Department of Surgery, Madigan Army Medical Center, Tacoma, Washington, USA.
J Surg Res. 2011 Sep;170(1):120-32. doi: 10.1016/j.jss.2011.01.014. Epub 2011 Feb 5.
Trauma leading to massive hemorrhage results in widespread tissue hypoxia, anaerobic metabolism, and production of inflammatory cytokines and oxidative molecules injurious to the vascular endothelium. Although trauma-related endothelial cell pathophysiology has been extensively studied, very little is known regarding gene transcriptional changes that occur during the event, particularly in endothelia. Thus, we employed fluorescent microarray analysis of gene transcription to elucidate critical pathways and gene products involved in endothelial dysfunction.
A trauma-hemorrhage/shock (T-H/S) model mimicking the physiologic changes seen in human trauma was performed on 10 Yorkshire swine, consisting of 35% blood volume hemorrhage followed by 6 h of full resuscitation. Aortic endothelium was analyzed by microarray and functional clusters were identified through the use of Database for Annotation, Visualization, and Integrated Discovery (DAVID) software.
Injured swine developed profound acidosis, coagulopathy, massive resuscitative fluid requirements, and microscopic changes of ischemia/reperfusion injury. While 1007 transcripts were down-regulated, 529 transcripts were up-regulated. DAVID functional clustering analysis revealed 21 significantly altered biological processes that were grouped into 12 distinct functional categories. The transforming growth factor beta (TGFβ) family of genes was the most interrelated. In addition, vascular endothelial growth factor (VEGF) signaling members and leukocyte chemoattractants were also altered.
Our model identified two major signaling pathways, TGFβ and VEGF, which undergo early transcriptional changes in injured endothelial cells. Our results suggest that TGFβ and VEGF may play a crucial role in the development of endothelial cell injury leading to increased vascular permeability during shock-trauma.
创伤导致大量出血会导致广泛的组织缺氧、无氧代谢以及炎症细胞因子和氧化分子的产生，这些物质会损伤血管内皮。虽然创伤相关的内皮细胞病理生理学已经得到了广泛的研究，但对于创伤发生时发生的基因转录变化知之甚少，特别是在内皮细胞中。因此，我们采用荧光微阵列分析基因转录，以阐明与内皮功能障碍相关的关键途径和基因产物。
对 10 头约克夏猪进行了模拟人类创伤生理变化的创伤性出血/休克（T-H/S）模型实验，包括 35%的血容量出血，然后进行 6 小时的完全复苏。通过微阵列分析主动脉内皮细胞，并使用数据库 for Annotation、Visualization、and Integrated Discovery (DAVID) 软件识别功能簇。
受伤的猪出现严重的酸中毒、凝血功能障碍、大量复苏液需求以及缺血/再灌注损伤的微观变化。有 1007 个转录本下调，529 个转录本上调。DAVID 功能聚类分析显示 21 个显著改变的生物学过程，这些过程被分为 12 个不同的功能类别。转化生长因子β（TGFβ）家族基因的相关性最高。此外，血管内皮生长因子（VEGF）信号成员和白细胞趋化因子也发生了改变。
我们的模型确定了两个主要的信号通路，即 TGFβ 和 VEGF，它们在受伤的内皮细胞中经历早期的转录变化。我们的结果表明，TGFβ 和 VEGF 可能在休克创伤导致的内皮细胞损伤和血管通透性增加的发展中发挥关键作用。
