A gene expression signature of emphysema-related lung destruction and its reversal by the tripeptide GHK.
A gene expression signature of emphysema-related lung destruction and its reversal by the tripeptide GHK.
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作者：
Campbell JD;McDonough JE;Zeskind JE;Hackett TL;Pechkovsky DV;Brandsma CA;Suzuki M;Gosselink JV;Liu G;Alekseyev YO;Xiao J;Zhang X;Hayashi S;Cooper JD;Timens W;Postma DS;Knight DA;Lenburg ME;Hogg JC;Spira A
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着丧失。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，我们分析了从患有 COPD 的吸烟者的同一肺内具有不同程度的肺气肿破坏的区域获得的肺组织样本中的基因表达（8 个区域 × 8 个肺 = 64 个样本）。使用微 CT 扫描肺泡壁之间的平均线性截距 (Lm) 量化每个组织样本中的区域肺气肿严重程度。我们确定了 127 个基因，其表达水平与区域肺气肿严重程度显着相关，同时控制个体之间的基因表达差异。随着肺气肿破坏的增加，表达增加的基因包括与炎症有关的基因，例如B细胞受体信号通路，而表达减少的基因则在组织修复过程中富集，包括转化生长因子β（TGFβ）通路、肌动蛋白组织和整联蛋白信号传导。我们在 COPD 的四项横断面研究中发现这些肺气肿严重程度相关基因的一致差异表达。使用连接图，我们确定 GHK 是一种化合物，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。用 GHK 处理人成纤维细胞重现了 TGFβ 诱导的基因表达模式，导致肌动蛋白细胞骨架组织化，并提高了整合素 β1 的表达。此外，与来自未患慢性阻塞性肺病的前吸烟者的成纤维细胞相比，添加 GHK 或 TGFβ 可以恢复来自慢性阻塞性肺病肺部的成纤维细胞的 I 型胶原收缩和重塑。这些结果表明，与个体肺部局部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发病机制，并为这种致命疾病确定新的治疗机会。他们还建议需要进行更多研究来检查 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。
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.
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影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
DOI：
10.1513/pats.200908-087rm
发表时间：
2009-12-01
期刊：
Proceedings of the American Thoracic Society
影响因子：
--
作者：
Morty, Rory E;Konigshoff, Melanie;Eickelberg, Oliver
通讯作者：
Eickelberg, Oliver
DOI：
10.1165/rcmb.2008-0114oc
发表时间：
2009-03-01
影响因子：
6.4
作者：
Bhattacharya, Soumyaroop;Srisuma, Sorachai;Mariani, Thomas J.
通讯作者：
Mariani, Thomas J.
影响因子：
6
作者：
Chambers, RC;Leoni, P;Heller, RA
通讯作者：
Heller, RA
影响因子：
5.8
作者：
Francis SM;Larsen JE;Pavey SJ;Bowman RV;Hayward NK;Fong KM;Yang IA
通讯作者：
Yang IA