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.