Effect of Losartan on Progression of Emphysema

 描述(申请人提供)：慢性阻塞性肺疾病(COPD)是美国死亡和残疾的主要原因。目前的治疗方法针对支气管痉挛和呼吸道炎症，目的是减轻症状和防止病情恶化。然而，除了戒烟之外，还没有发现任何治疗方法可以改变这种疾病的进展。此外，COPD是一种异质性疾病，涉及肺实质(肺气肿)和呼吸道(慢性支气管炎)的重塑。对暴露在香烟烟雾中的小鼠的研究表明，转化生长因子-β信号是导致肺气肿的细胞凋亡的中介。用氯沙坦等药物阻断血管紧张素-1(AT1)受体可以防止肺气肿的发展。在慢性阻塞性肺疾病患者中使用氯沙坦的初步研究没有显示总体改善，但与安慰剂组患者相比，具有肺气肿表型的患者在1年内没有出现肺气肿进展，后者增加了肺气肿占肺的百分比。这些结果没有达到统计学意义(p=0.06)，但强烈暗示对患有肺气肿的COPD患者有好处。这项建议的目的是进行一项明确的随机、安慰剂对照的临床试验，以测试与服用安慰剂的可比个体相比，对有肺气肿放射证据的患者每天服用100毫克的氯沙坦是否会减缓他们的疾病进展。肺气肿的进展将通过使用标准化程序的高分辨率计算机断层扫描来测量。这项试验是一项高度集中的务实试验，数据收集稀疏，可在社区和学术环境中完成。

 DESCRIPTION (provided by applicant): Chronic Obstructive Pulmonary Disease (COPD) is a major cause of death and disability in the United States. Current treatments target bronchospasm and inflammation of airways with the goal to reduce symptoms and prevent exacerbations. However, other than smoking cessation, no treatment has been found that modifies the progression of this disease. Moreover, COPD is a heterogeneous disease involving remodeling of both lung parenchyma (emphysema) and airways (chronic bronchitis). Research in mice exposed to cigarette smoke implicates TGF-beta signaling as a mediator of apoptosis that leads to emphysema. The development of emphysema can be prevented by blockade of the angiotensin-1 (AT1) receptor with drugs such as losartan. A pilot study of losartan in patients with COPD showed no overall improvement, but patients who had the emphysema phenotype demonstrated no progression of emphysema at 1 year compared to placebo treated patients who increased the percent of lung occupied by emphysema. These results did not reach statistical significance (p = 0.06) but were strongly suggestive of a benefit in COPD patients with emphysema. The aim of this proposal is to conduct a definitive randomized, placebo-controlled, clinical trial to test whether administration of 100mg/day of losartan to patients with radiographic evidence of emphysema will slow progression of their disease compared to comparable individuals given placebo. Emphysema progression will be measured by high-resolution computed tomography using standardized procedures. The trial is designed to be a highly-focused pragmatic trial with sparse data collection that can be accomplished in community as well as academic settings.