Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease.
Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease.
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粘液浓度和分泌的粘蛋白MUC5AC和MUC5B对粘液刺激性肺部疾病的发病机理的贡献。
DOI：
10.1038/mi.2016.63
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发表时间：
2017-03
影响因子：
8
通讯作者：
Boucher RC
中科院分区：
文献类型：
--
作者：
Livraghi-Butrico A;Grubb BR;Wilkinson KJ;Volmer AS;Burns KA;Evans CM;O'Neal WK;Boucher RC
呼吸道疾病，包括香烟烟雾引起的慢性支气管炎、囊性纤维化和原发性纤毛运动障碍与粘膜纤毛清除率（MCC）降低有关。然而，目前尚不清楚是否MCC或浓度依赖性粘液粘附到气道表面的简单减少主导疾病的发病机制，或是否降低分泌的粘蛋白的浓度可能是治疗性的。为了解决这些问题，将表现出气道粘液脱水/粘附的Scnn 1b-Tg小鼠与Muc 5 b和Muc 5ac缺陷小鼠进行比较并与之杂交。缺乏Muc 5 b导致MCC减少90%，而Scnn 1b-Tg小鼠表现出约50%的减少。然而，MCC减少的程度与支气管炎气道病理学无关，这仅在Scnn 1b-Tg小鼠中观察到。Muc 5 b的消融显著降低了Scnn 1b-Tg小鼠中粘液堵塞的程度。然而，在Scnn 1b-Tg小鼠中完全缺乏Muc 5 b与气道炎症增加相关，表明Muc 5 b是维持免疫稳态所必需的。Muc 5ac的丢失在Scnn 1b-Tg小鼠中几乎没有表型后果。这些数据表明：（1）粘液高浓度超过MCC单独减少，导致支气管炎气道病理;（2）Muc 5 b是Scnn 1b-Tg表型的主要贡献者;（3）限制粘蛋白分泌的治疗可能会减少堵塞，但从气道表面完全清除Muc 5 b可能是有害的。
Airway diseases, including cigarette smoke-induced chronic bronchitis, cystic fibrosis, and primary ciliary dyskinesia are associated with decreased mucociliary clearance (MCC). However, it is not known whether a simple reduction in MCC or concentration-dependent mucus adhesion to airway surfaces dominates disease pathogenesis or whether decreasing the concentration of secreted mucins may be therapeutic. To address these questions, Scnn1b-Tg mice, which exhibit airway mucus dehydration/adhesion, were compared to and crossed with Muc5b- and Muc5ac-deficient mice. Absence of Muc5b caused a 90% reduction in MCC, whereas Scnn1b-Tg mice exhibited an ~50% reduction. However, the degree of MCC reduction did not correlate with bronchitic airways pathology, which was observed only in Scnn1b-Tg mice. Ablation of Muc5b significantly reduced the extent of mucus plugging in Scnn1b-Tg mice. However, complete absence of Muc5b in Scnn1b-Tg mice was associated with increased airway inflammation, suggesting that Muc5b is required to maintain immune homeostasis. Loss of Muc5ac had few phenotypic consequences in Scnn1b-Tg mice. These data suggest that: (1) mucus hyperconcentration dominates over MCC reduction alone to produce bronchitic airways pathology; (2) Muc5b is the dominant contributor to the Scnn1b-Tg phenotype; and (3) therapies that limit mucin secretion may reduce plugging, but complete Muc5b removal from airway surfaces may be detrimental.