Saito Fumitake, Tasaka Sadatomo, Inoue Ken-Ichiro, Miyamoto Keisuke, Nakano Yasushi, Ogawa Yuko, Yamada Wakako, Shiraishi Yoshiki, Hasegawa Naoki, Fujishima Seitaro, Takano Hirohisa, Ishizaka Akitoshi
Division of Pulmonary Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Am J Respir Cell Mol Biol. 2008 May;38(5):566-71. doi: 10.1165/rcmb.2007-0299OC. Epub 2007 Dec 20.
Interleukin-6 (IL-6) is known to be involved in the pathogenesis of various inflammatory diseases, but its role in bleomycin (BLM)-induced lung injury and subsequent fibrotic changes remains to be determined. We evaluated the role of IL-6 in the lung inflammatory changes induced by BLM using wild-type (WT) and IL-6-deficient (IL-6(-/-)) mice. The mice were treated intratracheally with 1 mg/kg BLM and killed 2, 7, or 21 days later. Lung Inflammation in the acute phase (Days 2 and 7) was assessed by differential cell counts in bronchoalveolar lavage (BAL) fluid and cytokine levels in the lung. Lung fibrotic changes were evaluated on Day 21 by histopathology and collagen assay. On Day 2, BLM administration induced significant increases in the numbers of total cells, macrophages, and neutrophils in BAL fluid, which were attenuated in IL-6(-/-) mice (P < 0.05). Lung pathology also showed inflammatory cell accumulation, which was attenuated in the IL-6(-/-) mice compared with WT mice. In WT mice, elevated levels of TGF-beta(1) and CCL3 were observed 2 and 7 days after BLM challenge, respectively. On Day 7, BLM-induced inflammatory cell accumulation did not differ between the genotypes. Lung pathology 21 days after BLM challenge revealed significant fibrotic changes with increased collagen content, which was attenuated in IL-6(-/-) mice. Although the TGF-beta(1) level in the lung did not differ between the genotypes on Day 21, CCL3 was significantly lower in IL-6(-/-) mice. These results indicate that IL-6 may play an important role in the pathogenesis of BLM-induced lung injury and subsequent fibrotic changes.
白细胞介素-6（IL-6）已知参与多种炎症性疾病的发病机制，但其在博来霉素（BLM）诱导的肺损伤及随后的纤维化改变中的作用仍有待确定。我们使用野生型（WT）和IL-6基因缺陷型（IL-6(-/-)）小鼠评估了IL-6在BLM诱导的肺部炎症变化中的作用。小鼠经气管内给予1mg/kg BLM，并在2、7或21天后处死。通过支气管肺泡灌洗（BAL）液中的细胞分类计数和肺组织中的细胞因子水平评估急性期（第2天和第7天）的肺部炎症。通过组织病理学和胶原蛋白测定在第21天评估肺部纤维化改变。在第2天，BLM给药导致BAL液中总细胞、巨噬细胞和中性粒细胞数量显著增加，而在IL-6(-/-)小鼠中这些增加有所减弱（P<0.05）。肺病理学也显示有炎症细胞积聚，与WT小鼠相比，IL-6(-/-)小鼠中的这种积聚有所减弱。在WT小鼠中，分别在BLM攻击后2天和7天观察到TGF-β(1)和CCL3水平升高。在第7天，BLM诱导的炎症细胞积聚在不同基因型之间没有差异。BLM攻击21天后的肺病理学显示有明显的纤维化改变，胶原蛋白含量增加，而在IL-6(-/-)小鼠中这种改变有所减弱。尽管在第21天不同基因型之间肺组织中的TGF-β(1)水平没有差异，但IL-6(-/-)小鼠中的CCL3水平显著较低。这些结果表明，IL-6可能在BLM诱导的肺损伤及随后的纤维化改变的发病机制中起重要作用。
