Inhibitor of p42/44 mitogen-activated protein kinase, but nto p38 MAPK, attenuated antigen challenge of guinea pig airways in vitro

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 muM), but not SB220025 and PD169316 (3-30 muM), 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 D-4. 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 PD 169316 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. (C) 2004 Elsevier B.V. All rights reserved.