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Leukotriene B4 Release from Mast Cells in IgE-Mediated Airway Hyperresponsiveness and Inflammation

¹ Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado; and ² Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan

Correspondence and requests for reprints should be addressed to Erwin W. Gelfand, M.D., National Jewish Health, 1400 Jackson Street, Denver, CO 80206. E-mail: gelfande{at}njc.org

Previous studies have shown that leukotriene B4 (LTB4), a proinflammatory lipid mediator, is linked to the development of airway hyperresponsiveness through the accumulation of IL-13–producing CD8+ T cells, which express a high affinity receptor for LTB4, BLT1 (Miyahara et al., Am J Respir Crit Care Med 2005;172:161–167; J Immunol 2005;174:4979–4984). By using leukotriene A4 hydrolase–deficient (LTA4H–/–) mice, which fail to synthesize LTB4, we determined the role of this lipid mediator in allergen-induced airway responses. Two approaches were used. In the first, LTA4H–/– mice and wild-type (LTA4H+/+) mice were systemically sensitized and challenged via the airways to ovalbumin. In the second, mice were passively sensitized with anti-ovalbumin IgE and exposed to ovalbumin via the airways. Mast cells were generated from bone marrow of LTA4H+/+ mice or LTA4H–/– mice. After active sensitization and challenge, LTA4H–/– mice showed significantly lower airway hyperresponsiveness compared with LTA4H+/+ mice, and eosinophil numbers and IL-13 levels in the bronchoalveoloar lavage of LTA4H–/– mice were also significantly lower. LTA4H–/– mice also showed decreased airway reactivity after passive sensitization and challenge. After LTA4H+/+ mast cell transfer, LTA4H–/– mice showed increased airway reactivity after passive sensitization and challenge, but not after systemic sensitization and challenge. These data confirm the important role for LTB4 in the development of altered airway responses and suggest that LTB4 secretion from mast cells is critical to eliciting increased airway reactivity after passive sensitization with allergen-specific IgE.

Key Words: rodent • T cells • cytokines • lipid mediators • lung

CLINICAL RELEVANCE Lipid mediators play a major role in the pathophysiology of allergen-induced lung disease. Leukotriene B4 (LTB4) is emerging as a major chemoattractant for subsets of T cells in the lung which contribute to the pathophysiology of asthma. Mice genetically incapable of synthesizing LTB4 have limited capacity to develop allergen-induced altered airway dysfunction and inflammation. Mast cells are a major source of this lipid mediator and can reconstitute responses in LTB4-deficient mice.