PDF(Pubmed)
Abstract：
Oxidative stress is a prominent causal factor in the premature senescence of microvascular endothelial cells and the ensuing blood-brain barrier (BBB) dysfunction. Through the exposure of an in vitro model of human BBB, composed of brain microvascular endothelial cells (BMECs), astrocytes, and pericytes to H2O2, this study examined whether a specific targeting of the p38MAPK/NF-κB pathway and/or senescent cells could delay oxidative stress-mediated EC senescence and protect the BBB. Enlarged BMECs, displaying higher β-galactosidase activity, γH2AX staining, p16 expression, and impaired tubulogenic capacity, were regarded as senescent. The BBB established with senescent BMECs had reduced transendothelial electrical resistance and increased paracellular flux, which are markers of BBB integrity and function, respectively. Premature senescence disrupted plasma-membrane localization of the tight junction protein, zonula occludens-1, and elevated basement membrane-degrading matrix metalloproteinase-2 activity and pro-inflammatory cytokine release. Inhibition of p38MAPK by BIRB796 and NF-κB by QNZ and the elimination of senescent cells by a combination of dasatinib and quercetin attenuated the effects of H2O2 on senescence markers; suppressed release of the pro-inflammatory cytokines interleukin-8, monocyte chemoattractant protein-1, and intercellular adhesion molecule-1; restored tight junctional unity; and improved BBB function. In conclusion, therapeutic approaches that mitigate p38MAPK/NF-κB activity and senescent cell accumulation in the cerebrovasculature may successfully protect BBB from oxidative stress-induced BBB dysfunction.
摘要：
氧化应激是微血管内皮细胞过早衰老和随之而来的血脑屏障（BBB）功能障碍的主要原因。通过暴露人血脑屏障的体外模型，由脑微血管内皮细胞（BMECs）组成，星形胶质细胞,和周细胞对H2O2的作用，这项研究检查了p38MAPK/NF-κB途径和/或衰老细胞的特异性靶向是否可以延迟氧化应激介导的EC衰老并保护BBB。扩大了BMEC,表现出较高的β-半乳糖苷酶活性，γH2AX染色,p16表达，和受损的肾小管形成能力，被视为衰老。用衰老的BMEC建立的BBB具有降低的跨内皮电阻和增加的细胞旁通量，它们是BBB完整性和功能的标志物，分别。过早衰老破坏了紧密连接蛋白的质膜定位，闭塞带1，基底膜降解基质金属蛋白酶2活性升高和促炎细胞因子释放。QNZ通过BIRB796和NF-κB抑制p38MAPK，并通过达沙替尼和槲皮素的组合消除衰老细胞，可以减弱H2O2对衰老标志物的影响；抑制促炎细胞因子白介素8，单核细胞化学吸引蛋白1和细胞间粘附分子1的释放；恢复紧密连接；并改善BBB功能。总之,减轻p38MAPK/NF-κB活性和脑脉管系统中衰老细胞积累的治疗方法可能成功地保护BBB免受氧化应激诱导的BBB功能障碍。
