Leukotriene A4 Hydrolase Inhibition Attenuates Allergic Airway Inflammation and Hyperresponsiveness

NL Rao, JP Riley, H Banie, X Xue, B Sun… - American journal of …, 2010 - atsjournals.org
NL Rao, JP Riley, H Banie, X Xue, B Sun, S Crawford, KA Lundeen, F Yu, L Karlsson…
American journal of respiratory and critical care medicine, 2010atsjournals.org
Rationale: Allergic asthma is characterized by reversible airway obstruction, lung
inflammation, and airway hyperresponsiveness (AHR). Previous studies using leukotriene
B4 (LTB4) receptor 1–deficient mice and adoptive transfer experiments have suggested that
LTB4 plays a role in lung inflammation and AHR. Objectives: In this study, we used a
leukotriene A4 hydrolase (LTA4H) inhibitor as a pharmacological tool to directly examine the
role of LTB4 in a mast cell–dependent murine model of allergic airway inflammation …
Rationale: Allergic asthma is characterized by reversible airway obstruction, lung inflammation, and airway hyperresponsiveness (AHR). Previous studies using leukotriene B4 (LTB4) receptor 1–deficient mice and adoptive transfer experiments have suggested that LTB4 plays a role in lung inflammation and AHR.
Objectives: In this study, we used a leukotriene A4 hydrolase (LTA4H) inhibitor as a pharmacological tool to directly examine the role of LTB4 in a mast cell–dependent murine model of allergic airway inflammation.
Methods: We used the forced oscillation technique to test the effects of an LTA4H inhibitor dosed during the challenge phase on AHR. Lung tissue and lavage were collected for analysis.
Measurements and Main Results: Treatment with an LTA4H 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 LTA4H inhibitor treatment. Provocatively, inhibition of LTA4H increased lipoxin A4 levels in lung lavage fluid.
Conclusions: These data suggest that LTB4 plays a key role in driving lung inflammation and AHR. Mechanistically, we provide evidence that inhibition of LTA4H, 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 LTA4H is thus a potential therapeutic strategy that could modulate key aspects of asthma.
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