Leukotriene B4 release from mast cells in IgE-mediated airway hyperresponsiveness and inflammation.
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.
Miyahara
Nobuaki
N
Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado 80206, USA.
Ohnishi
Hiroshi
H
Miyahara
Satoko
S
Takeda
Katsuyuki
K
Matsubara
Shigeki
S
Matsuda
Hiroyuki
H
Okamoto
Masakazu
M
Loader
Joan E
JE
Joetham
Anthony
A
Tanimoto
Mitsune
M
Dakhama
Azzeddine
A
Gelfand
Erwin W
EW
D000485:Allergens / Q000737:chemistry; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D016535:Bronchial Hyperreactivity / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D007073:Immunoglobulin E / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D018793:Interleukin-13 / Q000378:metabolism; D007975:Leukotriene B4 / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry; D008407:Mast Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic
D000485:Allergens; D016207:Cytokines; D018793:Interleukin-13; D008055:Lipids; D007975:Leukotriene B4; D007073:Immunoglobulin E