Chronic Endotoxin Exposure Produces Airflow Obstruction and Lung Dendritic Cell Expansion
Chronic Endotoxin Exposure Produces Airflow Obstruction and Lung Dendritic Cell Expansion
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DOI：
10.1165/rcmb.2011-0447oc
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发表时间：
2012-08-01
影响因子：
6.4
通讯作者：
Baron, Rebecca M.
中科院分区：
文献类型：
--
作者：
Lai, Peggy S.;Fresco, Jennifer M.;Baron, Rebecca M.
对于慢性职业性内毒素暴露导致持续性气流阻塞的机制知之甚少。我们试图分析作为慢性职业性内毒素暴露结果的持续气流阻塞的炎症反应。我们建立了一种每天吸入内毒素5天至8周的小鼠模型。我们分析了生理性肺功能障碍、肺组织学、支气管肺泡灌洗液和总肺匀浆炎性细胞和细胞因子谱以及肺基因表达谱。我们观察到慢性内毒素暴露导致气道高反应性增加。8周后，小鼠表现出支气管肺泡灌洗液和肺中性粒细胞的增加，这与促炎细胞因子的增加相关。炎症细胞亚群的详细分析揭示了树突状细胞（DC）的扩增，特别是促炎性DC，巨噬细胞的百分比降低。基因表达谱分析显示一组基因的上调与DC募集一致，肺组织学显示在8周暴露动物的气道周围炎症聚集体中DC的积累。重复的低剂量LPS吸入，反映了职业暴露，导致气道高反应性，与未能解决促炎反应，倒置的巨噬细胞与DC的比例，以及炎性DC群体的显着上升。这些发现指出了职业性LPS暴露导致气流阻塞的一种新的潜在机制，并提出了治疗发展的分子和细胞靶点。
Little is known about the mechanisms of persistent airflow obstruction that result from chronic occupational endotoxin exposure. We sought to analyze the inflammatory response underlying persistent airflow obstruction as a result of chronic occupational endotoxin exposure. We developed a murine model of daily inhaled endotoxin for periods of 5 days to 8 weeks. We analyzed physiologic lung dysfunction, lung histology, bronchoalveolar lavage fluid and total lung homogenate inflammatory cell and cytokine profiles, and pulmonary gene expression profiles. We observed an increase in airway hyperresponsiveness as a result of chronic endotoxin exposure. After 8 weeks, the mice exhibited an increase in bronchoalveolar lavage and lung neutrophils that correlated with an increase in proinflammatory cytokines. Detailed analyses of inflammatory cell subsets revealed an expansion of dendritic cells (DCs), and in particular, proinflammatory DCs, with a reduced percentage of macrophages. Gene expression profiling revealed the up-regulation of a panel of genes that was consistent with DC recruitment, and lung histology revealed an accumulation of DCs in inflammatory aggregates around the airways in 8-week-exposed animals. Repeated, low-dose LPS inhalation, which mirrors occupational exposure, resulted in airway hyperresponsiveness, associated with a failure to resolve the proinflammatory response, an inverted macrophage to DC ratio, and a significant rise in the inflammatory DC population. These findings point to a novel underlying mechanism of airflow obstruction as a result of occupational LPS exposure, and suggest molecular and cellular targets for therapeutic development.