Targeting Defective Mucus Clearance in COPD

黏膜纤毛清除功能缺陷（MCC）是常见肺部疾病发病机制的核心，包括 COPD/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。在每个 例如，有缺陷的MCC导致肺部感染和炎性损伤的发展。我们长久以来- 长期目标是深入了解MCC在健康和疾病方面的作用， 支持和/或恢复患有这些疾病的患者的MCC的疗法。在拟议项目中，我们将 探索三种不同治疗类别的可用药物对实际测量的影响， 慢性支气管炎表型COPD患者的粘膜纤毛和咳嗽清除。所选 治疗活性包括渗透性水合剂（7%NaCl;高渗盐水），“去污剂”（lucinactant; KL 4表面活性剂）和上皮钠通道阻断剂（PS-552）。新的交付方式也正在 在HS和Lucinactant的研究中进行了测试。MCC测量将用于表征急性 效果（给药后1小时）和该效果持续4小时。对于高渗盐水 (HS)（目的1）和PS-552加HS的联合治疗（目的4），对MCC的持续作用（12小时） 将在给药2周后进行检测。此外，一组新的生物标志物，报告的活动， 这些疗法将用于更好地理解观察到的治疗效果。这些新的生物标志物可能 最终证明在将来类似药物的更大临床研究中也是有用的。 最后，将使用呼出气体来表征Lucinactant和PS-552的“气道表面”药代动力学。 呼吸冷凝物收集和质谱分析。如果得到证实，这些数据将帮助我们评估剂量- 我们在人类中测量的反应关系，将使我们能够直接比较体外和 在附带项目和核心中进行的动物研究。与其他项目和 在这个tPPG的核心，我们预计，这些拟议的研究将显着推进我们对新的 COPD的治疗策略 相关性（参见说明）： COPD影响超过1400万美国人，是第三大死亡原因。基于我们 根据囊性纤维化的经验，恢复MC的治疗预计将显著降低 肺恶化，这反过来又是疾病进展、生活质量和 相关的医疗费用。如果成功的话，我们提出的治疗模式可能会对 COPD及相关疾病的治疗方法。

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. RELEVANCE (See instructions): COPD affects more than 14 million Americans, and is the 3rd leading cause of death. Based on our experience in cystic fibrosis, therapies that restore MC are expected to significantly reduce the frequency of pulmonary exacerbations, which in turn are major determinants of disease progression, quality of life, and associated healthcare costs. If successful, our proposed treatment paradigms may have a major impact on the way that COPD and related disorders are treated.