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Am. J. Respir. Crit. Care Med., Volume 162, Number 1, July 2000, 126-133

Inhibitors of Tyrosine Kinase Signaling Cascade Attenuated Antigen Challenge of Guinea-Pig Airways In Vitro

FAI TSANG and W. S. FRED WONG

Department of Pharmacology, Faculty of Medicine, National University of Singapore, Republic of Singapore

Activation of nontransmembrane protein tyrosine kinases (PTKs), phosphatidylinositol 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK) has been shown to be responsible for high-affinity Fc receptor (Fcvarepsilon RI)-mediated mast cell degranulation. Effects of inhibitors of the PTK signaling cascade on ovalbumin (OA)-induced anaphylactic contraction of isolated guinea-pig bronchi and release of histamine and peptidoleukotrienes from chopped lung preparations were studied. Genistein (30 µM) and tyrphostin 47 (50 µM), two PTK inhibitors, as well as LY294002 (10 µM), a selective PI3K inhibitor, significantly reduced (p < 0.05) peak anaphylactic bronchial contraction and facilitated relaxation of the contracted bronchi. PD 098059 (30 µM), a selective MAPK kinase inhibitor, failed to suppress OA-induced peak bronchial contraction, but facilitated the relaxation of the contracted bronchi (p < 0.05). At the same concentrations, none of these inhibitors showed any inhibitory effects on histamine-, leukotriene D4 (LTD4)- or KCl-induced bronchial contraction. On the other hand, these inhibitors significantly prevented (p < 0.05) OA-induced release of both histamine and peptidoleukotrienes from chopped lung preparations. In addition, combined PD 098059 and LY294002 treatment markedly (p < 0.05) suppressed the peak anaphylactic bronchial contraction and facilitated relaxation of the contracted bronchi. The combination of these two inhibitors further inhibited the release of peptidoleukotrienes from chopped lung preparations. Taken together, our data show that inhibition of tyrosine kinase signaling cascade can markedly attenuate anaphylactic contraction of airways, probably via inhibition of mast cell degranulation, and that inhibitors of this signaling cascade may have therapeutic potential for the treatment of asthma.




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W. Duan, I. C. Kuo, S. Selvarajan, K. Y. Chua, B. H. Bay, and W. S. F. Wong
Antiinflammatory Effects of Genistein, a Tyrosine Kinase Inhibitor, on a Guinea Pig Model of Asthma
Am. J. Respir. Crit. Care Med., January 15, 2003; 167(2): 185 - 192.
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