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基质金属蛋白酶和肿瘤坏死因子释放酶在内毒素休克中都扮演重要角色。前期研究发现,同时抑制这两种酶的多肽抑制剂可保护内毒素休克小鼠。该研究合成多肽文库,筛选出了对基质金属蛋白酶和肿瘤坏死因子释放酶有选择性抑制活力的多肽抑制剂。在此基础上,建立了体外检测酶活力的模型,并比较了多肽抑制剂HQ 1～HQ4对中性粒细胞颗粒释放物中基质金属蛋白酶-9活力的抑制作用,发现5μmol/L的4种多肽抑制剂对基质金属蛋白酶-9酶活力的抑制率分别是79%,80%,43%和63%。同时建立了内毒素休克模型并考察了几种多肽抑制剂的体内活性,发现注射HQ1和HQ4组小鼠的生存率分别为50%和58.3%,而注射HQ2和HQ3组小鼠生存率仅为16.7%。这些结果证明了在该模型中,抑制基质金属蛋白酶具有更好的保护作用。这些工作使我们对内毒素休克模型的发病机理的认识又深入了一步。
Matrix metalloproteinases and tumor necrosis factor releasing enzymes play an important role in endotoxic shock. Previous studies have found that polypeptide inhibitors that inhibit both enzymes protect endotoxic shock mice. In this study, we synthesized a peptide library and screened out peptide inhibitors that selectively inhibit the activity of matrix metalloproteinase and tumor necrosis factor-releasing enzyme. On this basis, we established a model of detecting enzyme activity in vitro and compared the inhibitory effect of peptide inhibitors HQ 1 ~ HQ4 on the activity of MMP-9 in neutrophil granule release. It was found that 5μmol / L of 4 The inhibitory rates of polypeptide inhibitors on MMP-9 enzyme activity were 79%, 80%, 43% and 63%, respectively. At the same time, the model of endotoxic shock was established and the in vivo activities of several polypeptide inhibitors were investigated. The survival rates of mice injected with HQ1 and HQ4 were 50% and 58.3% respectively, while the survival rates of mice injected with HQ2 and HQ3 were only 16.7%. These results demonstrate that MMPs have a better protective effect in this model. These efforts have taken us one step further in our understanding of the pathogenesis of endotoxic shock models.