Immunology, Johnson & Johnson PRD, 3210 Merryfield Row, San Diego, CA 92121, USA.
Am J Respir Crit Care Med. 2010 May 1;181(9):899-907. doi: 10.1164/rccm.200807-1158OC. Epub 2010 Jan 28.
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.
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.
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.
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.
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.
过敏性哮喘的特征为气道阻塞可逆转、肺部炎症和气道高反应性（AHR）。先前使用白三烯 B4（LTB4）受体 1 缺陷小鼠和过继转移实验的研究表明，LTB4 在肺部炎症和 AHR 中发挥作用。
本研究中，我们使用白三烯 A4 水解酶（LTA4H）抑制剂作为药理学工具，直接研究 LTB4 在肥大细胞依赖性变应性气道炎症的小鼠模型中的作用。
我们使用强迫振荡技术来测试在激发阶段给予 LTA4H 抑制剂对 AHR 的影响。收集肺组织和灌洗液进行分析。
LTA4H 抑制剂治疗可改善包含 AHR 和肺功能的多个参数。观察到气道炎症细胞、细胞因子和粘蛋白在肺部腔中的显著减少。血清中抗原特异性 IgE 和 IgG1 水平也降低。用 LTA4H 抑制剂处理后，肺树突状细胞摄取标记的抗原以及随后向引流淋巴结和肺部的转移减少。值得注意的是，LTA4H 抑制增加了肺灌洗液中的脂氧素 A4 水平。
这些数据表明 LTB4 在驱动肺部炎症和 AHR 中发挥关键作用。从机制上讲，我们提供的证据表明抑制 LTA4H 会影响 CD4+和 CD8+T 细胞的募集，以及树突状细胞向引流淋巴结的迁移，并且可能有益地调节肺部的其他促炎和抗炎类二十烷酸。因此，抑制 LTA4H 是一种潜在的治疗策略，可调节哮喘的关键方面。
