Inhalation of LPS induces inflammatory airway responses mimicking characteristics of chronic obstructive pulmonary disease
Inhalation of LPS induces inflammatory airway responses mimicking characteristics of chronic obstructive pulmonary disease
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DOI：
10.1111/j.1475-097x.2011.01058.x
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发表时间：
2012-01-01
影响因子：
1.8
通讯作者：
Greiff, Lennart
中科院分区：
文献类型：
--
作者：
Korsgren, Magnus;Linden, Margareta;Greiff, Lennart
目的：吸入脂多糖（LPS）可引起全身和肺部炎症反应。本研究的目的是进一步表征对LPS的反应，以便开发适合用于治疗慢性阻塞性肺疾病（COPD）的候选药物的早期测试的人体模型。材料：分别于吸入生理盐水和LPS（5、50 μ g）后4、24、48 h取血和诱导痰。分析血液中的c反应蛋白（CRP）、α(1)-抗胰蛋白酶和中性粒细胞/白细胞，分析痰中中性粒细胞炎症和重塑活性的生物标志物，即中性粒细胞弹性蛋白酶（NE）蛋白/活性和α(1)-抗胰蛋白酶。测定血液和痰中肿瘤坏死因子α (TNF α)的水平。激发后0-24和24-48小时收集尿液，测量弹性蛋白降解的生物标志物-去氨酶。结果：脂多糖吸入引起剂量依赖性流感样症状，血浆CRP和α(1)-抗胰蛋白酶增加，以及血液中性粒细胞/白细胞数量增加。此外，LPS使痰中TNF α和NE活性增加。尿中氨基葡萄糖水平不受LPS刺激的影响。所有受试者均在48 h后恢复，且该观测点的炎症活性指标较24 h后明显降低。结论：健康志愿者吸入LPS可作为安全稳定的中性粒细胞炎症模型。血/血浆和痰指标可用于监测LPS的反应。我们建议该模型可用于新型copd活性药物的初步人体研究。
Aim: Inhalation of lipopolysaccharide (LPS) produces both systemic and pulmonary inflammatory responses. The aim of this study was to further characterize the response to LPS in order to develop a human model suitable for early testing of drug candidates developed for the treatment for chronic obstructive pulmonary disease (COPD).Materials: Blood and induced sputum were obtained 4, 24 and 48 h following inhalation of saline and LPS (5 and 50 mu g). Blood was analysed for C-reactive protein (CRP), alpha(1)-antitrypsin and neutrophils/leucocytes, and sputum was analysed for biomarkers of neutrophil inflammation and remodelling activities, i.e. neutrophil elastase (NE) protein/activity and alpha(1)-antitrypsin. Levels of tumour necrosis factor-alpha (TNF alpha) were measured in both blood and sputum. Urine was collected 0-24 and 24-48 h postchallenge, and desmosine, a biomarker of elastin degradation, was measured.Results: Lipopolysaccharide inhalation induced dose-dependent flu-like symptoms and increases in plasma CRP and alpha(1)-antitrypsin as well as increases in blood neutrophil/leucocyte numbers. Furthermore, LPS produced increases in sputum TNF alpha and sputum NE activity. Urine levels of desmosine were unaffected by the LPS challenge. All subjects recovered 48 h postchallenge, and indices of inflammatory activity were significantly lower at this observation point cf 24 h postchallenge.Conclusion: Inhalation of LPS in healthy volunteers can be used as a safe and stable model of neutrophil inflammation. Blood/plasma and sputum indices can be employed to monitor the response to LPS. We suggest that this model may be used for initial human studies of novel COPD-active drugs.