Effect of an inhibitor of Jun N‐terminal protein kinase, SP600125, in single allergen challenge in sensitized rats

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Abstract
Jun N‐terminal kinase (JNK) has been implicated in the pathogenesis of inflammatory diseases including asthma. We examined the effect of SP600125 (anthra [1,9‐cd] pyrazol‐6 (2H)‐one), a novel inhibitor of JNK in a model of asthma. Brown‐Norway rats were sensitized to ovalbumin and treated with SP600125 intraperitoneally (90 mg/kg in total). SP600125 inhibited allergen‐induced, increased activity of phosphorylated c‐jun but not of phosphorylated‐MAPKAPK2, indicative of activation of p38 MAPK, in the lung. SP600125 inhibited macrophage (P < 0·04), lymphocyte (P < 0·05), eosinophil (P < 0·04) and neutrophil (P < 0·005) numbers in bronchoalveolar lavage. Eosinophil and T‐cell accumulation in the airways, mRNA expression for interleukin‐1β, tumour necrosis factor‐β, interleukin‐3, interleukin‐4 and interleukin‐5, serum levels of allergen‐specific immunoglobulin E and bronchial hyperresponsiveness were not affected by SP600125. Selective inhibition of JNK reduced inflammatory cell egress into the airway lumen after single allergen exposure. The role of JNK mitogen‐activated protein kinase activation may be limited in the pathogenesis of bronchial hyperresponsiveness after single allergen exposure.