右美托咪定调控髓系抑制细胞及其机制研究

Dexmedetomidine (DEX) is a central α2-adrenergic receptor (α2-AR) agonist which has been widely used in general anesthesia intubation and ventilation sedation. There has been reported that DEX possess antisympathetic and relieve stress reaction effects. Our preliminary studies demonstrated that myeloid derived suppressor cells (MDSCs) significantly increased in peripheral blood and lung tissue when the body is suffered from surgery or lung injury. Further study revealed that MDSCs expressed high level of α2-AR in such acute stress conditions. Based on these results, we hypothesize that when a patient is infected or suffered from a surgery stress the administration of DEX may suppress MDSCs and then improve the prognosis of disease. To verify this hypothesis, we will use surgical operation on a mouse tumor model and acute respiratory distress syndrome (ARDS) model, to investigate the regulatory effects of DEX on MDSCs and the influence of DEX on the prognosis of tumor surgery and ARDS. An MDSCs induction system in vitro will be further performed to clarify the molecular mechanisms about the regulatory effect of DEX on MESCs. Our research will provide a foundation for verifying the mechanisms involved in immune regulatory of DEX through a new point of DEX regulating MDSCs, which will provide a new strategy for clinical application of DEX.

右美托咪定(DEX)是一种高选择性α2肾上腺素能受体(α2-AR)激动剂，多用于全麻手术插管和通气时的镇静。近年来研究表明DEX具有抑制交感活性、减轻应激反应的特性。我们的前期研究显示手术和肺损伤等急性应激状态时，外周血和肺组织中髓系抑制细胞(MDSCs)显著升高。进一步研究结果表明，应激状态下MDSCs表达α2-AR水平升高。为此，我们提出假说：在手术或感染等急性应激状态时给予DEX可能通过调控MDSCs减轻应激反应进而改善疾病预后。为验证该假说，本课题拟采用小鼠手术切除肿瘤和急性呼吸窘迫综合征(ARDS)模型，探讨围手术期或ARDS时给予DEX对MDSCs的调控以及给予DEX对肿瘤术后和ARDS预后的影响。并利用体外诱导MDSCs的方法，进一步揭示DEX调控MDSCs的分子机制。本研究将从DEX调控MDSCs这一新视点为揭示DEX的免疫调控机制奠定基础，为DEX的临床应用提供新的思路。

右美托咪定（Dexmedetomidine，DEX ）可促肿瘤转移，但其机制尚不明确。本项目探讨DEX对髓系来源抑制细胞（Myeloid-derived suppressor cells，MDSC）的调控作用及其相关的机制。本研究结果表明：（1）DEX诱导肺癌患者术后单核样MDSC（M-MDSC）：肺癌患者给予DEX于术后外周血中MDSC较术前显著升高，其中M-MDSC显著升高但粒细胞样MDSC（G-MDSC）无变化。（2）DEX诱导的M-MDSC具有免疫抑制和促血管生成活性：分选肺癌患者术后外周血中G-MDSC和M-MDSC，体外实验观察其对T细胞增殖的抑制作用。结果表明DEX诱导的M-MDSC具有更强的免疫抑制活性。给予DEX的肺癌患者术后外周血中VEGF水平显著升高，其外周血M-MDSC中VEGF表达水平也显著升高。（3）DEX诱导M-MDSC促进小鼠术后肿瘤肺转移：C57BL/6荷瘤小鼠于肿瘤切除后给予DEX，连续注射5天后小鼠外周血和肺组织中M-MDSC显著升高，小鼠肺转移灶数量显著增多。（4）DEX诱导M-MDSC减轻小鼠ARDS肺损伤：LPS诱导ARDS小鼠给予DEX后外周血和肺组织中M-MDSC显著升高，小鼠生存期显著延长。（5）DEX诱导MDSC向M-MDSC亚群分化：小鼠CD34+骨髓细胞诱导MDSC体系中加入DEX后M-MDSC数量显著升高，其免疫抑制和分泌VEGF活性显著增强。（6）DEX激活STAT-3调控MDSC的分化：对M-MDSC和G-MDSC亚群检测发现M-MDSC中STAT-3表达较G-MDSC显著升高；将STAT-3的表达抑制后可阻断DEX对MDSC的调控作用。综合上述研究结果，本研究揭示了DEX对MDSC的调控作用及其机制，为DEX的临床应用奠定了坚实的工作基础。项目资助发表SCI收录论著2篇。