The Role of Airway Surface Liquid Nucleotides/Nucleosides in Volume Homeostasis

控制呼吸道表面液体(ASL)量对肺防御吸入至关重要 病原体/毒物。ASL容量不足会导致呼吸道阻塞和呼吸道感染，反映 无睫状液(PCL)体积和脱水粘液粘连到呼吸道表面。大有可为 已知控制跨上皮离子通量的离子转运过程，但很少或根本没有。 描述如何协调调节这些过程以调节盐的质量，从而调节水的质量的数据 在健康所需的范围内的呼吸道表面。对遗传性肺部疾病患者的研究，例如， 囊性纤维化，表明CFTR和ENaC通道的调节对此至关重要 进程。最近，一些线索表明了核苷酸和核苷的作用。 ASL中(NSS)在调节Na+吸收和Cl-分泌平衡中的作用 动态平衡。事实上，我们假设1)ASL[NT+NS]S对ASL音量调节如此关键，以至于在 没有它们，呼吸道上皮细胞恢复到纯Na+吸收状态，并从呼吸道中耗尽所有ASL ASL的体积与呼吸道表面的ATP释放率(JATP)成正比。 为了检验这些假设并对ASL体积稳态进行全面描述，我们 提出三个具体目标：1)目标1-测定JATP和细胞外NT+NS代谢 将ASL-NT+NS浓度与离子传输的生物物理模型相结合的数学模型 描述ASL容量动态平衡的调节；2)人支气管上皮(HBE)的目的2-试验 培养急性调节ASL容量动态平衡对NTS和NSS的需求 调节这些调控过程的机制；以及3)目标3-测试NT+NS在 体内控制突变小鼠模型中ASL的体积。与公共卫生的相关性：准确的量化 了解控制ASL动态平衡的因素，即呼吸道表面的水合作用，将有助于 阐明人类主要呼吸道疾病的发病机制，如慢性阻塞性肺疾病、慢性阻塞性肺疾病和哮喘，并将 提供对新的治疗机制的见解，以水化呼吸道表面，从而恢复正常 主场防守。

Control of airway surface liquid (ASL) volume is vital for pulmonary defense against inhaled pathogens/toxicants. Deficits in ASL volume produce airways obstruction and airways infection, reflecting the absence of periciliary liquid (PCL) volume and adhesion of dehydrated mucus to airway surfaces. Much is known about the ion transport processes that control transepithelial ion fluxes, but there are little or no data describing how these processes are coordinately regulated to adjust the mass of salt and, hence, water on airway surfaces in the ranges required for health. Studies of patients with genetic lung diseases, e.g., cystic fibrosis, have suggested that regulation of both the CFTR and ENaC channels are vital for this process. More recently, a number of clues have suggested a role for nucleotides (NTs) and nucleosides (NSs) in ASL in regulating the balance between Na+ absorption and Cl- secretion to generate ASL volume homeostasis. Indeed, we hypothesize that 1) ASL [NT+NS]s are so critical for ASL volume regulation that in their absence, airway epithelia revert to a purely Na+-absorbing state and deplete all ASL from airway surfaces; and 2) the volume of ASL is proportional to the rate of ATP release (JATP) onto airway surfaces. To test these hypotheses and generate a comprehensive description of ASL volume homeostasis, we propose three Specific Aims: 1) Aim 1 - measure JATP and extracellular NT+NS metabolism to develop a mathematical model that will integrate ASL NT+NS concentrations with a biophysical model of ion transport to describe the regulation of ASL volume homeostasis; 2) Aim 2 - test in human bronchial epithelial (HBE) cultures the requirement for NTs and NSs in the acute regulation of ASL volume homeostasis and the mechanisms that mediate these regulatory processes; and 3) Aim 3 - test the requirement for NT+NS in controlling ASL volume in mutant mouse models in vivo. Relevance to Public Health: Accurate quantitative knowledge of the factors that control ASL homeostasis, i.e., the 'hydration' of airway surfaces, will aid in elucidation of the pathogenesis of major human airways diseases, e.g., COPD, CF, and asthma, and will provide insights into novel therapeutic mechanisms to hydrate airway surfaces and hence, restore normal host defense.