Division of Respirology, Neurology, and Rheumatology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
PLoS One. 2011;6(9):e24177. doi: 10.1371/journal.pone.0024177. Epub 2011 Sep 7.
We analyzed the lung mRNA expression profiles of a murine model of COPD developed using a lung-specific IL-18-transgenic mouse. In this transgenic mouse, the expression of 608 genes was found to vary more than 2-fold in comparison with control WT mice, and was clustered into 4 groups. The expression of 140 genes was constitutively increased at all ages, 215 genes increased gradually with aging, 171 genes decreased gradually with aging, and 82 genes decreased temporarily at 9 weeks of age. Interestingly, the levels of mRNA for the chitinase-related genes chitinase 3-like 1 (Chi3l1), Chi3l3, and acidic mammalian chitinase (AMCase) were significantly higher in the lungs of transgenic mice than in control mice. The level of Chi3l1 protein increased significantly with aging in the lungs and sera of IL-18 transgenic, but not WT mice. Previous studies have suggested Chi3l3 and AMCase are IL-13-driven chitinase-like proteins. However, IL-13 gene deletion did not reduce the level of Chi3l1 protein in the lungs of IL-18 transgenic mice. Based on our murine model gene expression data, we analyzed the protein level of YKL-40, the human homolog of Chi3l1, in sera of smokers and COPD patients. Sixteen COPD patients had undergone high resolution computed tomography (HRCT) examination. Emphysema was assessed by using a density mask with a cutoff of -950 Hounsfield units to calculate the low-attenuation area percentage (LAA%). We observed significantly higher serum levels in samples from 28 smokers and 45 COPD patients compared to 30 non-smokers. In COPD patients, there was a significant negative correlation between serum level of YKL-40 and %FEV(1). Moreover, there was a significant positive correlation between the serum levels of YKL-40 and LAA% in COPD patients. Thus our results suggest that chitinase-related genes may play an important role in establishing pulmonary inflammation and emphysematous changes in smokers and COPD patients.
我们分析了一种使用肺特异性 IL-18 转基因小鼠开发的 COPD 小鼠模型的肺 mRNA 表达谱。在这种转基因小鼠中，与对照 WT 小鼠相比，608 个基因的表达变化超过 2 倍，并聚类为 4 组。140 个基因的表达在所有年龄段均持续增加，215 个基因随年龄逐渐增加，171 个基因随年龄逐渐减少，82 个基因在 9 周龄时暂时减少。有趣的是，在转基因小鼠的肺中，几丁质酶相关基因几丁质酶 3 样 1（Chi3l1）、Chi3l3 和酸性哺乳动物几丁质酶（AMCase）的 mRNA 水平明显高于对照小鼠。IL-18 转基因但非 WT 小鼠的肺和血清中 Chi3l1 蛋白水平随年龄的增加而显著增加。先前的研究表明 Chi3l3 和 AMCase 是由 IL-13 驱动的几丁质酶样蛋白。然而，IL-13 基因缺失并未降低 IL-18 转基因小鼠肺中 Chi3l1 蛋白的水平。根据我们的小鼠模型基因表达数据，我们分析了吸烟者和 COPD 患者血清中 Chi3l1 人同源物 YKL-40 的蛋白水平。16 名 COPD 患者接受了高分辨率计算机断层扫描（HRCT）检查。使用密度掩模（截止值为-950 亨斯菲尔德单位）评估肺气肿，以计算低衰减区百分比（LAA%）。我们观察到，与 30 名非吸烟者相比，28 名吸烟者和 45 名 COPD 患者的样本中血清水平明显更高。在 COPD 患者中，YKL-40 血清水平与 %FEV(1) 呈显著负相关。此外，在 COPD 患者中，YKL-40 血清水平与 LAA% 呈显著正相关。因此，我们的结果表明，几丁质酶相关基因可能在吸烟者和 COPD 患者的肺部炎症和肺气肿变化中发挥重要作用。
