Inhibitors of the tyrosine kinase signaling cascade attenuated thrombin-induced guinea pig airway smooth muscle cell proliferation.
Airway remodeling is one of the major hallmarks of asthma. The present study examined the effects of tyrosine kinase inhibitors on thrombin-induced guinea pig ASM cell proliferation, in comparison with inhibitors of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K). The ASM cells expressed smooth muscle alpha-actin and myosin, and responded to thrombin by increasing cytosolic Ca(+2). Thrombin (1-10 U/ml) induced [(3)H]thymidine incorporation into ASM cells. Tyrphostin 47, a broad-spectrum tyrosine kinase inhibitor, PP2, a Src-specific inhibitor, and piceatannol, a Syk-selective inhibitor, significantly attenuated thrombin-induced [(3)H]thymidine incorporation. In addition, the tyrosine kinase inhibitors significantly reduced thrombin-induced cyclin D(1) expression in ASM cells. PD098059 and U0126, two MAPK kinase inhibitors, and LY294002, a PI3K inhibitor, significantly blocked thrombin-induced [(3)H]thymidine incorporation and cyclin D(1) expression in ASM cells. Our data show that inhibitors of Src and, probably Syk, can modulate thrombin-induced ASM cell proliferation, which may have therapeutic potential for asthma.
Tsang
Fai
F
Department of Pharmacology, Faculty of Medicine, National University of Singapore, MD2 18 Medical Drive, Singapore 119260, Singapore.
Choo
Hui Hwa
HH
Dawe
Gavin S
GS
Wong
W S Fred
WS
D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D019938:Cyclin D1 / Q000235:genetics; D004261:DNA Replication; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D006168:Guinea Pigs; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012143:Respiratory Physiological Phenomena; D013917:Thrombin / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism
D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009025:Morpholines; D019938:Cyclin D1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D011505:Protein-Tyrosine Kinases; D013917:Thrombin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D013936:Thymidine