AIRWAY SUBMUCOSAL GLANDS AND CYSTIC FIBROSIS DISEASE

描述(摘自申请者摘要)：囊性纤维化的死亡率 (Cf)通常是由疾病的肺部并发症引起的， 包括带有浓厚脱水粘液的进行性呼吸道阻塞， 粘液纤毛运输减少、慢性呼吸道感染和支气管扩张。 而已知的慢性萎缩性胃炎是由囊性癌编码基因的突变引起的 CAMP调节的纤维化跨膜电导调节蛋白(CFTR) 阴离子通道，该通道功能中的缺陷与 CF的肺部发病机制目前尚不清楚，也存在争议。使用猪 航空公司，首席调查员最近表明，CFTR通常 调节呼吸道粘膜下腺的氯离子和HCO3的分泌 这一过程驱使腺液分泌。当腺液分泌时 通过应用选择性的C1-和HCO3分泌抑制剂被阻断，呼吸道 经历与早期CF呼吸道疾病相似的变化--粘液 腺管阻塞，产生异常稠密的脱水粘液， 以及粘液纤毛运输的减少。从这些观察来看，校长 研究人员假设，CF肺病理是不可避免的后果 粘膜下腺的氯离子和HCO3分泌受损。为了支持这一点 假设，申请人提出了以下目标。首先，这种机制是通过 哪种腺液分泌抑制剂会减少粘液纤毛运输 下定决心。第二，分泌囊泡在粘液凝胶形成中的作用 更好地了解粘液成熟的机制和动力学 在航空公司。第三，潜在的呼吸道分泌物的疗效和作用机制 将进行评估，以确定可能的CFTR独立路由，这些路由可能 用于治疗诱导液体分泌的操作。第四，能力 抑制氯离子和HCO3分泌以复制粘液阻塞 航空公司将在隔离的、灌流的肺叶中确定。这些建议 研究将提供关键信息，以了解 腺体Cl-和HCO3分泌在CF发病机制中的作用如果这个假设是 证实，这些研究可以构成治疗的重要基础 治疗这种致命疾病的策略。

DESCRIPTION(adapted from applicant's abstract): Mortality in cystic fibrosis (CF) typically results from the pulmonary complications of the disease, which include progressive obstruction of the airways with a thick dehydrated mucus, reduced mucociliary transport, chronic airway infections, and bronchiectasis. While CF is known to be caused by mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator protein (CFTR), a cAMP-regulated anion channel, the functional link between defects in this channel function and the pulmonary pathogenesis of CF is unclear and controversial. Using porcine airways, the principal investigator has recently shown that CFTR normally mediates secretion of both Cl- and HCO3 by submucosal glands of the airways and that this process drives secretion of gland liquid. When gland liquid secretion is blocked by applying selective C1- and HCO3 secretion inhibitors, airways undergo changes that parallel those observed in early CF airway disease-- mucus obstruction of gland ducts, production of an abnormally thick dehydrated mucus, and reductions in mucociliary transport. From these observations, the principal investigator hypothesizes that CF lung pathology is the inevitable consequence of impaired Cl- and HCO3 secretion from submucosal glands. In support of this hypothesis, the applicant proposes the following aims. First, the mechanism by which gland liquid secretion inhibitors reduce mucociliary transport will be determined. Second, the role of secretory vesicles in mucus gel formation will be studied to better understand the mechanism and dynamics of mucus maturation in airways. Third, the efficacy and mechanism of potential airway secretogogues will be evaluated to identify possible CFTR-independent routes which could be manipulated for therapeutic induction of liquid secretion. Fourth, the ability of inhibitors of Cl- and HCO3 secretion to reproduce mucus obstruction of airways will be determined in isolated, perfused lung lobes. These proposed studies will provide critical information for understanding the role of glandular Cl- and HCO3 secretion in the etiology of CF. If this hypothesis is confirmed, these studies could form the important basis of therapeutic strategies for the treatment of this lethal disease.