Department of Translational Pulmonology, Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research, University of Heidelberg, Heidelberg, Germany.
PLoS One. 2012;7(8):e44059. doi: 10.1371/journal.pone.0044059. Epub 2012 Aug 24.
Factors determining the onset and severity of chronic obstructive pulmonary disease remain poorly understood. Previous studies demonstrated that airway surface dehydration in βENaC-overexpressing (βENaC-Tg) mice on a mixed genetic background caused either neonatal mortality or chronic obstructive lung disease suggesting that the onset of lung disease was modulated by the genetic background.
To test this hypothesis, we backcrossed βENaC-Tg mice onto two inbred strains (C57BL/6 and BALB/c) and studied effects of the genetic background on neonatal mortality, airway ion transport and airway morphology. Further, we crossed βENaC-Tg mice with CFTR-deficient mice to validate the role of CFTR in early lung disease.
We demonstrate that the C57BL/6 background conferred increased CFTR-mediated Cl(-) secretion, which was associated with decreased mucus plugging and mortality in neonatal βENaC-Tg C57BL/6 compared to βENaC-Tg BALB/c mice. Conversely, genetic deletion of CFTR increased early mucus obstruction and mortality in βENaC-Tg mice.
We conclude that a decrease or absence of CFTR function in airway epithelia aggravates the severity of early airway mucus obstruction and related mortality in βENaC-Tg mice. These results suggest that genetic or environmental factors that reduce CFTR activity may contribute to the onset and severity of chronic obstructive pulmonary disease and that CFTR may serve as a novel therapeutic target.
慢性阻塞性肺疾病发病和严重程度的决定因素仍知之甚少。先前的研究表明，在混合遗传背景下过表达βENaC（βENaC-Tg）的小鼠气道表面脱水会导致新生儿死亡或慢性阻塞性肺病，这表明肺部疾病的发病是由遗传背景所调节的。
为了验证这一假设，我们将βENaC-Tg 小鼠进行回交，使其与两个近交系（C57BL/6 和 BALB/c）杂交，并研究遗传背景对新生儿死亡率、气道离子转运和气道形态的影响。此外，我们将βENaC-Tg 小鼠与 CFTR 缺陷型小鼠杂交，以验证 CFTR 在早期肺部疾病中的作用。
我们证明 C57BL/6 背景赋予了 CFTR 介导的 Cl(-)分泌增加，这与βENaC-Tg C57BL/6 小鼠相比，βENaC-Tg BALB/c 小鼠中气道粘液栓形成和死亡率降低有关。相反，CFTR 的遗传缺失增加了βENaC-Tg 小鼠的早期粘液阻塞和死亡率。
我们得出结论，气道上皮细胞中 CFTR 功能的降低或缺失会加重βENaC-Tg 小鼠早期气道粘液阻塞的严重程度和相关死亡率。这些结果表明，降低 CFTR 活性的遗传或环境因素可能导致慢性阻塞性肺疾病的发病和严重程度，并且 CFTR 可能成为一种新的治疗靶点。
