPD). Beta2-adrenergic agonists have been widely used for the treatment of COPD, but their effects on the growth of airway epithelial cells is unknown. Growth of three human airway epithelial cell lines was studied in vitro. Exposure to salbutamol in serum-free medium increased 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide reduction and intracellular deoxyribonucleic acid (DNA) contents in 16-human bronchial epithelium (16-HBE) cells and NCI-H292 cells, but not in A549 cells. The growth-promoting effect of salbutamol in 16-HBE cells was equipotent to 10% foetal bovine serum and was inhibited by propranolol and a cyclic adenosine monophosphate (cAMP) antagonist, Rp-adenosine 3',5'-cyclic monophosphorothioate triethylammonium salt (Rp-cAMPS). Likewise, forskolin and 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) caused cell growth and DNA synthesis. Western blot analysis showed that salbutamol, forskolin, and 8-Br-cAMP each induced expression of the phosphorylated form of mitogen-activated protein (MAP) kinase, and that the salbutamol-induced phosphorylation was inhibited by propranolol, Rp-cAMPS, and the MAP kinase-kinase inhibitor PD98059. These results suggest that in certain airway epithelial cell lines stimulation of beta2-adrenergic receptors and the consequent production of cyclic adenosine monophosphate may upregulate cell growth, probably through activation of the mitogen-activated protein kinase cascade.
Nishimura
K
K
First Dept of Medicine, Tokyo Women's Medical University School of Medicine, Japan.
Tamaoki
J
J
Isono
K
K
Aoshiba
K
K
Nagai
A
A
D000318:Adrenergic beta-Agonists / Q000494:pharmacology* / Q000627:therapeutic use*; D000420:Albuterol / Q000494:pharmacology* / Q000627:therapeutic use*; D015153:Blotting, Western; D001980:Bronchi / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D013997:Time Factors
D000318:Adrenergic beta-Agonists; D017868:Cyclic AMP-Dependent Protein Kinases; D000420:Albuterol