Fusion Peptides CPU1 and CPU2 Inhibit Matrix Metalloproteinases and Protect Mice from Endotoxin Shock Within a Strict Time Window

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• 作者：Zheng Qiu ; Fengguo Zhang ; Chengxin Gong ; Hanmei Xu ; Jialiang Hu
• 关键词：endotoxin shock ; matrix metalloproteinase ; peptide inhibitor ; indirect competitive ELISA ; zymography
• 刊名：Inflammation
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：38
• 期：6
• 页码：2092-2104
• 全文大小：1,417 KB
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• 作者单位：Zheng Qiu (1)
  Fengguo Zhang (1)
  Chengxin Gong (1) (2)
  Hanmei Xu (1) (2)
  Jialiang Hu (1) (2)
  
  1. State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, 210009, Peoples Republic of China
  2. The Engineering Research Center of Peptide Drug Discovery and Development, China Pharmaceutical University, Nanjing, 210009, Peoples Republic of China
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Rheumatology
  Internal Medicine
  Pharmacology and Toxicology
  Pathology
  
• 出版者：Springer Netherlands
• ISSN：1573-2576

文摘

Endotoxin shock induction in mice is a commonly used animal model to evaluate the protective effect of biologically active reagents. After an lipopolysaccharides (LPS) stimulus, matrix metalloproteinase-8 (MMP-8) and matrix metalloproteinase-9 (MMP-9) are rapidly degranulated and released by neutrophils, aside other enzymes and effector molecules. MMPs cleave extracellular matrix components and cytokines, and such processes contribute to shock syndrome development. CPU1 and CPU2 are two peptide MMP inhibitors with different in vitro IC50 values to several key enzymes, including MMP-8 and MMP-9. In vivo work confirmed that CPU1 and CPU2 protected mice from endotoxin shock after intravenous and intraperitoneal injections. Furthermore, their minimal effective dose after an intravenous injection and the maximum time interval between intraperitoneal peptide injection (150 mg/kg) and intravenous LPS injection were determined. With the use of an indirect competitive ELISA, plasma CPU1 and CPU2 concentrations in different experimental settings were measured. In addition, the acuteness of MMP-9 release in the mouse circulation after an intravenous LPS injection was confirmed with the zymography technique. Our findings reinforce previous work with other inhibitors about a strict time window within which effective MMP inhibition is needed to obtain significant survival rate improvements and also show that, with strict pharmacokinetic monitoring, potent protease inhibitors may in the future become life-savers in shock conditions. KEY WORDS endotoxin shock matrix metalloproteinase peptide inhibitor indirect competitive ELISA zymography