Effect of Losartan on Progression of Emphysema

 描述（由申请人提供）：慢性阻塞性肺疾病（COPD）是美国死亡和残疾的主要原因。目前的治疗目标是支气管痉挛和气道炎症，目的是减轻症状和预防恶化。然而，除了戒烟，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）和气道（慢性支气管炎）的重塑。对暴露于香烟烟雾中的小鼠的研究表明，TGF-β信号转导是导致肺气肿的细胞凋亡的介导者。肺气肿的发展可以通过用药物如氯沙坦阻断血管紧张素-1（AT 1）受体来预防。在COPD患者中进行的一项氯沙坦初步研究显示没有总体改善，但与安慰剂治疗的患者相比，具有肺气肿表型的患者在1年时没有肺气肿进展，安慰剂治疗的患者增加了肺气肿占据的百分比。这些结果未达到统计学显著性（p = 0.06），但强烈提示COPD合并肺气肿患者获益。该提案的目的是进行一项明确的随机、安慰剂对照临床试验，以测试与给予安慰剂的可比个体相比，给予放射学证据显示肺气肿的患者100 mg/天氯沙坦是否会减缓其疾病进展。将使用标准化程序通过高分辨率计算机断层扫描测量肺气肿进展。该试验旨在成为一项高度集中的务实试验，数据收集稀疏，可以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.