title: Leukotriene A(4) hydrolase inhibition attenuates allergic airway inflammation and hyperresponsiveness.
abstract: 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.
authors.affiliation: Immunology, Johnson & Johnson PRD, 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Navin L
authors.initials: NL
authors.lastname: Rao
authors.forename: Jason P
authors.initials: JP
authors.lastname: Riley
authors.forename: Homayon
authors.initials: H
authors.lastname: Banie
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Xue
authors.forename: Binggang
authors.initials: B
authors.lastname: Sun
authors.forename: Shelby
authors.initials: S
authors.lastname: Crawford
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Lundeen
authors.forename: Fuqu
authors.initials: F
authors.lastname: Yu
authors.forename: Lars
authors.initials: L
authors.lastname: Karlsson
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fourie
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dunford
mesh_terms: 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
chemical_list: D016207:Cytokines; D009077:Mucins; D007975:Leukotriene B4; D007073:Immunoglobulin E; D010047:Ovalbumin; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase