Jin Liang, Nation Roger L, Li Jian, Nicolazzo Joseph A
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
Antimicrob Agents Chemother. 2013 Sep;57(9):4336-4342. doi: 10.1128/AAC.00765-13. Epub 2013 Jun 24.
The aim of this study was to use and models to assess the impact of lipopolysaccharide (LPS) from two different bacterial species on blood-brain barrier (BBB) integrity and brain uptake of colistin. Following repeated administration of LPS from , the brain-to-plasma ratio of [C]sucrose in Swiss outbred mice was not significantly increased. Furthermore, while the brain uptake of colistin in mice increased 3-fold following administration of LPS from , LPS from had no significant effect on colistin brain uptake. This apparent species-dependent effect did not appear to correlate with differences in plasma cytokine levels, as the concentrations of tumor necrosis factor alpha and interleukin-6 following administration of each LPS were not different ( > 0.05). To clarify whether this species-specific effect of LPS was due to direct effects on the BBB, human brain capillary endothelial (hCMEC/D3) cells were treated with LPS from or and claudin-5 expression was measured by Western blotting. LPS significantly ( < 0.05) reduced claudin-5 expression at a concentration of 7.5 μg/ml. In contrast, LPS decreased ( < 0.05) claudin-5 expression only at the highest concentration tested (i.e., 30 μg/ml). Coadministration of therapeutic concentrations of colistin ameliorated the LPS-induced reduction in claudin-5 expression in hCMEC/D3 cells and the perturbation in BBB function in mice. This study demonstrates that BBB disruption induced by LPS is species dependent, at least between and , and can be ameliorated by colistin.
本研究的目的是使用[具体模型名称未给出]模型来评估来自两种不同细菌物种的脂多糖（LPS）对血脑屏障（BBB）完整性和黏菌素脑摄取的影响。在重复给予[细菌物种一名称未给出]的LPS后，瑞士远交系小鼠中[C]蔗糖的脑-血浆比值未显著增加。此外，虽然在给予[细菌物种二名称未给出]的LPS后小鼠中黏菌素的脑摄取增加了3倍，但[细菌物种一名称未给出]的LPS对黏菌素脑摄取没有显著影响。这种明显的物种依赖性效应似乎与血浆细胞因子水平的差异无关，因为给予每种LPS后肿瘤坏死因子α和白细胞介素-6的浓度没有差异（P>0.05）。为了阐明LPS的这种物种特异性效应是否是由于对血脑屏障的直接作用，用人脑微血管内皮（hCMEC/D3）细胞分别用[细菌物种一名称未给出]或[细菌物种二名称未给出]的LPS处理，并通过蛋白质印迹法测量紧密连接蛋白-5（claudin-5）的表达。[细菌物种一名称未给出]的LPS在浓度为7.5μg/ml时显著（P<0.05）降低了claudin-5的表达。相比之下，[细菌物种二名称未给出]的LPS仅在测试的最高浓度（即30μg/ml）时降低（P<0.05）claudin-5的表达。联合给予治疗浓度的黏菌素可改善[细菌物种一名称未给出]的LPS诱导的hCMEC/D3细胞中claudin-5表达的降低以及小鼠血脑屏障功能的紊乱。本研究表明，LPS诱导的血脑屏障破坏具有物种依赖性，至少在[细菌物种一名称未给出]和[细菌物种二名称未给出]之间是这样，并且可以被黏菌素改善。
