Chen Delphine L, Huang Howard J, Byers Derek E, Shifren Adrian, Belikoff Bryan, Engle Jacquelyn T, Arentson Elizabeth, Kemp Debra, Phillips Sharon, Scherrer David E, Fujiwara Hideji, Spayd Katherine J, Brooks Frank J, Pierce Richard A, Castro Mario, Isakow Warren
Mallinckrodt Institute of Radiology, Division of Radiological Sciences, Washington University School of Medicine, St. Louis, MO, United States of America.
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, MO, United States of America.
PLoS One. 2018 Feb 7;13(2):e0191783. doi: 10.1371/journal.pone.0191783. eCollection 2018.
Anti-inflammatory drug development efforts for lung disease have been hampered in part by the lack of noninvasive inflammation biomarkers and the limited ability of animal models to predict efficacy in humans. We used 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in a human model of lung inflammation to assess whether pioglitazone, a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, and zileuton, a 5-lipoxygenase inhibitor, reduce lung inflammation.
For this single center, single-blind, placebo-controlled cohort study, we enrolled healthy volunteers sequentially into the following treatment cohorts (N = 6 per cohort): pioglitazone plus placebo, zileuton plus placebo, or dual placebo prior to bronchoscopic endotoxin instillation. 18F-FDG uptake pre- and post-endotoxin was quantified as the Patlak graphical analysis-determined Ki (primary outcome measure). Secondary outcome measures included the mean standard uptake value (SUVmean), post-endotoxin bronchoalveolar lavage (BAL) cell counts and differentials and blood adiponectin and urinary leukotriene E4 (LTE4) levels, determined by enzyme-linked immunosorbent assay, to verify treatment compliance. One- or two-way analysis of variance assessed for differences among cohorts in the outcome measures (expressed as mean ± standard deviation).
Ten females and eight males (29±6 years of age) completed all study procedures except for one volunteer who did not complete the post-endotoxin BAL. Ki and SUVmean increased in all cohorts after endotoxin instillation (Ki increased by 0.0021±0.0019, 0.0023±0.0017, and 0.0024±0.0020 and SUVmean by 0.47±0.14, 0.55±0.15, and 0.54±0.38 in placebo, pioglitazone, and zileuton cohorts, respectively, p<0.001) with no differences among treatment cohorts (p = 0.933). Adiponectin levels increased as expected with pioglitazone treatment but not urinary LTE4 levels as expected with zileuton treatment. BAL cell counts (p = 0.442) and neutrophil percentage (p = 0.773) were similar among the treatment cohorts.
Endotoxin-induced lung inflammation in humans is not responsive to pioglitazone or zileuton, highlighting the challenge in translating anti-inflammatory drug efficacy results from murine models to humans.
ClinicalTrials.gov NCT01174056.
肺部疾病的抗炎药物研发工作在一定程度上受到无创炎症生物标志物的缺乏以及动物模型预测人类疗效能力有限的阻碍。我们在人类肺部炎症模型中使用18F-氟脱氧葡萄糖（18F-FDG）正电子发射断层扫描（PET）来评估吡格列酮（一种过氧化物酶体增殖物激活受体-γ（PPAR-γ）激动剂）和齐留通（一种5-脂氧合酶抑制剂）是否能减轻肺部炎症。
在这项单中心、单盲、安慰剂对照的队列研究中，我们在支气管镜内注入内毒素之前，将健康志愿者依次纳入以下治疗队列（每个队列N = 6）：吡格列酮加安慰剂、齐留通加安慰剂或双重安慰剂。内毒素注入前后的18F-FDG摄取量通过Patlak图形分析确定的Ki进行量化（主要结局指标）。次要结局指标包括平均标准摄取值（SUVmean）、内毒素注入后的支气管肺泡灌洗（BAL）细胞计数及分类，以及通过酶联免疫吸附测定法测定的血液脂联素和尿液白三烯E4（LTE4）水平，以验证治疗依从性。采用单因素或双因素方差分析评估各队列在结局指标上的差异（以均值±标准差表示）。
10名女性和8名男性（29±6岁）完成了所有研究程序，但有一名志愿者未完成内毒素注入后的BAL。内毒素注入后，所有队列的Ki和SUVmean均升高（安慰剂、吡格列酮和齐留通队列中，Ki分别升高0.0021±0.0019、0.0023±0.0017和0.0024±0.0020，SUVmean分别升高0.47±0.14、0.55±0.15和0.54±0.38，p<0.001），各治疗队列之间无差异（p = 0.933）。吡格列酮治疗后脂联素水平如预期升高，但齐留通治疗后尿液LTE4水平未如预期升高。各治疗队列的BAL细胞计数（p = 0.442）和中性粒细胞百分比（p = 0.773）相似。
内毒素诱导的人类肺部炎症对吡格列酮或齐留通无反应，这凸显了将抗炎药物疗效结果从鼠类模型转化至人类的挑战。
ClinicalTrials.gov NCT01174056。
