Department of Anesthesiology and Pain Medicine, University of Alberta, Edmonton, Alberta, Canada.
Anesthesiology. 2012 Apr;116(4):841-56. doi: 10.1097/ALN.0b013e31824babfe.
Mesenchymal stem cells (MSC) are self-renewing clonal progenitor cells of nonhematopoietic tissues that exhibit a marked tropism to wounds and tumors. The authors' studies aimed at exploring how local anesthetics would affect MSC biology.
Proliferation, colony formation, in vitro wound healing, and bone differentiation assays of culture-expanded bone-marrow-derived murine MSC were performed in the presence of increasing concentrations of lidocaine, ropivacaine, and bupivacaine. Cytotoxicity was monitored by measuring lactate dehydrogenase activity and phosphatidylserine exposure/propidium iodide staining (early apoptotic cells/necrotic cells). Measurements of mitochondrial function in intact and permeabilized cells, transcriptional changes, and changes in nuclear factor κ-light-chain-enhancer of activated B cells signaling in MSC treated with ropivacaine were used to further characterize the biologic effects of local anesthetics on MSC.
All local anesthetics reduced MSC proliferation at 100 μM, consistent with cell cycle delay or arrest at the G0/1-S phase transition. They increased lactate dehydrogenase release and the number of annexin V-positive MSC but not necrotic MSC. Colony formation was decreased, differentiation into osteoblasts impaired, and in vitro wound healing delayed. Mitochondrial respiration and adenosine 5'-triphosphate concentrations were reduced. Microarray analysis revealed significant expression changes in lysosomal genes and genes controlling sterol metabolism, indicating an impaired phospholipid metabolism in the lysosome. Multiple transcriptional programs related to cell differentiation, tumorigenesis, and metastasis were negatively affected by ropivacaine.
The authors' studies demonstrate that local anesthetics significantly affect important aspects of MSC biology. These experiments provide novel rationales for the perioperative use of local anesthetics in patients with cancer but also highlight the potentially detrimental effects of local anesthetics on wound healing.
间充质干细胞（MSC）是自我更新的非造血组织克隆祖细胞，对创伤和肿瘤具有明显的趋向性。作者的研究旨在探索局部麻醉剂将如何影响 MSC 生物学。
在不同浓度的利多卡因、罗哌卡因和布比卡因存在的情况下，对体外扩增的骨髓源性鼠 MSC 进行增殖、集落形成、体外伤口愈合和骨分化测定。通过测量乳酸脱氢酶活性和磷脂酰丝氨酸暴露/碘化丙啶染色（早期凋亡细胞/坏死细胞）来监测细胞毒性。还使用完整和通透细胞的线粒体功能测量、转录变化以及罗哌卡因处理的 MSC 中核因子 κB 轻链增强子激活 B 细胞信号转导的变化来进一步表征局部麻醉剂对 MSC 的生物学影响。
所有局部麻醉剂在 100μM 时均降低 MSC 增殖，这与细胞周期在 G0/1-S 期转变时的延迟或阻滞一致。它们增加了乳酸脱氢酶的释放和膜联蛋白 V 阳性 MSC 的数量，但不增加坏死 MSC 的数量。集落形成减少，向成骨细胞分化受损，体外伤口愈合延迟。线粒体呼吸和三磷酸腺苷浓度降低。微阵列分析显示溶酶体基因和控制固醇代谢的基因的表达发生显著变化，表明溶酶体中磷脂代谢受损。与细胞分化、肿瘤发生和转移相关的多个转录程序受到罗哌卡因的负面影响。
作者的研究表明，局部麻醉剂显著影响 MSC 生物学的重要方面。这些实验为癌症患者围手术期使用局部麻醉剂提供了新的理由，但也强调了局部麻醉剂对伤口愈合的潜在有害影响。
