Targeting Defective Mucus Clearance in COPD

粘液纤毛清除缺陷(MCC)是常见肺部疾病发病机制的核心，包括 慢性阻塞性肺疾病/慢性支气管炎、囊性纤维化、支气管扩张和呼吸机相关性肺炎。在每一个中 例如，MCC缺陷会导致肺部感染和炎症损伤的发展。我们的长- 学期目标是对MCC在健康和疾病方面的深入了解，并开发有效的 支持和/或恢复患有这些疾病的患者的MCC的治疗。在拟议的项目中，我们将 探讨来自三个不同治疗类别的可用制剂对实际测量的影响 慢性阻塞性肺疾病慢性支气管炎患者的粘液纤毛和咳嗽清除。选定的 治疗活动包括渗透水化器(7%NaCI；高渗盐水)、“洗涤剂”(荧光素； KL4表面活性剂)和上皮钠通道阻滞剂(PS-552)。新的交付方式也在不断涌现 在HS和Lucinacant的研究中进行了测试。MCC测量将被用来表征急性 药效(服药后1小时)和持续4小时的效果。在高渗盐水的情况下 (HS)(目标1)和PS-552加HS联合治疗(目标4)，对MCC的持续作用(12小时) 服药2周后将进行测试。此外，一组新的生物标记物报告了 这些疗法将用于更好地了解观察到的治疗效果。这些新的生物标志物可能 最终证明在未来对类似药物进行更大规模的临床研究时也是有用的。 最后，将使用Exhaled来表征Lucinacant和PS-552的“呼吸道表面”药代动力学。 呼吸冷凝液收集和质谱学。如果得到证实，这些数据将帮助我们评估剂量- 我们在人体内测量的反应关系，将使我们能够直接与体外和 在伴随的项目和核心中进行的动物研究。与其他项目和 我们预计，这些拟议的研究将极大地推动我们走向新的 慢阻肺的治疗策略。

Defective mucociliary clearance (MCC) is central to the pathogenesis of prevalent lung diseases, including COPD/chronic bronchitis, cystic fibrosis, bronchiectasis, and ventilator associated pneumonia. In each instance, defective MCC leads to the development of lung infection and inflammatory damage. Our long- term goals are to reach an indepth understanding of MCC in health and disease and to develop effective therapies that support and/or restore MCC in patients with these diseases. In the proposed project, we will explore the effects of available agents from three different therapeutic classes on actual measurements of mucociliary and cough clearance in patients with the chronic bronchitis phenotype of COPD. The selected therapeutic activities include an osmotic hydrator (7% NaCI; hypertonic saline), a "detergent" (lucinactant; KL4 surfactant), and an epithelial sodium channel blocker (PS-552). New delivery methods are also being tested in studies of HS and lucinactant. MCC measurements will be used to characterize both the acute effect (1 hour after dosing) and the durability of this effect through 4 hours. In the case of hypertonic saline (HS) (Aim 1) and combination therapy with PS-552 plus HS (Aim 4), the sustained effect on MCC (12 hours) after 2 weeks of dosing will be tested. In addition, a panel of novel biomarkers that report on the activities of these therapies will be used to better understand observed treatment effects. These novel biomarkers may ultimately prove to be useful in the conduct of larger clinical studies of similar agents in the future as well. Finally, the "airway surface" pharmacokinetics of lucinactant and PS-552 will be characterized using exhaled breath condensate collections and mass spectroscopy. If validated, these data will help us evaluate dose- response relationships we measure in humans, and will allow us to make direct comparisons to in vitro and animal studies performed in the accompanying projects and cores. In concert with the other Projects and Cores in this tPPG, we anticipate that these proposed studies will significantly advance us toward new treatment strategies for COPD.