From Neuroprotection Research Laboratories (H.T., S.H.-Y.C., G.H., R.O., M.R.I., J.M., E.R.-B., K.H., C.X., M.M.N., X.W., K.A., E.H.L., J.L.), Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown; Departments of Neurology (S.H.-Y.C., J.W.L.) and Radiology (L.H.), Brigham and Women's Hospital, Boston; Department of Pediatrics, Pediatric Critical Care Medicine (J.L.), Department of Radiology (E.H.L.), and Department of Neurology (M.M.N., E.H.L.), Massachusetts General Hospital, Boston; Department of Neurosurgery (H.T.), Yokohama City University, Yokohama, Japan; and Departments of Critical Care Medicine, Neurology, and Neurosurgery (S.H.-Y.C.), University of Pittsburgh, PA.
Neurology. 2020 Mar 24;94(12):e1281-e1293. doi: 10.1212/WNL.0000000000008868. Epub 2020 Feb 27.
To determine if CSF and plasma levels of soluble vascular endothelial (sVE)-cadherin are associated with functional outcome after subarachnoid hemorrhage (SAH) and to investigate sVE-cadherin effects on microglia.
Serial CSF and plasma were collected from prospectively enrolled patients with nontraumatic SAH from a ruptured aneurysm in the anterior circulation and who required an external ventricular drain for clinical indications. Patients with normal-pressure hydrocephalus without SAH served as controls. For prospective assessment of long-term outcomes at 3 and 6 months after SAH, modified Rankin Scale scores (mRS) were obtained and dichotomized into good (mRS ≤ 2) vs poor (mRS > 2) outcome groups. For SAH severity, Hunt and Hess grade was assessed. Association of CSF sVE-cadherin levels with long-term outcomes, HH grade, and CSF tumor necrosis factor (TNF)-α levels were evaluated. sVE-cadherin effects on microglia were also studied.
sVE-cadherin levels in CSF, but not in plasma, were higher in patients with SAH and were associated with higher clinical severity and higher CSF TNF-α levels. Patients with SAH with higher CSF sVE-cadherin levels over time were more likely to develop worse functional outcome at 3 months after SAH. Incubation of cultured microglia with sVE-cadherin resulted in increased inducible nitric oxide synthase, interleukin-1β, reactive oxygen species, cell soma size, and metabolic activity, consistent with microglia activation. Microinjection of sVE-cadherin fragments into mouse brain results in an increased number of microglia surrounding the injection site, compared to injection of denatured vascular endothelial-cadherin fragments.
These results support the existence of a novel pathway by which sVE-cadherin, released from injured endothelium after SAH, can shift microglia into a more proinflammatory phenotype and contribute to neuroinflammation and poor outcome in SAH.
确定蛛网膜下腔出血（SAH）后脑脊液（CSF）和血浆中可溶性血管内皮（sVE）-钙黏蛋白水平是否与功能预后相关，并研究 sVE-钙黏蛋白对小胶质细胞的影响。
前瞻性纳入前循环破裂动脉瘤所致非创伤性 SAH 患者的连续 CSF 和血浆，并根据临床指征需要外部脑室引流。正常压力脑积水但无 SAH 的患者作为对照。为了前瞻性评估 SAH 后 3 个月和 6 个月的长期结局，获得改良Rankin 量表评分（mRS），并分为良好（mRS≤2）与不良（mRS＞2）结局组。SAH 严重程度采用 Hunt 和 Hess 分级评估。评估 CSF sVE-钙黏蛋白水平与长期结局、HH 分级和 CSF 肿瘤坏死因子（TNF）-α水平的相关性。还研究了 sVE-钙黏蛋白对小胶质细胞的影响。
CSF 中而非血浆中的 sVE-钙黏蛋白水平在 SAH 患者中升高，且与较高的临床严重程度和较高的 CSF TNF-α水平相关。CSF sVE-钙黏蛋白水平随时间升高的 SAH 患者，在 SAH 后 3 个月时更有可能出现功能结局恶化。sVE-钙黏蛋白孵育培养的小胶质细胞，可导致诱导型一氧化氮合酶、白细胞介素-1β、活性氧、细胞体大小和代谢活性增加，与小胶质细胞激活一致。与注射变性血管内皮钙黏蛋白片段相比，将 sVE-钙黏蛋白片段微注射到小鼠脑内，导致注射部位周围的小胶质细胞数量增加。
这些结果支持了一种新的途径的存在，即 SAH 后受损内皮释放的 sVE-钙黏蛋白可以使小胶质细胞转变为更具促炎表型，并导致 SAH 中的神经炎症和不良结局。
