Gonzalez Raymond J, Lin Shu-An, Bednar Bohumil, Connolly Brett, LaFranco-Scheuch Lisa, Mesfin Gebre M, Philip Thomas, Patel Shetal, Johnson Timothy, Sistare Frank D, Glaab Warren E
1 Safety Assessment and Laboratory Animal Resources, West Point, Pennsylvania, USA.
2 MRL, West Point, Pennsylvania, USA.
Toxicol Pathol. 2017 Jul;45(5):633-648. doi: 10.1177/0192623317720731.
Lack of biomarkers specific to and either predictive or diagnostic of drug-induced vascular injury (DIVI) continues to be a major obstacle during drug development. Biomarkers derived from physiologic responses to vessel injury, such as inflammation and vascular remodeling, could make good candidates; however, they characteristically lack specificity for vasculature. We evaluated whether vascular remodeling-associated protease activity, as well as changes to vessel permeability resulting from DIVI, could be visualized ex vivo in affected vessels, thereby allowing for visual monitoring of the pathology to address specificity. We found that visualization of matrix metalloproteinase activation accompanied by increased vascular leakage in the mesentery of rats treated with agents known to induce vascular injury correlated well with incidence and severity of histopathological findings and associated inflammation as well as with circulating levels of tissue inhibitors of metalloproteinase 1 and neutrophil gelatinase-associated lipocalin. The weight of evidence approach reported here shows promise as a composite DIVI preclinical tool by means of complementing noninvasive monitoring of circulating biomarkers of inflammation with direct imaging of affected vasculature and thus lending specificity to its interpretation. These findings are supportive of a potential strategy that relies on translational imaging tools in conjunction with circulating biomarker data for high-specificity monitoring of VI both preclinically and clinically.
缺乏针对药物性血管损伤（DIVI）的特异性且具有预测或诊断价值的生物标志物，仍然是药物研发过程中的一个主要障碍。源自对血管损伤的生理反应（如炎症和血管重塑）的生物标志物可能是不错的候选者；然而，它们通常缺乏对脉管系统的特异性。我们评估了与血管重塑相关的蛋白酶活性以及DIVI导致的血管通透性变化是否可以在体外受影响的血管中可视化，从而能够对病理学进行视觉监测以解决特异性问题。我们发现，在用已知可诱导血管损伤的药物处理的大鼠肠系膜中，基质金属蛋白酶激活的可视化伴随着血管渗漏增加，这与组织病理学发现、相关炎症的发生率和严重程度以及金属蛋白酶组织抑制剂1和中性粒细胞明胶酶相关脂质运载蛋白的循环水平密切相关。此处报告的证据权重方法显示出有望成为一种综合的DIVI临床前工具，通过将炎症循环生物标志物的无创监测与受影响脉管系统的直接成像相结合，从而为其解释赋予特异性。这些发现支持了一种潜在策略，即依靠转化成像工具结合循环生物标志物数据，在临床前和临床阶段对血管损伤进行高特异性监测。
