A Functional Anatomic Defect of the Cystic Fibrosis Airway
A Functional Anatomic Defect of the Cystic Fibrosis Airway
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DOI：
10.1164/rccm.201404-0670oc
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发表时间：
2014-08-15
影响因子：
24.7
通讯作者：
Rowe, Steven M.
中科院分区：
文献类型：
--
作者：
Birket, Susan E.;Chu, Kengyeh K.;Rowe, Steven M.
目的：在选择性阴离子抑制剂存在下，我们评估了正常和囊性纤维化(CF)仔猪以及成年猪的气管。方法：我们使用显微光学相干断层扫描技术研究了呼吸道功能显微解剖，这是一种新的成像手段，可以同时以共定位的方式量化呼吸道上皮的多个功能参数。测量和主要结果：来自野生型猪的气管外植体证实了睫状液(PCL)水化和粘液纤毛传输(MCT)率之间的直接联系，这种关系经常被引用，但从未得到实验证实。然而，在CF航空公司，这种关系被完全打破，PCL深度越大，传输速度越慢。通过选择性地抑制碳酸氢盐在体外和体外的转运，可以重现这种被破坏的关系。由于缺少碳酸氢盐的转运，CF黏液表现出原位粘度增加，这解释了即使在PCL水合充足的情况下也会发生MCT缺陷。结论：CF呼吸道表面液体的固有缺陷导致了延迟的MCT，而不仅仅是由呼吸道脱水引起的，并确定了在没有既往感染或炎症的情况下CF肺部疾病发病的基本机制。
Rationale: The mechanisms underlying cystic fibrosis (CF) lung disease pathogenesis are unknown.Objectives: To establish mechanisms linking anion transport with the functional microanatomy, we evaluated normal and CF piglet trachea as well as adult swine trachea in the presence of selective anion inhibitors.Methods: We investigated airway functional microanatomy using microoptical coherence tomography, a new imaging modality that concurrently quantifies multiple functional parameters of airway epithelium in a colocalized fashion.Measurements and Main Results: Tracheal explants from wild-type swine demonstrated a direct link between periciliary liquid (PCL) hydration and mucociliary transport (MCT) rates, a relationship frequently invoked but never experimentally confirmed. However, in CF airways this relationship was completely disrupted, with greater PCL depths associated with slowest transport rates. This disrupted relationship was recapitulated by selectively inhibiting bicarbonate transport in vitro and ex vivo. CF mucus exhibited increased viscosity in situ due to the absence of bicarbonate transport, explaining defective MCT that occurs even in the presence of adequate PCL hydration.Conclusions: An inherent defect in CF airway surface liquid contributes to delayed MCT beyond that caused by airway dehydration alone and identifies a fundamental mechanism underlying the pathogenesis of CF lung disease in the absence of antecedent infection or inflammation.