当前位置： SCI文献检索 > AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE期刊下所有文献 > A Randomized, Placebo-controlled Trial of Roflumilast. Effect on Proline-Glycine-Proline and Neutrophilic Inflammation in Chronic Obstructive Pulmonary Disease.

A Randomized, Placebo-controlled Trial of Roflumilast. Effect on Proline-Glycine-Proline and Neutrophilic Inflammation in Chronic Obstructive Pulmonary Disease.

Abstract：

RATIONALE:Roflumilast is a therapeutic agent in the treatment of chronic obstructive pulmonary disease (COPD). It has antiinflammatory effects; however, it is not known whether it can affect a biologic pathway implicated in COPD pathogenesis and progression. The self-propagating acetyl-proline-glycine-proline (AcPGP) pathway is a novel means of neutrophilic inflammation that is pathologic in the development of COPD. AcPGP is produced by extracellular matrix collagen breakdown with prolyl endopeptidase and leukotriene A4 hydrolase serving as the enzymes responsible for its production and degradation, respectively. OBJECTIVES:We hypothesized that roflumilast would decrease AcPGP, halting the feed-forward cycle of inflammation. METHODS:We conducted a single-center, placebo-controlled, randomized study investigating 12 weeks of roflumilast treatment added to current therapy in moderate-to-severe COPD with chronic bronchitis. Subjects underwent sputum and blood analyses, pulmonary function testing, exercise tolerance, and quality-of-life assessment at 0, 4, and 12 weeks. MEASUREMENTS AND MAIN RESULTS:Twenty-seven patients were enrolled in the intention-to-treat analysis. Roflumilast treatment decreased sputum AcPGP by more than 50% (P < 0.01) and prolyl endopeptidase by 46% (P = 0.02), without significant improvement in leukotriene A4 hydrolase activity compared with placebo. Roflumilast also reduces other inflammatory markers. There were no significant changes in lung function, quality of life, or exercise tolerance between roflumilast- and placebo-treated groups. CONCLUSIONS:Roflumilast reduces pulmonary inflammation through decreasing prolyl endopeptidase activity and AcPGP. As expected for lower AcPGP levels, markers of neutrophilic inflammation are blunted. Inhibiting this self-propagating pathway lessens the overall inflammatory burden, which may alter the natural history of COPD, including the risk of exacerbation. Clinical trial registered with www.clinicaltrials.gov (NCT 01572948).

journal_name

Am J Respir Crit Care Med

journal_title

American journal of respiratory and critical care medicine

authors

Wells JM,Jackson PL,Viera L,Bhatt SP,Gautney J,Handley G,King RW,Xu X,Gaggar A,Bailey WC,Dransfield MT,Blalock JE

doi

10.1164/rccm.201503-0543OC

subject

Has Abstract

pub_date

2015-10-15 00:00:00

pages

934-42

issue

eissn

1073-449X

issn

1535-4970

journal_volume

192

pub_type

杂志文章,随机对照试验

在线工具

A Randomized, Placebo-controlled Trial of Roflumilast. Effect on Proline-Glycine-Proline and Neutrophilic Inflammation in Chronic Obstructive Pulmonary Disease.