Effects of tyrosine kinase inhibitors on antigen challenge of guinea pig lung in vitro.
The present study was conducted to examine the effects of two protein tyrosine kinase inhibitors, genistein and tyrphostin 47, on an in vitro model of allergic asthma. Guinea pigs were sensitized with purified IgG raised against ovalbumin (OA). Isolated sensitized bronchial rings contracted in response to OA in a concentration-dependent manner, maximum contraction being achieved at 1 microg/ml. Genistein and tyrphostin 47 concentration-dependently (10-100 microM) inhibited OA-induced anaphylactic contraction of the bronchi, as well as release of histamine and peptidoleukotrienes from chopped lung preparations. Genistein, but not tyrphostin 47, significantly suppressed bronchial contraction to leukotriene D4 at 50 microM and to histamine at 100 microM. Daidzein, an inactive congener of genistein, did not alter OA-induced anaphylactic contraction. However, it slightly reduced bronchial contraction to leukotriene D4 and the OA-stimulated release of peptidoleukotrienes. The inhibitory effects were significantly weaker than those of genistein. Taken together, our results show that tyrphostin 47 inhibited anaphylactic contraction mainly by preventing mast cell degranulation, whereas genistein exerted inhibitory effects partly by blocking mast cell degranulation and partly by attenuating leukotriene D4-induced bronchial contraction. These findings suggest that protein tyrosine kinase inhibitors have a therapeutic potential as mast cell stabilizers in the treatment of allergic diseases such as bronchial asthma.
Wong
W S
WS
Department of Pharmacology, Faculty of Medicine, National University of Singapore, Republic of Singapore.
Koh
D S
DS
Koh
A H
AH
Ting
W L
WL
Wong
P T
PT
D000707:Anaphylaxis / Q000517:prevention & control; D000818:Animals; D000941:Antigens / Q000276:immunology*; D001249:Asthma / Q000188:drug therapy; D016084:Bronchoconstriction / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019833:Genistein / Q000494:pharmacology*; D006168:Guinea Pigs; D006636:Histamine Release / Q000187:drug effects; D066298:In Vitro Techniques; D007529:Isoflavones / Q000494:pharmacology; D017998:Leukotriene D4 / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology*; D010636:Phenols / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011817:Rabbits; D020032:Tyrphostins
D000941:Antigens; D004791:Enzyme Inhibitors; D007529:Isoflavones; D009570:Nitriles; D010636:Phenols; D020032:Tyrphostins; C060152:tyrphostin 47; C004742:daidzein; D017998:Leukotriene D4; D019833:Genistein; D011505:Protein-Tyrosine Kinases