Cerebrovascular and Neuroscience Research Institute (J.S., H.A., Y.D., D.W., X.J.), Capital Medical University, Beijing, China.
Neuroprotection Research Laboratories, Departments of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School, Boston (J.S., W.L., F.Z., J.H.P., H.A., S.G., D.W., K.H., E.H.L.).
Stroke. 2021 Nov;52(11):3670-3679. doi: 10.1161/STROKEAHA.120.032782. Epub 2021 Sep 30.
Inflammatory mediators in blood have been proposed as potential biomarkers in stroke. However, a direct relationship between these circulating factors and brain-specific ischemic injury remains to be fully defined.
An unbiased screen in a nonhuman primate model of stroke was used to find out the most responsive circulating biomarker flowing ischemic stroke. Then this phenomenon was checked in human beings and mice. Finally, we observed the temporospatial responsive characteristics of this biomarker after ischemic brain injury in mice to evaluate the direct relationship between this circulating factor and central nervous system–specific ischemic injury.
In a nonhuman primate model, an unbiased screen revealed CCL2 (C-C motif chemokine ligand 2) as a major response factor in plasma after stroke. In mouse models of focal cerebral ischemia, plasma levels of CCL2 showed a transient response, that is, rapidly elevated by 2 to 3 hours postischemia but then renormalized back to baseline levels by 24 hours. However, a different CCL2 temporal profile was observed in whole brain homogenate, cerebrospinal fluid, and isolated brain microvessels, with a progressive increase over 24 hours, demonstrating a mismatch between brain versus plasma responses. In contrast to the lack of correlation with central nervous system responses, 2 peripheral compartments showed transient profiles that matched circulating plasma signatures. CCL2 protein in lymph nodes and adipose tissue was significantly increased at 2 hours and renormalized by 24 hours.
These findings may provide a cautionary tale for biomarker pursuits in plasma. Besides a direct central nervous system response, peripheral organs may also contribute to blood signatures in complex and indirect ways.
血液中的炎症介质已被提出作为中风的潜在生物标志物。然而，这些循环因子与脑特异性缺血性损伤之间的直接关系仍有待充分定义。
在非人类灵长类动物中风模型中使用了一种无偏筛选方法，以找出对缺血性中风反应最敏感的循环生物标志物。然后在人类和小鼠中检查了这种现象。最后，我们观察了这种生物标志物在小鼠缺血性脑损伤后的时空反应特征，以评估这种循环因子与中枢神经系统特异性缺血性损伤之间的直接关系。
在非人类灵长类动物模型中，无偏筛选揭示 CCL2（C 型趋化因子配体 2）是中风后血浆中的主要反应因子。在局灶性脑缺血的小鼠模型中，CCL2 的血浆水平表现出短暂的反应，即在缺血后 2 至 3 小时迅速升高，但在 24 小时后恢复到基线水平。然而，在全脑匀浆、脑脊液和分离的脑微血管中观察到了不同的 CCL2 时间曲线，在 24 小时内逐渐增加，表明大脑与血浆反应之间存在不匹配。与与中枢神经系统反应缺乏相关性不同，2 个外周隔室显示出与循环血浆特征相匹配的短暂曲线。淋巴结和脂肪组织中的 CCL2 蛋白在 2 小时时显著增加，并在 24 小时时恢复正常。
这些发现可能为在血浆中进行生物标志物研究提供了一个警示故事。除了直接的中枢神经系统反应外，外周器官也可能以复杂和间接的方式对血液特征产生影响。
