磷酸酶Wip1介导中性粒细胞功能，调控重症脓毒性腹膜炎机制探讨

项目名称： 磷酸酶Wip1介导中性粒细胞功能，调控重症脓毒性腹膜炎机制探讨

项目编号： No.81500432

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 沈晓菲

作者单位： 南京大学

项目金额： 18万元

中文摘要： Wip1是磷酸酶PP2C家族的一员，调控着神经、肝细胞再生、细胞修复等多种生命活动，但在重症感染领域的研究尚属空白。我们的前期研究发现脓毒性腹膜炎患者与健康志愿者相比，外周血中性粒细胞内Wip1表达水平有所下调，但在重症患者，Wip1的下调程度不如轻症患者显著，且伴随有趋化能力减弱；通过构建小鼠重症脓毒性腹膜炎模型，我们发现Wip1-/-小鼠生存率显著高于Wip1+/+小鼠，且腹腔内菌落计数显著减少，进一步地运用流式细胞术，我们发现Wip1-/-小鼠外周血粒细胞CXCR2表达水平显著高于Wip1+/+小鼠，上述结果提示Wip1可能通过影响粒细胞表达CXCR2，介导其在感染灶的浸润，从而对重症脓毒性腹膜炎起到调控作用。因此，运用Wip1-/-CXCR2-/-、Wip1-/-、CXCR2-/-等多种基因敲除小鼠，深入探索Wip1调控重症脓毒性腹膜炎的机制，将为临床治疗提供新的思路。

中文关键词： 磷酸酶Wip1；中性粒细胞；重症脓毒性腹膜炎；趋化因子受体CXCR2；脓毒血症

英文摘要： Emerging evidence highlights the importance of a new member of the PP2C family of phosphatase, Wild-type p53 induced phosphatase 1 (Wip1), in regulating DNA damage-induced and tumorigenesis-induced networks. Latest studies also showed that Wip1 played a critical role in regulating neural development and Hepatocyte regeneration. However, there is still no related reports on the exact role of Wip1 in the regulation of severe infection. In our clinical studies, we found that downrgulation of Wip1 occurs both in the neutrophils of non-severe septic peritonitis patients and severe septic peritonitis patients, while patients with non-severe septic peritonitis showed a sharpen reduction of Wip1 expression; with the use of animal model of severe septic peritonitis(CLP), we further found that Wip1 knock out mice showed resistent to severe septic peritonitis with more infiltration of neutrophils into abdominal cavity and less infiltration into lung tissues. With the help of cytometry, we discovered that the level of CXCR2 on neutrophils in Wip1 knock out mice after CLP was significantly higher than that in wild type mice. Taken together, these results suggested that Wip1 may influence the expression of CXCR2 on neutrophils to mediate the infiltration of neutrophils into abdominal cavity and further complete the function of eliminating pathogens. In the present study, we aimed to investigate the celluar and molecular mechanisms of Wip1 in regulating severe septic peritonitis. By employing transgenic mice such as Wip1-/- , CXCR2-/- and Wip1-/-CXCR2-/- mice, which would receive CLP and in vitro fuctional studies. Based on the experimental evidence, We hope to propose a new idea of the therapuetic strategy for severe septic peritonitis.

英文关键词： phosphatase Wip1;neutrophil;severe septic peritonitis;chemokine CXCR2;sepsis