Reduced three-dimensional motility in dehydrated airway mucus prevents neutrophil capture and killing bacteria on airway epithelial surfaces
Reduced three-dimensional motility in dehydrated airway mucus prevents neutrophil capture and killing bacteria on airway epithelial surfaces
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DOI：
10.4049/jimmunol.175.2.1090
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发表时间：
2005-07-15
影响因子：
4.4
通讯作者：
Boucher, RC
中科院分区：
文献类型：
--
作者：
Matsui, H;Verghese, MW;Boucher, RC
囊性纤维化（CF）肺病的特点是持续性肺部感染。 CF肺中粘液增稠（浓缩）会损害气道粘液清除，从而引发细菌感染。然而，气道还有其他机制来预防细菌感染，包括中性粒细胞介导的杀伤作用。因此，我们检查了增稠粘液中中性粒细胞运动以及细菌捕获和杀灭功能是否受损。三种浓度的粘液，代表正常范围（干重的 1.5% 和 2.5%）和 CF 样增稠粘液（6.5%），是从分化良好的人支气管上皮培养物中获得的，并为中性粒细胞迁移的三维研究做好准备。中性粒细胞在重力方向上的趋化性在 1.5% 粘液中是最佳的，而 2.5% 粘液最能支持中性粒细胞对抗重力的趋化性。在覆盖有 1.5% 粘液的气道上皮表面，横向趋化运动最快。相比之下，中性粒细胞在粘液变稠（6.5%）时几乎没有任何方向的运动性。在气道粘液塞的体内模型中，中性粒细胞迁移受到增稠粘液（CF模型）的抑制，但不受正常浓度粘液（“正常”模型）的抑制。与增稠粘液中中性粒细胞运动性下降相平行，CF样增稠粘液中的细菌捕获和杀灭能力也下降。用来自CF培养物的粘液获得了每个粘液浓度的相似结果，表明对中性粒细胞功能的抑制是粘液浓度依赖性的而不是CF来源依赖性的。我们得出结论，浓缩（“浓稠”）粘液抑制中性粒细胞迁移和杀伤，是 CF 中慢性气道感染防御失败的关键因素。
Cystic fibrosis (CF) lung disease is characterized by persistent lung infection. Thickened (concentrated) mucus in the CF lung impairs airway mucus clearance, which initiates bacterial infection. However, airways have other mechanisms to prevent bacterial infection, including neutrophil-mediated killing. Therefore, we examined whether neutrophil motility and bacterial capture and killing functions are impaired in thickened mucus. Mucus of three concentrations, representative of the range of normal (1.5 and 2.5% dry weight) and CF-like thickened (6.5%) mucus, Was obtained from well-differentiated human bronchial epithelial cultures and prepared for three-dimensional studies of neutrophil migration. Neutrophil chemotaxis in the, direction of gravity was optimal in 1.5% mucus, whereas 2.5% mucus best supported neutrophil chemotaxis against gravity. Lateral chemokinetic movement was fastest on airway epithelial surfaces covered with 1.5% mucus. In contrast, neutrophils exhibited little motility in any direction in thickened (6.5%) mucus. In in vivo models of airway mucus plugs, neutrophil migration was inhibited by thickened mucus (CF model) but not by normal concentrations of mucus ("normal" model). Paralleling the decreased neutrophil motility in thickened mucus, bacterial capture and killing capacity were decreased in CF-like thickened mucus. Similar results with each mucus concentration were obtained with mucus from CF cultures, indicating that inhibition of neutrophil functions was mucus concentration dependent not CF source dependent. We conclude that concentrated ("thick") mucus inhibits neutrophil migration and killing and is a key component in the failure of defense against chronic airways infection in CF.