ABSTRACT
Upon cross-linking of the high-affinity IgE receptors on mast cells, a family of mitogen-activated protein kinases (MAPKs) is activated. The present study examined the effects of p42/44 MAPK kinase inhibitor U0126 and p38 MAPK inhibitors SB220025 and PD169316 on ovalbumin (OVA)-induced anaphylactic contraction of isolated guinea pig bronchi and release of histamine and peptidoleukotrienes from lung fragments. Guinea pigs were actively sensitized by OVA. OVA induced anaphylactic bronchial contractions, and release of histamine and peptidoleukotrienes from lung fragments. U0126 (0.3-30 microM), but not SB220025 and PD169316 (3-30 microM), slightly suppressed peak OVA-induced bronchial contraction but markedly reduced anaphylactical contraction over a 50-min period in a dose-dependent manner. U0126 did not inhibit bronchial contractions induced by KCl, histamine or leukotriene D4. U0126 produced a slight reduction in OVA-induced release of histamine but a significant inhibition on the release of peptidoleukotrienes from lung fragments. Exogenous arachidonic acid-induced release of peptidoleukotrienes was not blocked by U0126. SB220025 and PD169316 had no effect on OVA-induced release of histamine and peptidoleukotrienes. Our data indicate that inhibitor of p42/44 MAPK kinase, but not p38 MAPK, can reduce antigen-induced release of peptidoleukotrienes leading to a rapid resolution of anaphylactic bronchial contraction, and may have therapeutic potential for allergic asthma.
Subject(s)
Anaphylaxis/drug therapy , Bronchi/drug effects , Enzyme Inhibitors/pharmacology , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Anaphylaxis/immunology , Anaphylaxis/physiopathology , Animals , Bronchi/physiopathology , Bronchoconstriction/drug effects , Butadienes/pharmacology , Calcium-Calmodulin-Dependent Protein Kinases/antagonists & inhibitors , Guinea Pigs , Histamine/metabolism , Imidazoles/pharmacology , In Vitro Techniques , Leukotrienes/metabolism , Male , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/physiopathology , Nitriles/pharmacology , Ovalbumin , Pyrimidines/pharmacology , Time FactorsABSTRACT
Activation of nontransmembrane protein tyrosine kinases, such as Lyn and Syk, has been shown to be the earliest detectable signaling response to Fc receptor (Fc epsilon RI) cross-linking on mast cells leading to mast cell degranulation. The present study examined the effects of piceatannol (3,4,3',5'-tetrahydroxy-trans-stilbene, 10-100 microM), a Syk-selective tyrosine kinase inhibitor, on ovalbumin-induced anaphylactic contraction of isolated guinea pig bronchi and release of histamine and peptidoleukotrienes from chopped lung preparations. Pretreatment with piceatannol slightly suppressed ovalbumin-induced peak anaphylactic bronchial contraction but markedly (P<0.05) facilitated relaxation of the anaphylactically contracted bronchi. Piceatannol did not inhibit direct histamine-, leukotriene D(4)- or KCl-induced bronchial contraction, nor revert an existing anaphylactic bronchial contraction. Piceatannol, at 30 microM and above, significantly (P<0.05) prevented ovalbumin-induced release of both histamine and peptidoleukotrienes from lung fragments. Piceatannol did not inhibit exogenous arachidonic acid-induced release of peptidoleukotrienes from lung fragments. Our data show for the first time that inhibition of Syk tyrosine kinase can attenuate anaphylactic bronchial contraction in vitro, probably via inhibition of mast cell degranulation.
