ASL volume and innate defense in CF and COPD Airways

CF 和 COPD 航空公司的 ASL 量和先天防御

• 批准号: 7917251
• 负责人: ROBERT TARRAN
• 金额: $ 48.3万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7917251
• 关键词: ATP phosphohydrolase; Accounting; Acute; Adenosine; Anti-Inflammatory Agents; Anti-inflammatory; Breathing; CLCA2 gene; Cells; Characteristics; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Chronic lung disease; Cigarette; Cystic Fibrosis Transmembrane Conductance Regulator; Defect; Development; Disease; Dose; Epithelial; Epithelial Cells; Event; Exhibits; Exposure to; Failure; Frequencies; Goals; Height; Homeostasis; Host Defense; Human; Impairment; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Inherited; Integration Host Factors; Ion Channel; Ion Transport; Knowledge; Lead; Mainstreaming; Measures; Mechanics; Mediating; Mucins; Mucociliary Clearance; Mucous body substance; Nose; Nucleosides; Pathway interactions; Patients; Physiological; Physiological Adaptation; Physiological Processes; Population; Public Health; Purine Nucleosides; Purine Nucleotides; Regulation; Research; Respiratory Tract Infections; Signal Pathway; Signal Transduction; Site; Surface; System; Testing; Time; Up-Regulation; Viral; Virus Diseases; absorption; airway epithelium; airway inflammation; airway remodeling; airway surface liquid; base; cigarette smoking; computerized data processing; cystic fibrosis airway; cytokine; density; design; effective therapy; extracellular; in vivo; macrophage; neutrophil; novel; pathogen; respiratory; respiratory infection virus; response; shear stress; therapy development; ATP phosphohydrolase; Accounting; Acute; Adenosine; Anti-Inflammatory Agents; Anti-inflammatory; Breathing; CLCA2 gene; Cells; Characteristics; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Chronic lung disease; Cigarette; Cystic Fibrosis Transmembrane Conductance Regulator; Defect; Development; Disease; Dose; Epithelial; Epithelial Cells; Event; Exhibits; Exposure to; Failure; Frequencies; Goals; Height; Homeostasis; Host Defense; Human; Impairment; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Inherited; Integration Host Factors; Ion Channel; Ion Transport; Knowledge; Lead; Mainstreaming; Measures; Mechanics; Mediating; Mucins; Mucociliary Clearance; Mucous body substance; Nose; Nucleosides; Pathway interactions; Patients; Physiological; Physiological Adaptation; Physiological Processes; Population; Public Health; Purine Nucleosides; Purine Nucleotides; Regulation; Research; Respiratory Tract Infections; Signal Pathway; Signal Transduction; Site; Surface; System; Testing; Time; Up-Regulation; Viral; Virus Diseases; absorption; airway epithelium; airway inflammation; airway remodeling; airway surface liquid; base; cigarette smoking; computerized data processing; cystic fibrosis airway; cytokine; density; design; effective therapy; extracellular; in vivo; macrophage; neutrophil; novel; pathogen; respiratory; respiratory infection virus; response; shear stress; therapy development

Mucus plugs form in the airway lumens of CF and COPD patients, raising the likelihood that ion transport and mucin secretion have become uncoupled. We have previously shown that the height (volume) of normal (NL) airway surface liquid (ASL) is regulated, and that dysregulation of CF airway ion transport due to a lack of CFTR causes ASL volume depletion and cessation of mucus transport. This defect is predicted to impair the mucus component of the innate host defense, leading to increased frequency of respiratory infections. The underlying mechanisms of ASL regulation and the relevance to CF and COPD are unknown. Our long term goal is to understand how ASL volume is autoregulated in normal as compared to diseased (CF and COPD) airways under physiological conditions, and in response to acute challenges such as cigarette smoke, inflammation and respiratory viral infections. We have previously observed that extracellular purine nucleoside (adenosine)-dependent pathways for ASL volume autoregulation are present in normal but not CF airways. However, when cultured with a novel system that mimics the shear stresses associated with normal tidal breathing in vivo, CF cultures exhibit ASL volume homeostasis and maintain mucus transport mediated by shear stress-dependent extracellular purine nucleotide (ATP) release. Superimposed on the acute regulation of ASL volume by ATP and ADO are chronic effects of cytokines/inflammatory mediators through regulation of ion channel density and signaling pathways. CF airways are uniquely vulnerable to viral (RSV) infections deplete ASL volume via upregulation of extracellular ATPases causing reduction of ASL ATP levels. Cigarette smoke exposure also inhibits CFTR and ADO-regulated ASL volume regulation. Based on these observations, we propose that an initiating event in the development of COPD and CF is a failure of ion transport to regulate ASL volume, resulting in the accumulation of poorly cleared mucus plaques/plugs on airway surfaces. These plaques/plugs then act as the primary site of pathogen infections, impair macrophage/neutrophil influx and ultimately lead to the airway remodeling that is characteristic of CF airway disease and COPD. Elucidation of the basic mechanisms that account for the major inherited (CF) and acquired (COPD) forms of chronic inflammatory airways disease is vital for the public health of the US population. Such knowledge will likely lead to the development of novel, uniquely effective therapies for these diseases.

CF和COPD患者的气道口腔中形成粘液塞，这增加了离子传输的可能性 和粘蛋白分泌已经没有偶联。我们以前已经表明了正常的高度（体积） （NL）气道表面液体（ASL）受到调节，并且由于缺乏CF气道离子运输的失调 CFTR引起的ASL体积耗竭和粘液转运的停止。该缺陷被预测 损害先天宿主防御的粘液成分，导致呼吸的频率增加 感染。 ASL调节的基本机制以及与CF和COPD的相关性尚不清楚。 我们的长期目标是了解与患病相比的ASL量如何正常进行自动调节 （CF和COPD）在生理条件下航空公司，并应对急性挑战 香烟烟雾，炎症和呼吸道病毒感染。我们以前已经观察到细胞外 嘌呤核苷（腺苷）依赖于ASL体积自动调节的途径在正常情况下，但 不是CF气道。但是，当用一种模拟与之相关的剪切应力的新型系统培养时 正常的潮汐呼吸在体内，CF培养物表现出ASL体积稳态并保持粘液转运 由剪切应力依赖性细胞外嘌呤核苷酸（ATP）释放介导。叠加在 ATP和ADO对ASL体积的急性调节是细胞因子/炎症介质的慢性作用 通过调节离子通道密度和信号通路。 CF航空公司非常容易受到病毒的影响 （RSV）感染通过上调细胞外ATPases耗尽ASL体积，导致ASL减少 ATP级别。香烟烟雾的暴露还抑制了CFTR和ADO调节的ASL体积调节。基于 在这些观察结果上，我们建议在COPD和CF开发中发生的启动事件是失败的 离子传输以调节ASL体积，从而导致粘液斑块/塞的积累 在气道表面上。然后，这些斑块/塞子充当病原体感染的主要部位，损害 巨噬细胞/中性粒细胞涌入，并最终导致CF气道特征的气道重塑 疾病和COPD。阐明说明主要遗传（CF）的基本机制和 获得的（COPD）形式的慢性炎症性气道疾病对美国的公共卫生至关重要 人口。这样的知识可能会导致新颖，独特的有效疗法的发展 这些疾病。