Leukotriene A(4) hydrolase inhibition attenuates allergic airway inflammation and hyperresponsiveness.
BACKGROUND
Allergic asthma is characterized by reversible airway obstruction, lung inflammation, and airway hyperresponsiveness (AHR). Previous studies using leukotriene B(4) (LTB(4)) receptor 1-deficient mice and adoptive transfer experiments have suggested that LTB(4) plays a role in lung inflammation and AHR.


OBJECTIVE
In this study, we used a leukotriene A(4) hydrolase (LTA(4)H) inhibitor as a pharmacological tool to directly examine the role of LTB(4) in a mast cell-dependent murine model of allergic airway inflammation.


METHODS
We used the forced oscillation technique to test the effects of an LTA(4)H inhibitor dosed during the challenge phase on AHR. Lung tissue and lavage were collected for analysis.


RESULTS
Treatment with an LTA(4)H inhibitor improved multiple parameters encompassing AHR and lung function. Significant decreases in inflammatory leukocytes, cytokines, and mucin were observed in the lung lumen. Serum levels of antigen-specific IgE and IgG1 were also decreased. Labeled antigen uptake by lung dendritic cells and subsequent trafficking to draining lymph nodes and the lung were decreased on LTA(4)H inhibitor treatment. Provocatively, inhibition of LTA(4)H increased lipoxin A(4) levels in lung lavage fluid.


CONCLUSIONS
These data suggest that LTB(4) plays a key role in driving lung inflammation and AHR. Mechanistically, we provide evidence that inhibition of LTA(4)H, affects recruitment of both CD4(+) and CD8(+) T cells, as well as trafficking of dendritic cells to draining lymph nodes, and may beneficially modulate other pro- and antiinflammatory eicosanoids in the lung. Inhibition of LTA(4)H is thus a potential therapeutic strategy that could modulate key aspects of asthma.
Rao
Navin L
NL
Immunology, Johnson & Johnson PRD, 3210 Merryfield Row, San Diego, CA 92121, USA.
Riley
Jason P
JP
Banie
Homayon
H
Xue
Xiaohua
X
Sun
Binggang
B
Crawford
Shelby
S
Lundeen
Katherine A
KA
Yu
Fuqu
F
Karlsson
Lars
L
Fourie
Anne M
AM
Dunford
Paul J
PJ
D000818:Animals; D001249:Asthma / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000503:physiopathology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002478:Cells, Cultured; D016207:Cytokines / Q000032:analysis; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D007073:Immunoglobulin E / Q000097:blood; D007975:Leukotriene B4 / Q000032:analysis / Q000502:physiology*; D008407:Mast Cells / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009077:Mucins / Q000032:analysis; D010047:Ovalbumin / Q000276:immunology
D016207:Cytokines; D009077:Mucins; D007975:Leukotriene B4; D007073:Immunoglobulin E; D010047:Ovalbumin; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase