Leukotriene A4 Hydrolase Inhibitors Decrease Allergic Airway Inflammation and Hyperreactivity by Modulating Leukocyte Recruitment and IL‐13 Production

Abstract

Leukotriene A4 hydrolase (LTA44H) produces the pro‐inflammatory mediator LTB4, a potent chemoattractant of allergy‐associated leukocytes such as mast cells, T cells, eosinophils, neutrophils and monocytes. The potential utility of a selective, LTA44H inhibitor was examined in vivo using a murine, mast cell‐dependent model of allergic airway inflammation. Treatment with a LTA44H inhibitor significantly decreased eosinophils, neutrophils and lymphocytes in bronchoalveolar lavage fluid (BALF) compared to vehicle‐treated animals. Cytokines such as IL‐4, IL‐5, IL‐13 and MCP‐1 were also decreased in the BALF. Airways hyperreactivity, measured by the forced oscillation technique, was significantly reduced in LTA44H inhibitor‐treated animals, as were serum levels of ova‐specific IgE and IgG1. Ex vivo antigen stimulation of peribronchiolar lymph node cells from inhibitor‐treated animals resulted in decreased IL‐13 production. Mechanistically, LTA44H inhibitors decreased CD4+ and CD8+ T cell infiltration into the lung and migration of Ova+ dendritic cell into draining lymph nodes. An associated decrease in T cell cytokine production and dendritic cell function in the lung potentially explains the decrease in multiple aspects of airway inflammation and hyperreactivity. These results demonstrate that inhibition of LTA44H has potential therapeutic utility in the treatment of allergic airway disease.