Effects of inhibitors of the tyrosine kinase signaling cascade on an in vitro model of allergic airways

It has been shown that activation of protein tyrosine kinases (PTKs) is the earliest detectable signaling response to Fc epsilon RI cross-linking on m ast cells. Following tyrosine kinase activation, a family of mitogen-activa ted protein kinases (MAPKs) was found to be activated as well. Activation o f this PTK signaling cascade wilt lead to mast cell degranulation. This rev iew summarizes our recent studies on the role of PTK signaling cascade in a n in vitro guinea pig model of allergic asthma using PTK inhibitors, genist ein and tyrphostin 47, and MAPK kinase inhibitor, PD098059. Inhibitors of t he PTK and MAPK signaling pathways significantly attenuated the ovalbumin ( OVA)-induced bronchial anaphylactic contraction and enhanced relaxation of constricted airways, respectively, and substantially blocked the release of histamine and peptidoleukotrienes from chopped lung preparations induced b y OVA. Based upon their substantial inhibitory effects on the Schultz-Dale reaction, further examination on the potential anti-asthmatic effects of PT K cascade inhibitors in an in vivo model of allergic asthma is recommended.