Vascular Biology and Therapeutics Program, the Department of Pathology, Yale University, New Haven, Connecticut 06520, USA.
Am J Pathol. 2011 Aug;179(2):860-8. doi: 10.1016/j.ajpath.2011.05.002. Epub 2011 Jun 23.
Thrombospondin (TSP)-2-null mice have an altered brain foreign body response (FBR) characterized by increases in inflammation, extracellular matrix deposition, and leakage of the blood-brain barrier (BBB). In the present study, we investigated the role of TSP-2 in BBB repair during the brain FBR to mixed cellulose ester filters implanted in the cortex of wild-type (WT) and TSP-2-null mice for 2 days to 8 weeks. Histological and immunohistochemical analysis revealed enhanced and prolonged neuroinflammation in TSP-2-null mice up to 8 weeks after implantation. In addition, recovery of the BBB was compromised and was associated with increased gelatinolytic activity and low levels of collagen type IV in the basement membranes of TSP-2-null blood vessels. An analysis of protein extracts from implantation sites revealed elevated levels of matrix metalloproteinase (MMP)-2 and MMP-9 in TSP-2-null brains. TSP-2-null astrocytes secreted higher levels of both MMPs in vitro compared with their WT counterparts. Furthermore, TSP-2-null astrocytes were deficient in supporting the recovery of barrier function in WT endothelial cells. Finally, Western blot analysis of astrocytes and brain endothelial cells revealed TSP-2 expression only in the former. Taken together, our observations suggest that astrocyte-derived TSP-2 is critical for the maintenance of physiological MMP-2 and MMP-9 levels during the FBR and contributes to the repair of the BBB.
血栓反应蛋白-2（TSP-2）缺失小鼠的脑异物反应（FBR）发生改变，其特征为炎症、细胞外基质沉积和血脑屏障（BBB）渗漏增加。在本研究中，我们研究了 TSP-2 在 FBR 期间对植入野生型（WT）和 TSP-2 缺失小鼠大脑皮质的混合纤维素酯过滤器的 BBB 修复中的作用，植入时间为 2 天至 8 周。组织学和免疫组织化学分析显示，TSP-2 缺失小鼠在植入后长达 8 周的时间内神经炎症增强且持续时间延长。此外，BBB 的恢复受到损害，与 TSP-2 缺失血管基底膜中明胶酶活性增加和 IV 型胶原水平降低有关。对植入部位蛋白提取物的分析显示，TSP-2 缺失大脑中的基质金属蛋白酶（MMP）-2 和 MMP-9 水平升高。与 WT 对照相比，TSP-2 缺失星形胶质细胞在体外分泌更高水平的两种 MMP。此外，TSP-2 缺失星形胶质细胞在支持 WT 内皮细胞恢复屏障功能方面存在缺陷。最后，对星形胶质细胞和脑内皮细胞的 Western blot 分析显示 TSP-2 仅在前者中表达。综上所述，我们的观察结果表明，星形胶质细胞衍生的 TSP-2 对于在 FBR 期间维持生理 MMP-2 和 MMP-9 水平至关重要，并有助于 BBB 的修复。
