一项大型肺部基因表达研究鉴定出纤连蛋白-5 是 COPD 组织修复中的一个新的参与者。
A large lung gene expression study identifying fibulin-5 as a novel player in tissue repair in COPD.
机构信息
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands.
University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
出版信息
Thorax. 2015 Jan;70(1):21-32. doi: 10.1136/thoraxjnl-2014-205091. Epub 2014 Jul 2.
BACKGROUND
Chronic obstructive pulmonary disease (COPD) is a progressive, incurable lung disease characterised by abnormal tissue repair causing emphysema and small airways fibrosis. Since current therapy cannot modify this abnormal repair, it is crucial to unravel its underlying molecular mechanisms. Unbiased analysis of genome-wide gene expression profiles in lung tissue provides a powerful tool to investigate this.
METHODS
We performed genome-wide gene expression profiling in 581 lung tissue samples from current and ex-smokers with (n=311) and without COPD (n=270). Subsequently, quantitative PCR, western blot and immunohistochemical analyses were performed to validate our main findings.
RESULTS
112 genes were found to be upregulated in patients with COPD compared with controls, whereas 61 genes were downregulated. Among the most upregulated genes were fibulin-5 (FBLN5), elastin (ELN), latent transforming growth factor β binding protein 2 (LTBP2) and microfibrillar associated protein 4 (MFAP4), all implicated in elastogenesis. Our gene expression findings were validated at mRNA and protein level. We demonstrated higher ELN gene expression in COPD lung tissue and similar trends for FBLN5 and MFAP4, and negative correlations with lung function. FBLN5 protein levels were increased in COPD lung tissue and cleaved, possibly non-functional FBLN5 protein was present. Strong coexpression of FBLN5, ELN, LTBP2 and MFAP4 in lung tissue and in silico analysis indicated cofunctionality of these genes. Finally, colocalisation of FBLN5, MFAP4 and LTBP2 with elastic fibres was demonstrated in lung tissue.
CONCLUSIONS
We identified a clear gene signature for elastogenesis in COPD and propose FBLN5 as a novel player in tissue repair in COPD.
背景
慢性阻塞性肺疾病（COPD）是一种进行性、不可治愈的肺部疾病，其特征是异常组织修复导致肺气肿和小气道纤维化。由于目前的治疗方法不能改变这种异常修复，因此揭示其潜在的分子机制至关重要。对肺组织进行全基因组基因表达谱的无偏分析为研究这一机制提供了有力工具。
方法
我们对 581 例现吸烟者和曾吸烟者的肺组织样本进行了全基因组基因表达谱分析，其中 COPD 患者 311 例，无 COPD 患者 270 例。随后，我们进行了定量 PCR、western blot 和免疫组织化学分析，以验证我们的主要发现。
结果
与对照组相比，COPD 患者有 112 个基因上调，61 个基因下调。上调最明显的基因包括纤维调蛋白 5（FBLN5）、弹性蛋白（ELN）、潜伏转化生长因子β结合蛋白 2（LTBP2）和微纤维相关蛋白 4（MFAP4），这些基因都与弹性蛋白生成有关。我们的基因表达发现得到了 mRNA 和蛋白质水平的验证。我们在 COPD 肺组织中证实了 ELN 基因表达较高，FBLN5 和 MFAP4 也呈现类似趋势，与肺功能呈负相关。FBLN5 蛋白水平在 COPD 肺组织中升高，且存在可能无功能的裂解 FBLN5 蛋白。FBLN5、ELN、LTBP2 和 MFAP4 在肺组织中的强共表达以及计算机模拟分析表明这些基因具有共同功能。最后，我们在肺组织中证实了 FBLN5、MFAP4 和 LTBP2 与弹性纤维的共定位。
结论
我们在 COPD 中确定了一个明确的弹性生成基因特征，并提出 FBLN5 是 COPD 组织修复中的一个新的参与者。
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