Department of Medicine and.
Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.
JCI Insight. 2018 Jan 11;3(1). doi: 10.1172/jci.insight.97199.
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.
气道黏液缺陷在囊性纤维化（CF）中的发展和自然进展的机制在很大程度上仍不清楚。新的 CF 动物模型，结合使用微光学相干断层扫描进行成像，可以为这些问题提供深入的了解。Cftr-/-（KO）大鼠允许对气道黏液异常的发展和进展进行纵向检查。KO 大鼠表现出纤毛旁深度降低、pH 值过酸和黏液固相含量百分比增加；然而，直到 KO 大鼠衰老，黏液的转运率和黏弹性特性才不受影响。气道黏膜下腺在 KO 大鼠中发生肥大，在 6 个月大时发生。只有这样，它才会引起黏液黏度增加、纤毛旁层塌陷和黏液纤毛转运延迟；腺体分泌的刺激会增强这种演变。这些发现可以通过补充重碳酸盐来逆转，但没有反离子供体则无法通过 pH 值校正来逆转。这些研究表明，在没有功能性腺体分泌的情况下，CF 中异常的表面上皮不会导致黏液转运延迟。此外，异常的碳酸氢盐转运代表了恢复黏液清除的特定目标，独立于对纤毛旁塌陷的影响。因此，成熟的气道分泌物是表现气道脱水和碳酸氢盐缺乏引发的 CF 缺陷所必需的。
