ASL volume and innate defense in CF and COPD Airways

慢性阻塞性肺疾病和慢性阻塞性肺疾病患者的气道腔内形成粘液塞，增加了离子转运的可能性 和粘蛋白的分泌已经变得不耦合。我们之前已经证明，正常的高度(体积) (NL)呼吸道表面液体(ASL)受到调节，由于缺乏CF气道离子转运的失调 CFTR的表达可导致ASL容量耗竭和粘液转运停止。这一缺陷被预测为 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慢性阻塞性肺疾病和慢性阻塞性肺疾病的相关性尚不清楚。 我们的长期目标是了解与疾病相比，ASL在正常情况下是如何自动调节的 (慢性阻塞性肺疾病和慢性阻塞性肺病)在生理条件下的呼吸道，并应对以下严重挑战 香烟烟雾、炎症和呼吸道病毒感染。我们之前已经观察到细胞外 依赖嘌呤核苷(腺苷)的ASL容量自动调节通路在正常BUT中存在 而不是CF航空公司。然而，当用一种新的系统培养时，这种系统模仿与 活体内正常潮气呼吸，CF培养显示ASL容量动态平衡并维持粘液运输 由剪切力依赖的胞外嘌呤核苷酸(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/炎症介质的慢性效应 通过调节离子通道密度和信号通路。Cf航空公司特别容易受到病毒的影响 呼吸道合胞病毒(RSV)感染通过细胞外ATPase上调导致ASL减少，从而耗尽ASL容量 三磷酸腺苷水平。香烟烟雾暴露还抑制CFTR和ADO调节的ASL容量调节。基座 根据这些观察，我们认为COPD和CF发展过程中的一个初始事件是 调节ASL体积的离子转运，导致清除不良的粘液斑块/塞子的堆积 在呼吸道表面。这些斑块/栓子然后作为病原体感染的主要部位，损害 巨噬细胞/中性粒细胞进入并最终导致以CF为特征的气道重塑 疾病和慢性阻塞性肺病。阐明导致主要遗传性(CF)和 获得性(COPD)形式的慢性炎症性呼吸道疾病对美国公共健康至关重要 人口。这些知识可能会导致开发出新的、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.