Novel Treatments to Prevent COPD Progression

对改变慢性阻塞性肺疾病进展的治疗的评估受到以下要求的限制 大量参与者和长时间的随访间隔以确定疗效。传统的成果是 文献记载COPD的进展是肺功能下降或死亡率下降。大鼠的动物模型 肺气肿和慢性阻塞性肺病对于剖析慢性阻塞性肺疾病的发病机制很有用，但还没有。 作为测试潜在疾病改良剂的平台而开发。在这个项目中，我们计划测试两个 有望延缓慢性阻塞性肺疾病进展的药物：免疫调节剂阿奇霉素 大环内酯类抗生素和血管紧张素受体阻滞剂氯沙坦。初步证据在人类和 动物实验表明，这两种药物有效地阻断了癌症进展过程中的重要途径。 慢性阻塞性肺疾病（慢阻肺）。W计划在180名患者中进行一项三组安慰剂对照概念验证临床试验 慢性阻塞性肺疾病患者每周三次服用阿奇霉素250毫克，每日服用氯沙坦50毫克，或服用安慰剂。初级阶段 结果指标为肺气肿的解剖肺重塑指标和定量指标 HRCT测量气道壁的大小。次要结果将是一组系统性和系统性的生物标志物 呼吸道炎症和氧化应激。临床相关的结果将包括肺功能和 呼吸道症状。新的成果包括使用超极化技术测量空域尺寸 氦核磁共振成像和肺泡灌洗细胞天然免疫反应性的测量。 同时，我们将在两个易感菌株中测试这些治疗方法的平行结果。 暴露在香烟烟雾中的小鼠进一步了解哪些分子途径参与其中。特别是， 我们将重点研究转化生长因子-β作为烟雾暴露小鼠肺重塑的中枢调节因子的作用。 疾病进展的测量将通过组织形态计量学和超极化氦进行。 核磁共振检查。其他结果指标包括肺和全身细胞因子、趋化因子、生长因子的活动， 氧化应激和细胞凋亡的指标。将进行研究以确定这些候选药物是否 如果与吸烟同时服用，或在吸烟后服用有效，可有效地减缓疾病的进展 吸烟伤害已经发生，接触已经停止.. 本项目的总体目标是提供有关有效性、可靠性和实用性的信息。 COPD临床研究中的中间终点和生物标志物以及动物模型在诊断中的价值 测试可以改变慢性阻塞性肺疾病进展的治疗方法。

Evaluation of treatments that modify the progression of COPD have been limited by the requirement for large numbers of participants and long follow-up intervals to establish efficacy. The traditional outcomes to document progression of COPD have been decline of lung function or mortality. Animal models of emphysema and COPD have been useful to dissect pathwaysfor COPD pathogenesis, but have not been developed as platforms for testing potential disease-modifying agents. In this project, we plan to test two promising treatments that may modify the progression of COPD: azithromycin, an immunomodulatory macrolide antibiotic, and losartan, an angiotensin receptor blocker. Preliminary evidence in humans and animals shows that these two drugs are effective in blocking pathways important in the progression of COPD. W plan to conduct a three-group placebo-controlled proof-of-concept clinical trial in 180 people with COPD assigned to azithromycin 250 mg thrice weekly., losartan 50 mg daily, or placebo. The primary outcome measures are indicators of anatomic lung remodeling quantitative measures of emphysema and airway wall dimensions by HRCT. Secondary outcomes will be a panel of biomarkers of systemic and respiratory inflammation and oxidative stress. Clinically relevant outcomes will include lung function and respiratory symptoms. Novel outcomes include measurement of airspace dimension using hyperpolarized helium MR imaging, and measures of innate immune responsivity of alveolar lavage cells. Concurrently, we will test these treatments using parallel outcomes in two strains of susceptible cigarette-smoke exposed mice to further understand which molecular pathways are involved. In particular, we will focus on the role of TGF-beta as a central regulator of lung remodeling in smoke-exposed mice. Measurements of disease progression will be made by histologic morphometry and hyper-polarized helium MRI. Other outcome measures include lung and systemic activity of cytokines, chemokines, growth factors, indicators of oxidative stress and apoptosis. Studies will be done to determine if these candidate drugs are effective in reducing progression of disease if given concurrently with smoking, or are effective after smoking injury has occurred and exposure has ceased.. The overall goal of this project is to provide information on the validity, reliability, and utility of intermediate endpoints and biomarkers in COPD clinical research and the value of animal models for testing treatments that can modify the progression of COPD.