Von-willebrand factor influences blood brain barrier permeability and brain inflammation in experimental allergic encephalomyelitis
Von-willebrand factor influences blood brain barrier permeability and brain inflammation in experimental allergic encephalomyelitis
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DOI：
10.2353/ajpath.2008.080001
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发表时间：
2008-09-01
影响因子：
6
通讯作者：
Teuscher, Cory
中科院分区：
文献类型：
--
作者：
Noubade, Rajkumar;del Rio, Roxana;Teuscher, Cory
内皮细胞内的韦伯-帕拉德体是已知在组胺暴露后释放血管性假血友病因子（vonWitlebrand Factor，VWF）、P-选择素、趋化因子和其他储存分子的分泌颗粒。具有破坏的VWF基因（VWFKO）的小鼠具有在韦伯-帕拉德体中缺陷的内皮细胞。这些小鼠用于评估VWF和/或韦伯-帕拉德小体在灌流波氏杆菌毒素诱导的组胺超敏反应中的作用，组胺是实验性过敏性脑脊髓炎的一种亚表型，是多发性硬化症的主要自身免疫模型。3天后，野生型和VWFKO小鼠之间对组胺的敏感性无显著差异;然而，VWFKO小鼠的组胺敏感性持续时间显著更长。相应地，与野生型小鼠相比，VWFKO小鼠脑脊髓炎发作更早，疾病更严重，血脑屏障（BBB）通透性显著增加。此外，与野生型小鼠相比，VWFKO小鼠的大脑中的炎症选择性增加，而不是脊髓。VWFKO小鼠中BBB渗透性的早期增加不是由于致脑炎T细胞活性增加，因为与用致脑炎肽加佐剂免疫的同窝小鼠相比，经促炎剂处理的VWFKO小鼠中BBB渗透性没有差异。总之，这些数据表明，VWF和/或韦伯-帕拉德体负调节BBB通透性变化和脑内由外周炎性刺激引起的自身免疫性炎性病变形成。
Weibel-Palade bodies within endothelial cells are secretory granules known to release von Witlebrand Factor (VWF), P-selectin, chemokines, and other stored molecules following histamine exposure. Mice with a disrupted VWF gene (VWFKO) have endothetial cells that are deficient in Weibel-Palade bodies. These mice were used to evaluate the role of VWF and/or Weibel-Palade bodies in Bordetella perfussis toxin-induced hypersensitivity to histamine, a subphenotype of experimental allergic encephalomyelitis, the principal autoimmune model of multiple sclerosis. No significant differences in susceptibility to histamine between wild-type and VWFKO mice were detected after 3 days; however, histamine sensitivity persisted significantly longer in VWFKO mice. Correspondingly, encephalomyelitis onset was earlier, disease was more severe, and blood brain barrier (BBB) permeability was significantly increased in VWFKO mice, as compared with wild-type mice. Moreover, inflammation was selectively increased in the brains, but not spinal cords, of VWFKO mice as compared with wild-type mice. Early increases in BBB permeability in VWFKO mice were not due to increased encephalitogenic T-cell activity since BBB permeability did not differ in adjuvant-treated VWFKO mice as compared with littermates immunized with encephalitogenic peptide plus adjuvant. Taken together, these data indicate that VWF and/or Weibel-Palade bodies negatively regulate BBB permeability changes and autoimmune inflammatory lesion formation within the brain elicited by peripheral inflammatory stimuli.