Cell-culture models of the blood-brain barrier.
Cell-culture models of the blood-brain barrier.
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血脑屏障的细胞培养模型。
DOI：
10.1161/strokeaha.114.005427
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发表时间：
2014-08
期刊：
影响因子：
8.3
通讯作者：
Cao Y
中科院分区：
文献类型：
--
作者：
He Y;Yao Y;Tsirka SE;Cao Y
He等人体外BBB模型2515的渗透性是通过囊泡转运。4，37-39 BMEC使用两种主要机制来调节细胞内运输。首先，小的亲脂性分子，如氧气和二氧化碳，自由扩散通过BMEC。40其次，一些亲水性分子通过特定的转运蛋白和受体跨BMEC转运。根据亚细胞分布，发现3种主要类型的转运蛋白和受体：（1）双向转运蛋白和受体表达于BMEC的腔侧和近腔侧。这些转运蛋白和受体通常起促进营养物质转运的作用。例如，葡萄糖转运蛋白1、单羧酸转运蛋白1、L1氨基酸转运蛋白和y+阳离子氨基酸转运蛋白分别将葡萄糖、乳酸盐和大的中性和阳离子必需氨基酸转运入和转运出BMEC。41，42（2）在BMEC的腔侧和近腔侧上表达的单向转运蛋白和受体。这组转运蛋白和受体将分子移入或移出大脑/血液系统。例如，转铁蛋白受体和胰岛素受体分别介导转铁蛋白和胰岛素的内吞作用，导致这些配体在BMEC中积累。43-45（3）在BMEC的腔侧或近腔侧表达的转运蛋白和受体。这些不均匀分布的转运蛋白和受体有助于BMEC的极性，并参与物质的单向转运。例如，多药耐药相关蛋白1（也称为ATP结合盒亚家族C成员1）、46-50 P-糖蛋白（也称为ATP结合盒亚家族B成员1）、51、52和乳腺癌耐药蛋白（也称为ATP结合盒亚家族G成员2）53-58主要在BMEC的腔侧表达。这些转运蛋白识别大范围的亲脂性底物，并将其泵入毛细血管腔以防止其穿透BBB。59除了BMEC之外，这些转运蛋白也在许多类型的肿瘤细胞中发现，包括神经胶质瘤、60白血病、61食管癌、62和结肠癌/肺癌/肾癌。63，64由于许多抗癌药物是这些转运蛋白的底物，59，65这些药物进入中枢神经系统组织或肿瘤是有限的，使患者对抗癌药物治疗产生耐药性，这种现象称为多药耐药性。65与肿瘤细胞相反，在供应中枢神经系统转移的血管中发现这些转运蛋白的表达较低。66例如，黑色素瘤和肺癌中枢神经系统转移瘤周围血管中的P-糖蛋白水平分别是正常脑组织中的0.5%和40%。67这些数据表明，系统性化疗可以到达中枢神经系统肿瘤细胞，但很难穿透和杀死它们。这些转运蛋白的各种抑制剂，包括维拉帕米、丙磺舒和烟曲霉素C，已被用于增加药物向脑肿瘤的递送并提高治疗效果。66另一方面，兴奋性氨基酸转运蛋白1至3仅在BMEC的近腔侧发现，以有效地从脑中去除兴奋性神经递质谷氨酸。68主要在BMEC近腔侧表达的低密度脂蛋白受体相关蛋白1促进β淀粉样蛋白从脑中消除，69-71尽管也有证据表明脂蛋白受体相关蛋白1可能不会促进β淀粉样蛋白流出血脑屏障。72，73仅在BMEC的近腔侧表达，（Na+-K.
He et al In Vitro BBB Models 2515 permeability is via vesicular transport. 4, 37–39 Two major mechanisms are used by BMECs to regulate intracellular transportation. First, small lipophilic molecules, such as oxygen and carbon dioxide, diffuse across BMECs freely. 40 Second, some hydrophilic molecules are transported across BMECs via specific transporters and receptors. Depending on the subcellular distribution, 3 major types of transporters and receptors are found:(1) Bidirectional transporters and receptors expressed on both the luminal and abluminal sides of BMECs. These transporters and receptors usually function to facilitate nutrient transportation. For example, glucose transporter 1, monocarboxylate transporter 1, L1 amino acid transporters, and y+ cationic amino acid transporter transport glucose, lactate, and large neutral and cationic essential amino acids in and out of BMECs, respectively. 41, 42 (2) Unidirectional transporters and receptors expressed on both the luminal and abluminal sides of BMECs. This group of transporters and receptors shifts molecules either in or out of the brain/blood system. For example, transferrin receptor and insulin receptor mediate endocytosis of transferrin and insulin, respectively, leading to accumulation of these ligands in BMECs. 43–45 (3) Transporters and receptors expressed on either the luminal or abluminal side of BMECs. These unevenly distributed transporters and receptors contribute to the polarity of BMECs and are involved in unidirectional transportation of substances. For instance, multidrug resistance-related protein 1 (also called ATP-binding cassette subfamily C member 1), 46–50 P-glycoprotein (also called ATP-binding cassette subfamily B member 1), 51, 52 and breast cancer resistance protein (also called ATP-binding cassette subfamily G member 2) 53–58 are predominantly expressed in the luminal side of BMECs. These transporters recognize a large spectrum of lipophilic substrates and pump them into capillary lumen to prevent their penetration across the BBB. 59 Beside BMECs, these transporters have also been found in many types of tumor cells, including glioma, 60 leukemia, 61 esophageal carcinoma, 62 and colon/lung/kidney cancer. 63, 64 Because many anticancer drugs are substrates of these transporters, 59, 65 the access of these drugs to CNS tissue or tumors is limited, making patients resistant to anticancer drug treatment, a phenomenon known as multidrug resistance. 65 In contrast to tumor cells, lower expression of these transporters was found in blood vessels supplying CNS metastases. 66 For example, P-glycoprotein levels in blood vessels around CNS metastases of melanoma and lung cancer were≈ 5% and 40% of that in normal brain tissue, respectively. 67 These data suggest that systematically delivered chemotherapy may reach CNS tumor cells, whereas it is hard to penetrate and kill them. Various inhibitors for these transporters, including verapamil, probenecid, and fumitremorgin C, have been used to increase drug delivery to brain tumors and improve the therapeutic efficacy. 66 On the other hand, excitatory amino acid transporters 1 to 3 are found solely on the abluminal side of BMECs to efficiently remove the excitatory neurotransmitter glutamate from the brain. 68 Low-density lipoprotein receptor-related protein 1, which is predominately expressed on the abluminal side of BMECs, facilitates the elimination of amyloid-β from the brain, 69–71 although there is also evidence suggesting that lipoprotein receptor-related protein 1 may not contribute to the efflux of amyloid-β across the BBB. 72, 73 Expressed only on the abluminal side of BMECs,(Na+-K …