Development of an airway mucus defect in the cystic fibrosis rat
Development of an airway mucus defect in the cystic fibrosis rat
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DOI：
10.1172/jci.insight.97199
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发表时间：
2018-01-11
期刊：
影响因子：
8
通讯作者：
Rowe, Steven M.
中科院分区：
文献类型：
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作者：
Birket, Susan E.;Davis, Joy M.;Rowe, Steven M.
囊性纤维化（CF）中气道粘液缺陷的发展和自然进展的机制仍不清楚。新的CF动物模型，加上使用显微光学相干断层扫描成像，可以导致对这些问题的见解。Cftr（-/-）（KO）大鼠允许纵向检查气道粘液异常的发展和进展。KO大鼠表现出纤毛周深度降低、pH值过酸和粘液固体含量百分比增加;然而，粘液的转运速率和粘弹性不受影响，直至KO大鼠老化。KO大鼠在6月龄时出现气道粘膜下腺肥大。只有这样，它才能诱导粘液粘度增加，纤毛周层塌陷，并延迟粘液纤毛运输;刺激腺体分泌增强这种演变。这些结果可以通过碳酸氢盐补充来逆转，但在没有碳酸氢盐捐赠的情况下不能进行pH校正。这些研究表明，CF中的异常表面上皮在没有功能性腺体分泌物的情况下不会引起粘液运输延迟。此外，异常碳酸氢盐转运代表了恢复粘液清除的特定目标，独立于对纤毛周围塌陷的影响。因此，需要成熟的气道分泌物来显示由气道脱水和碳酸氢盐缺乏引发的CF缺陷。
The mechanisms underlying the development and natural progression of the airway mucus defect in cystic fibrosis (CF) remain largely unclear. New animal models of CF, coupled with imaging using micro-optical coherence tomography, can lead to insights regarding these questions. The Cftr(-/-)(KO) rat allows for longitudinal examination of the development and progression of airway mucus abnormalities. The KO rat exhibits decreased periciliary depth, hyperacidic pH, and increased mucus solid content percentage; however, the transport rates and viscoelastic properties of the mucus are unaffected until the KO rat ages. Airway submucosal gland hypertrophy develops in the KO rat by 6 months of age. Only then does it induce increased mucus viscosity, collapse of the periciliary layer, and delayed mucociliary transport; stimulation of gland secretion potentiates this evolution. These findings could be reversed by bicarbonate repletion but not pH correction without counterion donation. These studies demonstrate that abnormal surface epithelium in CF does not cause delayed mucus transport in the absence of functional gland secretions. Furthermore, abnormal bicarbonate transport represents a specific target for restoring mucus clearance, independent of effects on periciliary collapse. Thus, mature airway secretions are required to manifest the CF defect primed by airway dehydration and bicarbonate deficiency.