Human bronchial smooth muscle cell proliferation via thromboxane A2 receptor.
Thromboxane A2 receptor (TP) mediates bronchial smooth muscle cell (BSMC) contraction, airway hyperresponsiveness, and airway inflammation in patients with asthma. In the present study, a pathogenic role of TP activation in airway remodeling was examined using primary cultures of human BSMC. A TP agonist, I-BOP, concentration-dependently enhanced not only bromodeoxyuridine (BrdU) uptake but also cell proliferation of BSMC. A TP-selective antagonist, AA-2414, blocked the effects of I-BOP on both BrdU uptake and cell proliferation. I-BOP-induced BrdU uptake was significantly blocked by two non-selective tyrosine kinase inhibitors, genistein and herbimycin A, or a Src family tyrosine kinase inhibitor, PP2, but not by an inhibitor of epidermal growth factor (EGF) receptor-associated tyrosine kinase, AG1478. In conclusion, TP receptor activation causes DNA synthesis and cell proliferation of human BSMC by activating tyrosine kinases including Src, but not by EGF receptor transactivation.
Suzuki
Yusuke
Y
Department of Medicine, Cardiopulmonary Division, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Asano
Koichiro
K
Shiraishi
Yoshiki
Y
Oguma
Tsuyoshi
T
Shiomi
Tetsuya
T
Fukunaga
Koichi
K
Nakajima
Takeshi
T
Niimi
Kyoko
K
Yamaguchi
Kazuhiro
K
Ishizaka
Akitoshi
A
D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000819:agonists; D001973:Bromodeoxyuridine / Q000494:pharmacology; D001980:Bronchi / Q000166:cytology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000819:agonists; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology; D009130:Muscle, Smooth / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000378:metabolism*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D047908:Intracellular Signaling Peptides and Proteins; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C015482:protein kinase modulator; C061750:7-(3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo(2.2.1)heptan-2-yl)-5-heptenoic acid; D004815:Epidermal Growth Factor; D011505:Protein-Tyrosine Kinases; D001973:Bromodeoxyuridine