BACKGROUND Bacterial colonization in cystic fibrosis (CF) lungs has been directly associated to the loss of CFTR function, and/or secondarily linked to repetitive cycles of chronic inflammation/infection. We hypothesized that altered molecular properties of mucins could contribute to this process. METHODS Newborn CFTR+/+ and CFTR-/- were sacrificed before and 6 h after inoculation with luminescent Pseudomonas aeruginosa into the tracheal carina. Tracheal mucosa and the bronchoalveolar lavage (BAL) fluid were collected to determine the level of mucin O-glycosylation, bacteria binding to mucins and the airways transcriptome. Disturbances in mucociliary transport were determined by ex-vivo imaging of luminescent Pseudomonas aeruginosa. RESULTS We provide evidence of an increased sialylation of CF airway mucins and impaired mucociliary transport that occur before the onset of inflammation. Hypersialylation of mucins was reproduced on tracheal explants from non CF animals treated with GlyH101, an inhibitor of CFTR channel activity, indicating a causal relationship between the absence of CFTR expression and the sialylation of mucins. This increased sialylation was correlated to an increased adherence of P. aeruginosa to mucins. In vivo infection of newborn CF piglets by live luminescent P. aeruginosa demonstrated an impairment of mucociliary transport of this bacterium, with no evidence of pre-existing inflammation. CONCLUSIONS Our results document for the first time in a well-defined CF animal model modifications that affect the O-glycan chains of mucins. These alterations precede infection and inflammation of airway tissues, and provide a favorable context for microbial development in CF lung that hallmarks this disease.

中文翻译：

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CFTR缺陷仔猪气道粘蛋白唾液酸化早期增加和粘液纤毛清除缺陷的证据

背景 囊性纤维化 (CF) 肺中的细菌定植与 CFTR 功能的丧失直接相关，和/或次要与慢性炎症/感染的重复循环有关。我们假设粘蛋白的分子特性改变可能有助于这一过程。方法 将发光的绿脓杆菌接种到气管隆突前和接种后 6 h 处死新生儿 CFTR+/+ 和 CFTR-/-。收集气管粘膜和支气管肺泡灌洗液 (BAL) 以确定粘蛋白 O-糖基化的水平、细菌与粘蛋白的结合和气道转录组。黏液纤毛运输的干扰由发光铜绿假单胞菌的离体成像确定。结果我们提供了在炎症发作前发生的 CF 气道粘蛋白唾液酸化增加和粘液纤毛运输受损的证据。在用 GlyH101（一种 CFTR 通道活性抑制剂）处理的非 CF 动物的气管外植体上再现了粘蛋白的过度唾液酸化，表明 CFTR 表达的缺失与粘蛋白的唾液酸化之间存在因果关系。这种增加的唾液酸化与铜绿假单胞菌对粘蛋白的粘附增加有关。活体发光铜绿假单胞菌对新生 CF 仔猪的体内感染表明这种细菌的黏液纤毛运输受损，没有预先存在炎症的证据。结论 我们的结果首次在明确定义的 CF 动物模型修改中记录，这些修改会影响粘蛋白的 O-聚糖链。