ASL volume and innate defense in CF and COPD Airways

CF和COPD患者的气道腔内形成粘液栓，增加了离子转运的可能性， 和粘蛋白分泌已经分离。我们以前已经表明，正常的高度（体积） (NL)气道表面液体（ASL）受到调节，CF气道离子转运由于缺乏 CFTR的释放会导致ASL容量耗尽和粘液运输停止。预计该缺陷将 损害固有宿主防御的粘液成分，导致呼吸频率增加 感染. ASL调节的潜在机制以及与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，正常情况下ASL体积是如何自动调节的 (CF和COPD）气道，以及响应急性挑战， 吸烟、炎症和呼吸道病毒感染。我们以前观察到细胞外 ASL容量自动调节的嘌呤核苷（腺苷）依赖性途径存在于正常但 不是CF航空然而，当用一种新的系统培养时， 在体内正常的潮气呼吸，CF培养物表现出ASL体积稳态并维持粘液转运 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容量的急性调节是细胞因子/炎症介质的慢性效应 通过调节离子通道密度和信号传导途径。CF航空公司是唯一容易受到病毒 (RSV)感染通过上调细胞外ATP酶消耗ASL体积，导致ASL减少 ATP水平。香烟烟雾暴露还抑制CFTR和ADO调节的ASL体积调节。基于 根据这些观察，我们认为COPD和CF发展的起始事件是治疗失败， 调节ASL体积的离子转运，导致清除不良的粘液斑块/栓的积聚 在气道表面。然后，这些斑块/栓塞充当病原体感染的主要部位，损害 巨噬细胞/中性粒细胞流入并最终导致CF气道特征性的气道重塑 疾病和COPD。阐明主要遗传（CF）和 获得性（COPD）形式的慢性炎症性气道疾病对美国的公共健康至关重要 人口这些知识将可能导致开发新的，独特有效的治疗方法， 这些疾病。

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.