ELECTROLYTE COMPOSITION OF SURFACE FLUID IN NORMAL AND CF AIRWAY EPITHELIA

(改编自申请人的摘要)调查人员最近提出了一项 CFTR缺失与分子和生理缺陷有关的假说 C1-通道功能和跨上皮c1-转运缺陷，与 慢性支气管炎的临床特征是呼吸道感染。他们和其他人发现， 正常和CF型呼吸道上皮细胞分泌抗菌物质进入薄壁 覆盖在根尖表面的一层液体。然而，他的杀戮活动 这些因素需要较低的氯化钠浓度。报道称，CF表面流体 有很高的NaCI浓度可以解释为什么在 参见 他们将测试关于呼吸道电解质组成的三个假说 表面流体。首先，气道面液盐浓度为 增加了CF。为了验证这一假设，调查人员将使用初级 培养正常和CF型呼吸道上皮细胞以测定其离子浓度 ASF，以及在动物和人类身上进行的活体测量。第二， 碳纤维中ASF盐浓度的增加是由于电解质受损 吸收。他们将通过询问Normal和CF如何来检验假设 上皮细胞改变ASF的电解质组成。第三，干预措施 降低盐浓度将恢复杀菌活性。为了测试 这一假设认为，它们将通过基因转移、激活 替代(非CFTR)C1通道和阻断上皮钠通道。 调查人员还将尝试使用新的方法来减少 ASF中的盐浓度。 考虑到ASF的重要性，令人惊讶的是ASF的组成并不 更好地理解。拟议的研究应该为我们提供新的见解 ASF的电解液浓度以及如何对其进行改性。结果是 了解CFTRc1-通道缺失是如何导致CF肺的关键 并开发新的治疗方法。

(Adapted from the applicant's abstract) The investigators recently proposed a hypothesis to link the molecular and physiologic defect in CF, loss of CFTR C1- channel function and defective transepithelial C1- transport, with the clinical hallmark of CF, airway infections. They and others found that both normal and CF airway epithelia secrete antibacterial substances into the thin layer of fluid covering the apical surface. However the killing activity of these factors require a low NaC1 concentration. Reports that CF surface fluid has a high NaC1 concentration would explain the lack of bacterial killing in CF. They will test three hypotheses about the electrolyte composition of airway surface fluid. First, the salt concentration of airway surface fluid is increased in CF. To test this hypothesis investigators will use primary cultures of normal and CF airway epithelia to measure ion concentrations of ASF, as well as in vivo measurements done in animals and humans. Second, the increase in ASF salt concentration in CF is due to impaired electrolyte absorption. They will test the hypothesis by asking how normal and CF epithelia modify the electrolyte composition of ASF. Third, interventions that decrease salt concentration will restore bactericidal activity. To test this hypothesis they will restore CFTR function by gene transfer, activate alternative (non-CFTR) C1 channels and block epithelial Na+ channels. Investigators will also attempt to use novel approaches to decrease the concentration of salt in ASF. Given its importance, it is surprising that the composition of ASF is not better understood. The studies proposed should provide new insight into the electrolyte concentration of ASF and how they are modified. The results are central to understanding how the lack of CFTR C1- channels causes CF lung disease and to develop new therapies.