Patel Naimish R, Cunoosamy Danen M, Fagerås Malin, Taib Ziad, Asimus Sara, Hegelund-Myrbäck Tove, Lundin Sofia, Pardali Katerina, Kurian Nisha, Ersdal Eva, Kristensson Cecilia, Korsback Katarina, Palmér Robert, Brown Mary N, Greenaway Steven, Siew Leonard, Clarke Graham W, Rennard Stephen I, Make Barry J, Wise Robert A, Jansson Paul
Innovative Medicines and Early Development, AstraZeneca, Gothenburg, Sweden.
Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Hospital, Boston, MA.
Int J Chron Obstruct Pulmon Dis. 2018 Mar 27;13:1009-1019. doi: 10.2147/COPD.S150576. eCollection 2018.
p38 mitogen-activated protein kinase (MAPK) plays a central role in the regulation and activation of pro-inflammatory mediators. COPD patients have increased levels of activated p38 MAPK, which correlate with increased lung function impairment, alveolar wall inflammation, and COPD exacerbations.
These studies aimed to assess the effect of p38 inhibition with AZD7624 in healthy volunteers and patients with COPD. The principal hypothesis was that decreasing lung inflammation via inhibition of p38α would reduce exacerbations and improve quality of life for COPD patients at high risk for acute exacerbations.
The p38 isoform most relevant to lung inflammation was assessed using an in situ proximity ligation assay in severe COPD patients and donor controls. Volunteers aged 18-55 years were randomized into the lipopolysaccharide (LPS) challenge study, which investigated the effect of a single dose of AZD7624 vs placebo on inflammatory biomarkers. The Proof of Principle study randomized patients aged 40-85 years with a diagnosis of COPD for >1 year to AZD7624 or placebo to assess the effect of p38 inhibition in decreasing the rate of exacerbations.
The p38 isoform most relevant to lung inflammation was p38α, and AZD7624 specifically inhibited p38α and p38β isoforms in human alveolar macrophages. Thirty volunteers were randomized in the LPS challenge study. AZD7624 reduced the increase from baseline in sputum neutrophils and TNF-α by 56.6% and 85.4%, respectively (<0.001). In the 213 patients randomized into the Proof of Principle study, there was no statistically significant difference between AZD7624 and placebo when comparing the number of days to the first moderate or severe exacerbation or early dropout.
Although p38α is upregulated in the lungs of COPD patients, AZD7624, an isoform-specific inhaled p38 MAPK inhibitor, failed to show any benefit in patients with COPD.
p38丝裂原活化蛋白激酶（MAPK）在促炎介质的调节和激活中起核心作用。慢性阻塞性肺疾病（COPD）患者体内活化的p38 MAPK水平升高，这与肺功能损害加重、肺泡壁炎症及COPD急性加重相关。
这些研究旨在评估AZD7624抑制p38对健康志愿者和COPD患者的影响。主要假设是，通过抑制p38α减轻肺部炎症可减少急性加重风险高的COPD患者的急性加重次数并改善生活质量。
在重度COPD患者和供体对照中，使用原位邻近连接分析法评估与肺部炎症最相关的p38亚型。将18 - 55岁的志愿者随机分组至脂多糖（LPS）激发试验，该试验研究单剂量AZD7624与安慰剂对炎症生物标志物的影响。原理验证试验将诊断为COPD超过1年的40 - 85岁患者随机分为AZD7624组或安慰剂组，以评估抑制p38对降低急性加重率的作用。
与肺部炎症最相关的p38亚型是p38α，AZD7624可特异性抑制人肺泡巨噬细胞中的p38α和p38β亚型。30名志愿者被随机分组至LPS激发试验。AZD7624使痰中性粒细胞和肿瘤坏死因子-α（TNF-α）较基线的升高分别降低了56.6%和85.4%（<0.001）。在随机分组至原理验证试验的213例患者中，比较首次中度或重度急性加重或早期退出的天数时，AZD7624与安慰剂之间无统计学显著差异。
尽管COPD患者肺部的p38α上调，但一种亚型特异性吸入型p38 MAPK抑制剂AZD7624在COPD患者中未显示出任何益处。
