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利奈唑胺诱导的血小板减少是由肌球蛋白轻链2磷酸化抑制血小板生成所致。

Linezolid-Induced Thrombocytopenia Is Caused by Suppression of Platelet Production via Phosphorylation of Myosin Light Chain 2.

作者信息

Tajima Masataka, Kato Yoshinori, Matsumoto Jun, Hirosawa Iori, Suzuki Mariko, Takashio Yuki, Yamamoto Mao, Nishi Yoshifumi, Yamada Harumi

机构信息

Department of Pharmaceutical Sciences, International University of Health and Welfare.

出版信息

Biol Pharm Bull. 2016;39(11):1846-1851. doi: 10.1248/bpb.b16-00427.

Abstract

Linezolid (LZD) is an antimicrobial that is commonly used for treatment of vancomycin-resistant Enterococci and methicillin-resistant Staphylococcus aureus infections. However, the development of thrombocytopenia, one of the most frequent adverse side effects of this antimicrobial, can lead to discontinuation of LZD treatment. While clinical studies indicate that risk factors for the development of LZD-induced thrombocytopenia include treatment for >14 consecutive days, renal dysfunction, and chronic liver disease, the fundamental mechanism governing the pathogenesis of this disorder remains unclear. In this study, we aimed to elucidate the mechanism of LZD-induced thrombocytopenia by investigating the impact of LZD treatment on platelet destruction and production using rat platelet-rich plasma (PRP) and human immortalized cell lines, respectively. Compared to the control population, an increase in lactate dehydrogenase release was not detected upon exposure of rat PRP to varying concentrations of LZD, indicating that this compound is not cytotoxic towards platelets. Meanwhile, LZD treatment resulted in a significant dose-dependent increase in the proliferation of HEL human erythroleukemia and MEG-01 human megakaryoblast cells in vitro, but did not influence the differentiation of these cell lines. Lastly, LZD treatment yielded elevated levels of phosphorylation of myosin light chain 2 (MLC2), which regulates platelet release, in MEG-01 cells. Based on these results, we speculate that LZD induces thrombocytopenia by promoting MLC2 phosphorylation and thereby suppressing the release of platelets from mature megakaryocytes. These findings provide the first insight into the mechanism of LZD-mediated thrombocytopenia and may facilitate the development of strategies to treat and/or prevent this disease.

摘要

利奈唑胺(LZD)是一种抗菌药物,常用于治疗耐万古霉素肠球菌和耐甲氧西林金黄色葡萄球菌感染。然而,血小板减少症作为这种抗菌药物最常见的副作用之一,其发生会导致利奈唑胺治疗中断。虽然临床研究表明,利奈唑胺诱导的血小板减少症的危险因素包括连续治疗超过14天、肾功能不全和慢性肝病,但这种疾病发病机制的根本原因仍不清楚。在本研究中,我们旨在通过分别使用大鼠富血小板血浆(PRP)和人永生化细胞系研究利奈唑胺治疗对血小板破坏和生成的影响,来阐明利奈唑胺诱导血小板减少症的机制。与对照组相比,将大鼠PRP暴露于不同浓度的利奈唑胺后,未检测到乳酸脱氢酶释放增加,这表明该化合物对血小板无细胞毒性。同时,利奈唑胺治疗导致体外HEL人红白血病细胞和MEG - 01人巨核母细胞的增殖显著呈剂量依赖性增加,但不影响这些细胞系的分化。最后,利奈唑胺治疗使MEG - 01细胞中调节血小板释放的肌球蛋白轻链2(MLC2)的磷酸化水平升高。基于这些结果,我们推测利奈唑胺通过促进MLC2磷酸化从而抑制成熟巨核细胞释放血小板来诱导血小板减少症。这些发现首次揭示了利奈唑胺介导的血小板减少症的机制,并可能有助于开发治疗和/或预防这种疾病的策略。

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