Zwitterionic chitosan for the systemic treatment of sepsis.
Zwitterionic chitosan for the systemic treatment of sepsis.
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DOI：
10.1038/srep29739
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发表时间：
2016-07-14
影响因子：
4.6
通讯作者：
Yeo Y
中科院分区：
文献类型：
--
作者：
Cho EJ;Doh KO;Park J;Hyun H;Wilson EM;Snyder PW;Tsifansky MD;Yeo Y
严重败血症和感染性休克是危及生命的疾病，大多数败血症死亡率由革兰氏阴性菌引起。阻断脂多糖（脂多糖是革兰氏阴性外细胞膜的组成部分）作用的化合物的全身管理受到其疏水性和阳离子电荷的阻碍，这些特性正是它们与脂多糖相互作用的原因。我们假设，一种壳聚糖衍生物两性离子壳聚糖（ZWC）可以抑制LPS挑战的巨噬细胞中促炎细胞介质的产生，对全身注射LPS诱导的脓毒症动物模型具有保护作用。在本研究中，我们利用PMJ2-PC腹腔巨噬细胞系，评估了ZWC是否能减弱LPS对C57BL/6小鼠的致死作用，并探讨了ZWC抵消LPS作用的机制。与低水溶性的母体化合物不同，腹腔注射的ZWC易于吸收，在注射部位没有局部残留或不良组织反应。无论是在LPS攻击中还是之前给药，ZWC都能使动物的中位生存时间增加一倍以上。ZWC似乎通过与LPS形成复合物来保护LPS挑战的生物体，从而减弱促炎信号通路。这些结果表明，ZWC作为一种系统性抗脂多糖剂具有实用价值。
Severe sepsis and septic shock are life-threatening conditions, with Gram-negative organisms responsible for most sepsis mortality. Systemic administration of compounds that block the action of lipopolysaccharide (LPS), a constituent of the Gram-negative outer cell membrane, is hampered by their hydrophobicity and cationic charge, the very properties responsible for their interactions with LPS. We hypothesize that a chitosan derivative zwitterionic chitosan (ZWC), previously shown to suppress the production of pro-inflammatory cellular mediators in LPS-challenged macrophages, will have protective effects in an animal model of sepsis induced by systemic injection of LPS. In this study, we evaluate whether ZWC attenuates the fatal effect of LPS in C57BL/6 mice and investigate the mechanism by which ZWC counteracts the LPS effect using a PMJ2-PC peritoneal macrophage cell line. Unlike its parent compound with low water solubility, intraperitoneally administered ZWC is readily absorbed with no local residue or adverse tissue reaction at the injection site. Whether administered at or prior to the LPS challenge, ZWC more than doubles the animals’ median survival time. ZWC appears to protect the LPS-challenged organisms by forming a complex with LPS and thus attenuating pro-inflammatory signaling pathways. These findings suggest that ZWC have utility as a systemic anti-LPS agent.