Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA ; Bioinformatics Program, Boston University, 44 Cummington Street, Boston, MA 02215, USA.
UBC James Hogg Research Centre, Providence Heart + Lung Institute, St. Paul's Hospital and Department of Pathology and Laboratory Medicine, University of British Columbia, 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada.
Genome Med. 2012 Aug 31;4(8):67. doi: 10.1186/gm367. eCollection 2012.
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease consisting of emphysema, small airway obstruction, and/or chronic bronchitis that results in significant loss of lung function over time.
In order to gain insights into the molecular pathways underlying progression of emphysema and explore computational strategies for identifying COPD therapeutics, we profiled gene expression in lung tissue samples obtained from regions within the same lung with varying amounts of emphysematous destruction from smokers with COPD (8 regions × 8 lungs = 64 samples). Regional emphysema severity was quantified in each tissue sample using the mean linear intercept (Lm) between alveolar walls from micro-CT scans.
We identified 127 genes whose expression levels were significantly associated with regional emphysema severity while controlling for gene expression differences between individuals. Genes increasing in expression with increasing emphysematous destruction included those involved in inflammation, such as the B-cell receptor signaling pathway, while genes decreasing in expression were enriched in tissue repair processes, including the transforming growth factor beta (TGFβ) pathway, actin organization, and integrin signaling. We found concordant differential expression of these emphysema severity-associated genes in four cross-sectional studies of COPD. Using the Connectivity Map, we identified GHK as a compound that can reverse the gene-expression signature associated with emphysematous destruction and induce expression patterns consistent with TGFβ pathway activation. Treatment of human fibroblasts with GHK recapitulated TGFβ-induced gene-expression patterns, led to the organization of the actin cytoskeleton, and elevated the expression of integrin β1. Furthermore, addition of GHK or TGFβ restored collagen I contraction and remodeling by fibroblasts derived from COPD lungs compared to fibroblasts from former smokers without COPD.
These results demonstrate that gene-expression changes associated with regional emphysema severity within an individual's lung can provide insights into emphysema pathogenesis and identify novel therapeutic opportunities for this deadly disease. They also suggest the need for additional studies to examine the mechanisms by which TGFβ and GHK each reverse the gene-expression signature of emphysematous destruction and the effects of this reversal on disease progression.
慢性阻塞性肺疾病（COPD）是一种异质性疾病，由肺气肿、小气道阻塞和/或慢性支气管炎组成，随着时间的推移，会导致肺功能显著丧失。
为了深入了解肺气肿进展的分子途径，并探索识别 COPD 治疗方法的计算策略，我们对来自 COPD 吸烟者同一肺部不同肺气肿破坏区域的肺组织样本进行了基因表达谱分析（8 个区域×8 个肺=64 个样本）。使用微 CT 扫描中肺泡壁之间的平均线性截距（Lm）在每个组织样本中定量区域肺气肿严重程度。
我们确定了 127 个基因，这些基因的表达水平与区域肺气肿严重程度显著相关，同时控制了个体之间的基因表达差异。随着肺气肿破坏的增加而表达增加的基因包括参与炎症的基因，如 B 细胞受体信号通路，而表达减少的基因则富集在组织修复过程中，包括转化生长因子β（TGFβ）途径、肌动蛋白组织和整合素信号。我们在四项 COPD 的横断面研究中发现了这些与肺气肿严重程度相关基因的一致差异表达。使用连接图谱，我们发现 GHK 是一种可以逆转与肺气肿破坏相关的基因表达特征并诱导与 TGFβ 途径激活一致的表达模式的化合物。GHK 处理人成纤维细胞可重现 TGFβ 诱导的基因表达模式，导致肌动蛋白细胞骨架的组织，并上调整合素β1 的表达。此外，与来自非 COPD 吸烟者的成纤维细胞相比，GHK 或 TGFβ 的添加恢复了来自 COPD 肺的成纤维细胞的胶原 I 收缩和重塑。
这些结果表明，个体肺部内与区域肺气肿严重程度相关的基因表达变化可以深入了解肺气肿的发病机制，并为这种致命疾病确定新的治疗机会。它们还表明需要进一步研究，以检查 TGFβ 和 GHK 各自逆转肺气肿破坏的基因表达特征的机制，以及这种逆转对疾病进展的影响。
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