Enerson Bradley E, Lin Aiping, Lu Bin, Zhao Hongyu, Lawton Michael P, Floyd Eugenia
Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut 06536, USA.
Toxicol Pathol. 2006;34(1):27-32. doi: 10.1080/01926230500512068.
Acute vascular injury that leads to vascular inflammation is a common finding in the preclinical toxicity testing of drugs in rats and dogs. However, the relevance of this finding for risk to humans is unclear. Concern about the safety of these drugs is heightened by the current lack of noninvasive clinical methods to predict the onset of vascular damage in animals or humans. Determining the relevance of this poorly understood preclinical outcome for humans requires a better understanding of the molecular mechanisms of injury in addition to the development of sensitive and specific leading biomarkers for the clinical diagnosis of acute vascular damage. Most molecular research on this toxicity has been performed in rats, but recent development of canine gene expression microarrays makes transcriptomic studies now possible in the dog. In this study, we investigated the molecular mechanisms of drug-induced vascular injury in dogs using gene arrays. After treating Beagles with toxic doses of CI-947, an adenosine receptor agonist, we profiled gene expression in the coronary arteries and correlated those changes with histopathology at 16 and 24 hours after dosing. The results demonstrated that pathobiological processes such as stimulation of the innate immune response, increased extracellular matrix turnover and oxidative stress were active at times of very early injury.
导致血管炎症的急性血管损伤在大鼠和犬类药物临床前毒性试验中是常见现象。然而，这一发现与人类风险的相关性尚不清楚。目前缺乏预测动物或人类血管损伤发作的非侵入性临床方法，这加剧了对这些药物安全性的担忧。要确定这一了解甚少的临床前结果与人类的相关性，除了开发用于急性血管损伤临床诊断的敏感且特异的先导生物标志物外，还需要更好地理解损伤的分子机制。关于这种毒性的大多数分子研究是在大鼠中进行的，但犬类基因表达微阵列的最新发展使得现在可以在犬类中进行转录组学研究。在本研究中，我们使用基因阵列研究了犬类药物诱导的血管损伤的分子机制。在用毒性剂量的腺苷受体激动剂CI - 947治疗比格犬后，我们分析了冠状动脉中的基因表达，并将这些变化与给药后16小时和24小时的组织病理学相关联。结果表明，在早期损伤时，诸如刺激先天免疫反应、增加细胞外基质周转和氧化应激等病理生物学过程是活跃的。
