Global Drug Discovery, Bayer HealthCare, Bayer Pharma AG, Wuppertal, Germany.
J Cyst Fibros. 2013 Dec;12(6):630-7. doi: 10.1016/j.jcf.2013.05.001. Epub 2013 Jun 13.
In 2005 Best and Quinton established the salivary secretion assay in mice for the in vivo characterization of new drugs against cystic fibrosis (CF). However, limited data are available and the predictive value of this in vivo assay for treatment effects in CF patients is not fully understood.
Therefore, we revisited the salivary secretion assay and systematically investigated the salivary secretion rates in different murine backgrounds and sexes, as well as in different CF mouse models. Moreover, we established quantification of salivary chloride content.
We found a strain- and sex-dependency of salivary secretion rates and were able to confirm the decreased β-adrenergic salivary secretion response in CFTR knockout mice (CFTR(tm1Unc)) as well as in the F508del CFTR mice of different origins (CFTR(tm1Kth) and CFTR(tm1Eur)). In heterozygous Cftr+/- and Cftr+/F508del mice, the isoprenaline-stimulated salivary secretion rate and the Cl(-) content were intermediate between values measured in WT and CF mice, indicating that this assay is also able to detect CF carriership. Pilocarpine-induced abnormalities in saliva chloride content in CF mice resembled the changes observed in the human sweat test.
Determination of murine salivary chloride content in combination with salivary secretion rate in CF mice may render the salivary secretion assay as a powerful tool for validation of new CF treatments.
2005 年，Best 和 Quinton 在小鼠体内建立了唾液分泌测定法，用于对囊性纤维化（CF）的新型药物进行体内特征分析。然而，目前可用的数据有限，并且这种体内测定法对 CF 患者治疗效果的预测价值尚未完全了解。
因此，我们重新研究了唾液分泌测定法，并系统地研究了不同小鼠背景和性别的唾液分泌率，以及不同 CF 小鼠模型中的唾液分泌率。此外，我们建立了唾液氯化物含量的定量方法。
我们发现唾液分泌率存在品系和性别依赖性，并且能够证实 CFTR 敲除小鼠（CFTR(tm1Unc)）以及不同来源的 F508del CFTR 小鼠（CFTR(tm1Kth)和 CFTR(tm1Eur)）中β-肾上腺素能唾液分泌反应降低。在杂合子 Cftr+/-和 Cftr+/F508del 小鼠中，异丙肾上腺素刺激的唾液分泌率和 Cl(-)含量介于 WT 和 CF 小鼠之间，表明该测定法也能够检测 CF 携带者。CF 小鼠中毛果芸香碱诱导的唾液氯化物含量异常与在人类汗液试验中观察到的变化相似。
在 CF 小鼠中测定小鼠唾液氯化物含量与唾液分泌率相结合，可能使唾液分泌测定法成为验证新型 CF 治疗方法的有力工具。
