武汉云克隆科技股份有限公司

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.

摘要：

背景：

罗氟司特是一种治疗慢性阻塞性肺疾病(COPD)的药物，具有抗炎作用，但它是否影响COPD发病机制及疾病发展相关的生物途径尚未知晓。乙酰脯氨酸-甘氨酸-脯氨酸(AcPGP)途径是慢性阻塞性肺病(COPD)发病过程中一种新的中性粒细胞炎症反应途径。AcPGP是由细胞外基质胶原蛋白分解而成的，丙醇内肽酶和白三烯A4水解酶分别作为其产生和降解的酶。

目的：

我们假设罗氟司特通过阻断AcPGP途径来阻止炎症的前馈循环。

方法：

我们进行了一项单中心、安慰剂对照的随机实验。研究了重度慢性支气管炎的COPD患者使用罗氟司特治疗12周的情况。受试者分别在0、4和12周时进行痰和血液分析、肺功能测试、运动耐受性以及生活质量评估。

结果：

27例患者参加意向性治疗分析。罗氟米拉治疗组的AcPGP减少50%(P < 0.01)以上，脯氨酰内肽酶增加46%(P=0.02)。与安慰剂组相比，白三烯A4水解酶活性未发生显著变化，同时研究发现罗氟司特使其他炎症标志物减少。但是罗氟司特组与安慰剂组在肺功能、生活质量和运动耐受性方面未发生显著变化。

结论：

罗氟米拉司特通过降低脯氨酰内肽酶活性和AcPGP来减轻肺部炎症。当AcPGP水平较低时，中性粒细胞炎症的标志减弱。通过这种抑制自我繁殖途径可以减轻总体炎症负担，这可能会改变慢性阻塞性肺病的病情发展，但是也存在恶化的风险。

使用试剂原文信息：LTA 4 H (Uscn), LTB 4 (R&D Systems), IL-8 (CXCL8/IL-8 Quantikine kit, R&D Systems), and MPO (CalBiochem) were detected in induced sputum by commercially available enzyme immunoassays (17, 34, 35).