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ß-adrenergic receptor-mediated growth of human airway epithelial cell lines

First Dept of Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, Japan

CORRESPONDENCE: A. Nagai, First Dept of Medicine, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-Cho, Shinjuku, Tokyo, 162-8666, Japan. Fax: 81 353795457. E-mail: anagai@chi.twmu.ac.jp

Keywords: airway epithelium, cyclic adenosine monophosphate, deoxyribonucleic acid synthesis, mitogen-activated protein kinase, remodelling

Received: August 17, 2001
Accepted February 1, 2002

This study was supported in part by Grant No. 06670243 from the Ministry of Education, Science and Culture, Japan.

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). ß₂-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 ß₂-adrenergic receptors and the consequent production of cyclic adenosine monophosphate may upregulate cell growth, probably through activation of the mitogen-activated protein kinase cascade.

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