Inhibitors of tyrosine kinase signaling cascade attenuated antigen challenge of guinea-pig airways in vitro

Citation
F. Tsang et Wsf. Wong, Inhibitors of tyrosine kinase signaling cascade attenuated antigen challenge of guinea-pig airways in vitro, AM J R CRIT, 162(1), 2000, pp. 126-133
Citations number
34
Categorie Soggetti
Cardiovascular & Respiratory Systems","da verificare
Journal title
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
ISSN journal
1073449X → ACNP
Volume
162
Issue
1
Year of publication
2000
Pages
126 - 133
Database
ISI
SICI code
1073-449X(200007)162:1<126:IOTKSC>2.0.ZU;2-W
Abstract
Activation of nontransmembrane protein tyrosine kinases (PTKs), phosphatidy linositol 3-kinase (P13K), and mitogen-activated protein kinase (MAPK) has been shown to be responsible for high-affinity Fc receptor (Fc epsilon RI)- mediated mast cell degranulation. Effects of inhibitors of the PTK signalin g cascade on ovalbumin (OA)-induced anaphylactic contraction of isolated gu inea-pig bronchi and release of histamine and peptidoleukotrienes from chop ped lung preparations were studied. Genistein (30 mu M) and tyrphostin 47 ( 50 mu M), two PTK inhibitors, as well as LY294002 (10 mu M), a selective P1 3K inhibitor, significantly reduced (p < 0.05) peak anaphylactic bronchial contraction and facilitated relaxation of the contracted bronchi. PD 098059 (30 mu M), a selective MAPK kinase inhibitor, failed to suppress OA-induce d peak bronchial contraction, but facilitated the relaxation of the contrac ted bronchi (p < 0.05). At the same concentrations, none of these inhibitor s showed any inhibitory effects on histamine-, leukotriene D-4 (LTD4)- or K Cl-induced bronchial contraction. On the other hand, these inhibitors signi ficantly prevented (p < 0.05) OA-induced release of both histamine and pept idoleukotrienes from chopped lung preparations. In addition, combined PD 09 8059 and LY294002 treatment markedly (p < 0.05) suppressed the peak anaphyl actic bronchial contraction and facilitated relaxation of the contracted br onchi. The combination of these two inhibitors further inhibited the releas e of peptidoleukotrienes from chopped lung preparations. Taken together, ou r data show that inhibition of tyrosine kinase signaling cascade can marked ly attenuate anaphylactic contraction of airways, probably via inhibition o f mast cell degranulation, and that inhibitors of this signaling cascade ma y have therapeutic potential for the treatment of asthma.