Multimodal Molecular Imaging Demonstrates Myeloperoxidase Regulation of Matrix Metalloproteinase Activity in Neuroinflammation.
Multimodal Molecular Imaging Demonstrates Myeloperoxidase Regulation of Matrix Metalloproteinase Activity in Neuroinflammation.
复制标题
多模态分子成像证明髓过氧化物酶对神经炎症中基质金属蛋白酶活性的调节
DOI：
10.1007/s12035-018-1137-2
复制
发表时间：
2019-03
影响因子：
5.1
通讯作者：
Chen JW
中科院分区：
文献类型：
--
作者：
Zhang Y;Dong H;Seeburg DP;Wojtkiewicz GR;Waterman P;Pulli B;Forghani R;Ali M;Iwamoto Y;Swirski FK;Chen JW
髓过氧化物酶（MPO）被发现既能激活基质金属蛋白酶（MMPs）又能抑制MMPs。然而，这些调节作用尚未在体内观察到，并且尚不清楚哪种途径在体内相关。我们的目的是跟踪MPO调节MMP活性在活体动物神经炎症。用MPO特异性抑制剂4-氨基苯甲酸酰肼或生理盐水作为对照，对实验性自身免疫性脑脊髓炎（EAE）诱导的小鼠（神经炎症和多发性硬化的小鼠模型）进行治疗。在诱导后第12天，小鼠同时接受MPO特异性分子成像剂MPO-Gd的磁共振成像（MRI）和MMP靶向剂MMPsense的荧光分子断层扫描（FMT）。进行生化和组织病理学相关性分析。利用同时MRI和FMT成像，我们发现MPO抑制脑中MMP活性降低，表明MPO活性在体内正调节MMP活性。体内MMP-9活性与MPO-Gd+病变体积和疾病严重程度相关。体外实验和组织病理学分析证实了这一点，显示MMP活性和MMP-9+细胞与MPO活性和MPO+细胞相关。总之，多模式分子成像首次证明MPO调节MMP活性在活体动物。这种方法可以作为一个模型来研究生物体中其他生物学上有趣的分子之间的相互作用。
Myeloperoxidase (MPO) has paradoxically been found to be able to both activate matrix metalloproteinases (MMPs) as well as inhibit MMPs. However, these regulatory effects have not yet been observed in vivo, and it is unclear which pathway is relevant in vivo. We aim to track MPO regulation of MMP activity in living animals in neuroinflammation. Mice induced with experimental autoimmune encephalomyelitis (EAE), a mouse model of neuroinflammation and multiple sclerosis, were treated with either the MPO-specific inhibitor 4-aminobenzoic acid hydrazide or saline as control. Mice underwent concurrent magnetic resonance imaging (MRI) with the MPO-specific molecular imaging agent MPO-Gd and fluorescence molecular tomography (FMT) with the MMP-targeting agent MMPsense on day 12 after induction. Biochemical and histopathological correlations were performed. Utilizing concurrent MRI and FMT imaging, we found reduced MMP activity in the brain with MPO inhibition, demonstrating MPO activity positively regulates MMP activity in vivo. In vivo MMPSense activation and MMP-9 activity correlated with MPO-Gd+lesion volume and disease severity. This was corroborated by in vitro assays and histopathological analyses that showed MMP activity and MMP-9+cells correlated with MPO activity and MPO+cells. In conclusion, multimodal molecular imaging demonstrates for the first time MPO regulation of MMP activity in living animals. This approach could serve as a model to study the interactions of other biologically interesting molecules in living organisms.
登录
查看更多内容
影响因子：
19.7
作者：
Chen, John W.;Sans, Manel Querol;Weissleder, Ralph
通讯作者：
Weissleder, Ralph
影响因子：
5.7
作者：
McCann CM;Waterman P;Figueiredo JL;Aikawa E;Weissleder R;Chen JW
通讯作者：
Chen JW
影响因子：
4.4
作者：
Toft-Hansen, H;Nuttall, RK;Owens, T
通讯作者：
Owens, T
影响因子：
5.8
作者：
Fainardi, E;Castellazzi, M;Dallocchio, F
通讯作者：
Dallocchio, F
影响因子：
6.4
作者：
Gray, Elizabeth;Thomas, Taya L.;Love, Seth
通讯作者：
Love, Seth