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 (P13K). 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 [H-3]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 [H-3]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 P13K inhibitor, significantly blocked thrombin-induced [H-3]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. (C) 2002 Elsevier Science (USA). All rights reserved.