Novel Murine Model of Chronic Granulomatous Lung Inflammation Elicited by Carbon Nanotubes
Novel Murine Model of Chronic Granulomatous Lung Inflammation Elicited by Carbon Nanotubes
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DOI：
10.1165/rcmb.2010-0401oc
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发表时间：
2011-10-01
影响因子：
6.4
通讯作者：
Thomassen, Mary Jane
中科院分区：
文献类型：
--
作者：
Huizar, Isham;Malur, Anagha;Thomassen, Mary Jane
肺肉芽肿与多种情况有关，包括炎症障碍、暴露于环境污染物和感染。骨桥蛋白是一种由巨噬细胞产生的趋化细胞因子，与细胞外基质重塑有关。此外，骨桥蛋白在肉芽肿性疾病中表达上调，骨桥蛋白缺失的小鼠表现出肉芽肿形成的减少。目前用于研究慢性肺肉芽肿性炎症的动物模型具有病理学上的相似性，但缺乏人类肉芽肿性疾病的慢性本质。碳纳米颗粒是燃烧的副产品。有趣的是，实验性暴露于碳纳米颗粒会导致肺肉芽肿样病变。然而，这些病变内招募的细胞群体和细胞外基质基因表达谱尚未被探索。由于在目前的动物模型中肉芽肿迅速消退，导致持久性的机制一直难以捉摸。为了克服以前模型的局限性，我们调查了使用多壁碳纳米颗粒的模型是否会类似于人类慢性肺肉芽肿性炎症。我们假设，肺暴露于多壁碳纳米颗粒会导致肉芽肿，引发巨噬细胞和T细胞反应，并通过上调骨桥蛋白来模拟其他肉芽肿疾病。该模型显示：(1)肉芽肿性炎症，伴有巨噬细胞和T细胞的渗透；(2)与人类肉芽肿的慢性相似，可持续90天；(3)激光捕获显微解剖分离的肉芽肿灶和支气管肺泡灌洗液中的肺泡巨噬细胞中，骨桥蛋白、金属蛋白酶和细胞黏附分子显著升高。该模型的建立为肉芽肿持续性的机制研究提供了重要的平台。
Lung granulomas are associated with numerous conditions, including inflammatory disorders, exposure to environmental pollutants, and infection. Osteopontin is a chemotactic cytokine produced by macrophages, and is implicated in extracellular matrix remodeling. Furthermore, osteopontin is up-regulated in granulomatous disease, and osteopontin null mice exhibit reduced granuloma formation. Animal models currently used to investigate chronic lung granulomatous inflammation bear a pathological resemblance, but lack the chronic nature of human granulomatous disease. Carbon nanoparticles are generated as byproducts of combustion. Interestingly, experimental exposures to carbon nanoparticles induce pulmonary granuloma-like lesions. However, the recruited cellular populations and extracellular matrix gene expression profiles within these lesions have not been explored. Because of the rapid resolution of granulomas in current animal models, the mechanisms responsible for persistence have been elusive. To overcome the limitations of previous models, we investigated whether a model using multiwall carbon nanoparticles would resemble chronic human lung granulomatous inflammation. We hypothesized that pulmonary exposure to multiwall carbon nanoparticles would induce granulomas, elicit a macrophage and T-cell response, and mimic other granulomatous disorders with an up-regulation of osteopontin. This model demonstrates: (1) granulomatous inflammation, with macrophage and T-cell infiltration; (2) resemblance to the chronicity of human granulomas, with persistence up to 90 days; and (3) a marked elevation of osteopontin, metalloproteinases, and cell adhesion molecules in granulomatous foci isolated by laser-capture microdissection and in alveolar macrophages from bronchoalveolar lavage. The establishment of such a model provides an important platform for mechanistic studies on the persistence of granuloma.