Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Brody School of Medicine, East Carolina University, 3E-149 Brody Medical Sciences Building, Greenville, NC 27834, USA.
Am J Respir Cell Mol Biol. 2011 Oct;45(4):858-66. doi: 10.1165/rcmb.2010-0401OC. Epub 2011 Mar 11.
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.
肺肉芽肿与许多疾病相关，包括炎症性疾病、暴露于环境污染物和感染。骨桥蛋白是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上调，骨桥蛋白缺失小鼠表现出肉芽肿形成减少。目前用于研究慢性肺部肉芽肿性炎症的动物模型在病理上具有相似性，但缺乏人类肉芽肿性疾病的慢性性质。碳纳米颗粒是燃烧的副产品。有趣的是，实验暴露于碳纳米颗粒会诱导肺部肉芽肿样病变。然而，这些病变中募集的细胞群体和细胞外基质基因表达谱尚未得到探索。由于目前动物模型中的肉芽肿迅速消退，因此持续性的机制一直难以捉摸。为了克服以前模型的局限性，我们研究了使用多壁碳纳米颗粒的模型是否会类似于慢性人类肺部肉芽肿性炎症。我们假设，肺部暴露于多壁碳纳米颗粒会诱导肉芽肿，引发巨噬细胞和 T 细胞反应，并通过骨桥蛋白的上调模拟其他肉芽肿性疾病。该模型表明：（1）有巨噬细胞和 T 细胞浸润的肉芽肿性炎症；（2）类似于人类肉芽肿的慢性，持续时间长达 90 天；（3）通过激光捕获显微切割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一个重要的平台。
