MDSC在脓毒症急性肺损伤发生发展中的作用及分子机制

Acute lung injury (ALI) is a common respiratory critical illness with higher incidence and mortality，of which the most common risk factor is sepsis. The pathogenesis of acute lung injury is not well understood, thus specific remedies to treat the disease remain limited. Myeloid-derived suppressor cell (MDSC), a population of cells with immunosuppressive activity, plays an important role in lung disease. Studies including our previous work have found that a large numbers of MDSC gathered in lungs of patients and mice with sepsis-induced ALI, but its role in the pathogenesis of sepsis-induced ALI has not been described. Based on the previous work and using technology platforms (such as cellular adoptive transfer, cell coculture, knock-out animal models, et al.), this project is designed to identify critical roles of MDSC in sepsis-induced ALI and explore the molecular mechanisms, and find out the correlation between MDSC and progression of the disease in patients with sepsis-induced ALI. From bench to bedside, this project will clarify that MDSC plays an important role in sepsis-induced ALI on systemic, cellular and molecular levels. This has not only important theoretical significance in deepening the pathogenesis of sepsis-induced ALI from the perspective of immune cell regulation, but also substantial clinical significance to explore new targets for the prevention and treatment of sepsis-induced ALI, and lay the foundation for opening the door to new immunomodulatory therapeutic approaches.

急性肺损伤(ALI)是发病率和死亡率较高的常见呼吸系统危重症，以脓毒症ALI最为常见，其发病机制尚未完全明确。髓系来源的抑制性细胞(MDSC)是机体内重要的免疫抑制细胞,在肺部疾病中有重要作用。国外研究和我们的前期研究发现脓毒症ALI患者和小鼠肺部聚集大量MDSC，但其在脓毒症ALI发病中的作用尚未阐述。本项目采用细胞过继转移、细胞共培养以及knock-out动物模型等技术平台，明确MDSC在脓毒症ALI中的作用和重要地位，探讨MDSC在脓毒症ALI中作用的分子机制，并临床观察MDSC与脓毒症ALI患者病程发展的相关性。本项目从bench到bedside，在整体、细胞、分子水平上阐明MDSC是脓毒症ALI的一个重要因素。不仅从免疫细胞调控角度对深化脓毒症ALI的发病机制具有重要理论意义，而且为脓毒症ALI的防治探索新的靶标，为开辟免疫调节治疗新策略奠定基础，具有重大的临床意义。

本项目采用细胞及动物模型，运用流式细胞术等多种免疫学和细胞生物学技术，比照经典肿瘤来源的MDSCs和naïve MDSCs，①阐述了脓毒症小鼠MDSCs的表型特点：脓毒症模型来源的MDSCs的单核样MDSCs亚群比例增高；两种模型MDSCs均表达CD115，CD34，CD11C和F4/80等表面标记物，相对于肿瘤来源的MDSCs，脓毒症来源的细胞表面集落刺激因子受体CD115明显下降；②阐明了MDSCs在脓毒症中的功能特征：脓毒症来源的MDSCs与肿瘤来源的相比，抑制T细胞为核心的获得性免疫功能较弱，而对于巨噬细胞为主的固有免疫，则呈现于肿瘤来源MDSCs截然相反的功能，且脓毒症病理状态下MDSCs在LPS刺激后分泌更多的促炎因子；③发现脓毒症来源MDSCs mRNAs的全基因组表达谱特征，分析差异表达，探索了脓毒症MDSCs表型及功能特点的内在机制: 脓毒症来源MDSCs相对naïve MDSCs，53个转录本表达上调，而肿瘤来源细胞有423个上调，二者有41个基因为共同上调基因；脓毒症来源MDSCs相对naïve MDSCs，47个转录本表达下调，而肿瘤来源细胞有576个上调，二者有21个基因共同下调。本项目从免疫细胞调控角度对阐述脓毒症的发病机制具有一定的理论意义。本项目共发表SCI 收录论文6 篇；获奖2项；授权实用新型专利1项；在国内学术会议作特邀报告1次、参加国际学术会议3人次；获国家卫计委有突出贡献中青年专家、浙江省卫生领军人才培养对象；培养了博士研究生3名。