Targeting neutrophil collagenase/matrix metalloproteinase-8 and gelatinase B/matrix metalloproteinase-9 with a peptidomimetic inhibitor protects against endotoxin shock
Targeting neutrophil collagenase/matrix metalloproteinase-8 and gelatinase B/matrix metalloproteinase-9 with a peptidomimetic inhibitor protects against endotoxin shock
复制标题
DOI：
10.1016/j.bcp.2005.04.047
复制
发表时间：
2005-08-15
影响因子：
5.8
通讯作者：
Opdenakker, G
中科院分区：
文献类型：
--
作者：
Hu, JL;Van den Steen, PE;Opdenakker, G
革兰氏阴性脓毒症、细菌性脑膜炎和内毒素休克是危及生命的疾病，与中性粒细胞酶的快速释放有关。中性粒细胞胶原酶/基质金属蛋白酶-8（MMP-8）和明胶酶B/基质金属蛋白酶-9（MMP-9）包含在颗粒中，在粒细胞活化后迅速胞吐，并分别有效地切割完整和变性的胶原。明胶酶B的基因消除可防止内毒素诱导的死亡。因此，我们设计并合成了一种拟肽明胶酶B抑制剂Regasepinl，并比较了其对胶原酶MMP-1、MMP-8和MMP-13的选择性。Regasepini在体外对中性粒细胞酶MMP-8和MMP-9以及单核细胞肿瘤坏死因子-α（TNF-α）转化酶（TACE/ADAM- 17）的抑制程度几乎相同。使用质谱分析，在小鼠中腹膜内推注后测定抑制剂水平的血浆半衰期。抑制剂的血浆峰值水平在腹腔注射后50分钟达到，随后在循环中的半衰期超过40分钟。Regasepinl通过腹腔和静脉注射途径保护小鼠免受致死性内毒素血症。这证明了以下原则：早期中性粒细胞MMP抑制，随后进行TACE阻断，可能成为革兰氏阴性脓毒症、内毒素血症和其他危及生命的炎症反应的治疗策略。(c)2005年爱思唯尔公司All rights reserved.
Gram-negative sepsis, bacterial meningitis and endotoxin shock are life-threatening disorders, associated with the rapid release of neutrophil enzymes. Neutrophil collagenase/matrix metalloproteinase-8 (MMP-8) and gelatinase B/matrix metalloproteinase-9 (MMP-9) are contained in granules, are quickly exocytosed upon granulocyte activation and efficiently cleave intact and denatured collagens, respectively. Genetic ablation of gelatinase B protects against endotoxin- induced mortality. Therefore, we designed and synthesized a peptidomimetic gelatinase B inhibitor Regasepinl, and compared the selectivity for the collagenases MMP-1, MMP-8 and MMP-13. Regasepini was found to inhibit, almost to the same degree, the neutrophil enzymes MMP-8 and MMP-9 and the monocytic tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE/ADAM- 17) in vitro. With the use of mass spectrometry analysis, the plasma half-life of inhibitor levels was determined after an intraperitoneal bolus injection in mice. Plasma peak levels of the inhibitor were reached at 50 min after intraperitoneal injection and the subsequent half-life in the circulation exceeded 40 min. Regasepinl protected mice against lethal endotoxinemia by intraperitoneal and intravenous injection routes. This proofs the principle that early neutrophil MMP inhibition followed by TACE blockade may become a treatment strategy of gram-negative sepsis, endotoxinernia and other life-threatening inflammatory reactions. (c) 2005 Elsevier Inc. All rights reserved.