Reis Julia, Tan Xiaoyu, Yang Rongjie, Rockwell Cheryl E, Papasian Christopher J, Vogel Stefanie N, Morrison David C, Qureshi Asaf A, Qureshi Nilofer
Departments of Basic Medical Science, Pharmacology/Toxicology, Surgery, and Shock/Trauma Research Center, University of Missouri-Kansas City, Kansas City Missouri, USA.
Innate Immun. 2008 Oct;14(5):319-29. doi: 10.1177/1753425908096855.
Our recent studies with lactacystin, a prototype proteasome inhibitor, have suggested that the proteasome is a key regulator of LPS-induced signaling pathways contributing to the inflammatory process. Moreover, lactacystin protects animals from LPS-induced shock. Therefore, we sought to identify other less toxic compounds that would block the chymotrypsin-like activity of the proteasome or LPS-induced nitric oxide (NO). After screening over 100 natural compounds (based on chemistry and inhibition of LPS-induced biological activities), we now report for the first time that quercetin, like lactacystin (the prototype proteasome inhibitor), and mevinolin are also inhibitors of the chymotrypsin-like activity of the cellular proteasome within living cells. In addition, this study also suggests that mevinolin and quercetin both have relatively potent anti-inflammatory effects on LPS-treated macrophages in vitro. Interestingly, both of these compounds behave like lactacystin in that they block LPS-induced NO to a greater extent than TNF-alpha. The results of our experiments clearly suggest that mevinolin, in combination with the antibiotic imipenem, can provide protection against polymicrobial septic lethality induced by cecal-ligation and puncture in mice. Collectively, these studies strongly support the conclusion that therapeutic targeting of cellular proteasomes, in conjunction with standard antimicrobial therapy, may be of considerable survival benefit in the treatment of septic shock.
我们近期使用蛋白酶体抑制剂原型乳胞素进行的研究表明，蛋白酶体是脂多糖（LPS）诱导的、导致炎症过程的信号通路的关键调节因子。此外，乳胞素可保护动物免受LPS诱导的休克。因此，我们试图寻找其他毒性较小的化合物，这些化合物能够阻断蛋白酶体的类胰凝乳蛋白酶活性或LPS诱导的一氧化氮（NO）。在筛选了100多种天然化合物（基于化学性质以及对LPS诱导的生物活性的抑制作用）之后，我们首次报告，槲皮素与乳胞素（蛋白酶体抑制剂原型）和洛伐他汀一样，也是活细胞内细胞蛋白酶体类胰凝乳蛋白酶活性的抑制剂。此外，本研究还表明，洛伐他汀和槲皮素在体外对LPS处理的巨噬细胞均具有较强的抗炎作用。有趣的是，这两种化合物的作用方式与乳胞素类似，即它们对LPS诱导的NO的阻断作用比对肿瘤坏死因子-α（TNF-α）的阻断作用更强。我们的实验结果清楚地表明，洛伐他汀与抗生素亚胺培南联合使用，可保护小鼠免受盲肠结扎和穿刺诱导的多微生物败血症致死作用。总的来说，这些研究有力地支持了以下结论：在治疗败血症性休克时，以细胞蛋白酶体为治疗靶点并结合标准抗菌疗法，可能对提高生存率有显著益处。
