Neutralization of endotoxin in vitro and in vivo by a human lactoferrin-derived peptide
Neutralization of endotoxin in vitro and in vivo by a human lactoferrin-derived peptide
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DOI：
10.1128/iai.67.3.1353-1358.1999
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发表时间：
1999-03-01
影响因子：
3.1
通讯作者：
Tsai, CM
中科院分区：
文献类型：
--
作者：
Zhang, GH;Mann, DM;Tsai, CM
内毒素（脂多糖[LPS]）是革兰氏阴性菌感染性休克的主要致病因子，内毒素诱导的死亡与宿主过量产生肿瘤坏死因子α（TNF-α）有关。在寻找新的抗内毒素分子的过程中，我们研究了人乳铁蛋白衍生的33聚体合成肽（GRRRRSVQWCAVSQPEATKCFQWQRNMRKVRGP;命名为LF-33）的内毒素中和能力，该肽代表了乳铁蛋白与糖胺聚糖结合的最小序列。LF-33可抑制由脂质A和4种不同内毒素诱导的鲎变形细胞裂解物凝固和RAW 264.7细胞分泌TNF-α，其效力与多粘菌素B相当。LF-33 N端的前6个残基是其抗内毒素活性的关键。LF-33和多粘菌素B的内毒素中和能力被人血清减弱。在半乳糖胺致敏小鼠模型中，共注射大肠杆菌LPS（125 ng）和LF-33（2.5 μ g）可显著降低LPS的致死率。当在腹腔内注射LPS后静脉内给予LF-33（100 μ g）时，也观察到小鼠对致死性LPS攻击的显著保护。保护作用与小鼠血清中TNF-α水平的降低相关。这些结果证明了LF-33在体外和体内的内毒素中和能力及其用于治疗内毒素诱导的脓毒性休克的潜在用途。
Endotoxin (lipopolysaccharide [LPS]) is the major pathogenic factor of gram-negative septic shock, and endotoxin-induced death is associated with the host overproduction of tumor necrosis factor alpha (TNF-alpha). In the search for new antiendotoxin molecules, we studied the endotoxin-neutralizing capacity of a human lactoferrin-derived 33-mer synthetic peptide (GRRRRSVQWCAVSQPEATKCFQWQRNMRKVRGP; designated LF-33) representing the minimal sequence for lactoferrin binding to glycosaminoglycans. LF-33 inhibited the coagulation of the Limulus amebocyte lysate and the secretion of TNF-alpha by RAW 264.7 cells induced by lipid A and four different endotoxins with a potency comparable to that of polymyxin B. The first six residues at the N terminus of LF-33 were critical for its antiendotoxin activity. The endotoxin-neutralizing capacity of LF-33 and polymyxin B was attenuated by human serum. Coinjection of Escherichia coli LPS (125 ng) with LF-33 (2.5 mu g) dramatically reduced the lethality of LPS in the galactosamine-sensitized mouse model. Significant protection of the mice against the lethal LPS challenge was also observed when LF-33 (100 mu g) was given intravenously after intraperitoneal injection of LPS. protection was correlated with a reduction in TNF-alpha levels in the mouse serum. These results demonstrate the endotoxin-neutralizing capability of LF-33 in vitro and in vivo and its potential use for the treatment of endotoxin-induced septic shock.