NJK14047 Suppression of the p38 MAPK Ameliorates OVA-Induced Allergic Asthma during Sensitization and Challenge Periods.

Abstract

p38 MAPK has been implicated in the pathogenesis of asthma as well as pro-allergic Th2 cytokines, orosomucoid-like protein isoform 3 (ORMDL3), regulation of sphingolipid biosynthesis, and regulatory T cell-derived IL-35. To elucidate the role of p38 MAPK in the pathogenesis of asthma, we examined the effect of NJK14047, an inhibitor of p38 MAPK, against ovalbumin (OVA)-induced allergic asthma; we administrated NJK14047 before OVA sensitization or challenge in BALB/c mice. As ORMDL3 regulation of sphingolipid biosynthesis has been implicated in childhood asthma, ORMDL3 expression and sphingolipids contents were also analyzed. NJK14047 inhibited antigen-induced degranulation of RBL-2H3 mast cells. NJK14047 administration both before OVA sensitization and challenge strongly inhibited the increase in eosinophil and lymphocyte counts in the bronchoalveolar lavage fluid. In addition, NJK14047 administration inhibited the increase in the levels of Th2 cytokines. Moreover, NJK14047 reduced the inflammatory score and the number of periodic acid-Schiff-stained cells in the lungs. Further, OVA-induced increase in the levels of C16:0 and C24:1 ceramides was not altered by NJK14047. These results suggest that p38 MAPK plays crucial roles in activation of dendritic and mast cells during sensitization and challenge periods, but not in ORMDL3 and sphingolipid biosynthesis.