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 vitr o 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, max imum contraction being achieved at 1 mu g/ml. Genistein and tyrphostin 47 concentration-dependently (10-100 mu M) inhibited OA-induced anaph ylactic contraction of the bronchi, as well as release of histamine an d peptidoleukotrienes from chopped lung preparations. Genistein, but n ot tyrphostin 47, significantly suppressed bronchial contraction to le ukotriene D-4 at 50 mu M and to histamine at 100 mu M. Daidzein, an in active congener of genistein, did not alter OA-induced anaphylactic co ntraction. However, it slightly reduced bronchial contraction to leuko triene D-4 and the OA-stimulated release of peptidoleukotrienes. The i nhibitory effects were significantly weaker than those of genistein. T aken together, our results show that tyrphostin 47 inhibited anaphylac tic contraction mainly by preventing mast cell degranulation, whereas genistein exerted inhibitory effects partly by blocking mast cell degr anulation and partly by attenuating leukotriene D-4-induced bronchial contraction. These findings suggest that protein tyrosine kinase inhib itors have a therapeutic potential as mast cell stabilizers in the tre atment of allergic diseases such as bronchial asthma.