Airway Submucosal Glands and Cystic Fibrosis Disease

描述（由申请人提供）：囊性纤维化（CF）是由编码囊性纤维化跨膜传导调节因子（CFTR）基因的有害突变引起的，CFTR是一种camp激活的阴离子通道。许多器官系统在CF中受到影响，但死亡通常是由肺部疾病引起的，其典型特征是产生异常粘稠的粘液，严重的慢性细菌感染和支气管扩张。不幸的是，导致这种病理模式的事件的潜在顺序是不清楚和有争议的。我们长期以来的假设是CFTR介导气管支气管粘膜下腺的液体分泌，这对于水合腺体分泌的大分子成分并将这些物质通过腺体导管冲洗到气道表面是重要的。因此，在CF中，CFTR功能的丧失会导致腺体分泌过厚的粘液，气道表面的睫状体液耗竭。粘膜纤毛运输因此中断，使气道易受细菌定植。我们之前对猪气道的研究表明，阴离子和液体分泌的抑制再现了CF的许多肺部病理，包括粘膜下腺体的粘液阻塞、浓稠粘液的分泌、睫周液的消耗和粘膜纤毛运输受损。根据目前的应用，我们提出了一系列的研究，我们预计将加强这一假设。以猪气道为模型，我们将定义生理上重要的内源性促分泌物的细胞内信号转导元件的关键方面，这将有助于定义分泌是如何调节的，阐明CFTR的作用，并确定治疗操作的可能靶点。我们将获得并研究人类CF气道，以证明在这种疾病中哪些腺体分泌途径是残疾的或完整的。我们将继续开发一种体外技术，通过利用shRNA降低气道组织外植体中CFTR的表达来模拟猪气道中的CF。使用阴离子和液体分泌抑制剂来模拟猪气道中的CF缺陷，我们将研究粘稠粘液对铜绿假单胞菌在气道粘膜定植的影响。我们相信，这些研究将为气道腺在CF气道疾病肺发病机制中的作用提供重要的新信息。毫无疑问，CF的未来治疗策略的发展将取决于对疾病过程的潜在原因的更好理解。

DESCRIPTION (provided by applicant): Cystic Fibrosis (CF) is caused by deleterious mutations in the gene that codes for the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated anion channel. Numerous organ systems are affected in CF, but death typically results from the lung disease which is typified by the production of unusually thick mucus, severe chronic bacterial infections, and bronchiectasis. Unfortunately, the underlying sequence of events which leads to this pattern of pathology is unclear and controversial. Our longstanding hypothesis is that CFTR mediates liquid secretion by tracheobronchial submucosal glands which is important for hydrating the macromolecular component of gland secretion and flushing this material through the gland ducts to the airway surface. Thereby, in CF, loss of CFTR function would lead to secretion of overly thick mucus from glands and depletion of periciliary fluid at the airway surface. Disruption of mucociliary transport thus occurs, predisposing the airways to bacterial colonization. Our previous studies of pig airways demonstrated that inhibition of anion and liquid secretion reproduces much of the lung pathology of CF including mucus occlusion of submucosal glands, secretion of inspissated mucus, depletion of periciliary fluid, and impaired mucociliary transport. With the present application, we propose a series of studies which we anticipate will strengthen this hypothesis. Using pig airways as a model, we will define critical aspects of the intracellular signal transduction elements for physiologically important endogenous secretogogues that will help define how secretion is regulated, clarify the role played by CFTR, and identify possible targets for therapeutic manipulation. We will obtain and study human CF airways to document which gland secretion pathways are disabled or intact in this disease. We will pursue development of an in vitro technique to model CF in porcine airways by utilizing shRNA to reduce CFTR expression in explants of airway tissue. Using anion and liquid secretion inhibitors to model the CF defect in pigs airways, we will examine the consequences of thick mucus on Pseudomonas aeruginosa colonization of the airway mucosa. We believe that these studies will provide crucial new information regarding the role of airway glands in the pulmonary pathogenesis of CF airway disease. Without doubt, development of future treatment strategies for CF will depend upon a better understanding of the underlying causes of the disease process.