Low-dose endotoxin inhalation in healthy volunteers - a challenge model for early clinical drug development
Low-dose endotoxin inhalation in healthy volunteers - a challenge model for early clinical drug development
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DOI：
10.1186/1471-2466-13-19
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发表时间：
2013-03-28
影响因子：
3.1
通讯作者：
Hohlfeld, Jens M.
中科院分区：
文献类型：
--
作者：
Janssen, Ole;Schaumann, Frank;Hohlfeld, Jens M.
背景：吸入内毒素(LPS)可诱导以中性粒细胞为主的呼吸道炎症，已被用作测试新药抗炎活性的模型。在过去，一般需要超过15-50微克的剂量才能诱导足够的炎症反应。对于人体研究，一些国家的监管机构现在要求使用GMP级脂多糖，但这种药物的供应有限。因此，这项研究的目的是测试使用流量和容量控制吸入技术来增加内毒素沉积的小剂量内毒素攻击(20000 Eu；2 mU)的效果和重复性。方法：在基线诱导痰后2-4周，12名不吸烟的健康志愿者三次吸入内毒素，间隔至少4周。为了调节内毒素的炎症效应，在最后一次挑战之前，进行了为期5天的PDE4抑制剂(罗氟司特)治疗。结果：小剂量LPS吸入耐受性良好，平均痰中性粒细胞百分率由25%提高到72%。第二次激发后，中性粒细胞占62%，单核细胞百分率增加。与基线相比，脂多糖诱导的中性粒细胞内流和累积的炎症反应是可重复性的。罗氟司特治疗5d对痰成分无明显影响。结论：健康受试者吸入2mgGMP级脂多糖足以引起明显的中性粒细胞呼吸道炎症。反复低剂量的脂多糖挑战可能会导致中性粒细胞/单核细胞比率的微小变化；然而，累积反应是可重复性的，使该模型能够在早期药物开发期间用于抗炎化合物的“概念验证”研究。
Background: Inhalation of endotoxin (LPS) induces a predominantly neutrophilic airway inflammation and has been used as model to test the anti-inflammatory activity of novel drugs. In the past, a dose exceeding 15-50 mu g was generally needed to induce a sufficient inflammatory response. For human studies, regulatory authorities in some countries now request the use of GMP-grade LPS, which is of limited availability. It was therefore the aim of this study to test the effect and reproducibility of a low-dose LPS challenge (20,000 E. U.; 2 mu g) using a flow-and volume-controlled inhalation technique to increase LPS deposition.Methods: Two to four weeks after a baseline sputum induction, 12 non-smoking healthy volunteers inhaled LPS on three occasions, separated by at least 4 weeks. To modulate the inflammatory effect of LPS, a 5-day PDE4 inhibitor (Roflumilast) treatment preceded the last challenge. Six hours after each LPS inhalation, sputum induction was performed.Results: The low-dose LPS inhalation was well tolerated and increased the mean percentage of sputum neutrophils from 25% to 72%. After the second LPS challenge, 62% neutrophils and an increased percentage of monocytes were observed. The LPS induced influx of neutrophils and the cumulative inflammatory response compared with baseline were reproducible. Treatment with Roflumilast for 5 days did not have a significant effect on sputum composition.Conclusion: The controlled inhalation of 2 mu g GMP-grade LPS is sufficient to induce a significant neutrophilic airway inflammation in healthy volunteers. Repeated low-dose LPS challenges potentially result in a small shift of the neutrophil/monocyte ratio; however, the cumulative response is reproducible, enabling the use of this model for "proof-of-concept" studies for anti-inflammatory compounds during early drug development.