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.