血管紧张素II在高血压介导的牙周病骨吸收过程中作用机制的研究

The consequence of primary hypertension (PH) is a serious disease that will cause severe damage of human body, which is also considered as a systematic disease that will cause abnormal of immune system. Periodontal diseases are also considered to have close relationship with dysregulation of immune response. Retrospective studies have shown that periodontal diseases are closely related to PH. However, there is still no experimental studies show that how PH affect the development of periodontal diseases. Our preliminary studies demonstrated that PH may affect the periodontal diseases by Angiotensin (AngII), which will regulate the expression and function of Toll-like receptor 4 (TLR4) and the continued immune responses in the lesion areas. The in vitro study further showed that Signal transducer and activator of transcription 3 (STAT3) may play a critical function during the process of regulation of AngII on TLR4 in dendritic cells (DCs).Therefore, we hypothesize that AngII may activate the STATs, which will then increase the function and expression of TLR4 by unclear mechanism in DCs. The increase of TLR4 will lead to uncontrolled immune response and the following activation of osteoclasts mediated bone destruction in periodontitis lesion areas. To prove our hypothesize, we will establish the periodontitis accompanied by PH mouse model, to explore the possible mechanism of STAT3 on how AngII regulates expression and function of TLR4, which will make a great impact on the progress of how PH affect the oral infectious bone diseases.

原发性高血压（PH）可导致严重的全身病变，且其作为全身性的系统疾病，可引起机体免疫反应的异常。机体免疫失调也被认为是牙周病的主要病因，临床回顾性研究表明其与PH有着密切的关系。但PH如何对牙周病产生影响，并无实验研究其在作用机制。我们的前期研究表明PH可通过血管紧张素II（AngII）对Toll样受体4（TLR4）在牙周病变区域进行调控，导致持续的免疫反应。体外研究进一步证明，树突细胞（DCs）中信号传导与转录激活因子3（STAT3）在AngII对TLR4的调控过程中可能起着关键的作用。我们推测在牙周病伴发PH时，AngII通过STAT3促进TLR4样受体在DCs中的表达增加，从而活化DCs使其持续参与免疫反应并导致牙周组织破坏。为了验证这一假设，我们将建立PH牙周病小鼠模型，探讨STAT3在AngII对TLR4调控过程中可能的作用方式，从新的视角阐明PH促进牙周病骨吸的分子机制。

研究背景：原发性高血压(PH)可导致严重的全身病变，且其作为全身性的系统疾病，可引起机体免疫反应的异常。机体免疫失调也被认为是牙周病的主要病因，临床回顾性研究表明其与PH有着密切的关系。但PH如何对牙周病产生影响，并无实验研究其内在作用机制。.研究内容：本研究旨在通过描述这种关联的机制，并揭示共同的病理特征来探索治疗牙周炎和高血压的新疗法。通过构建Nos3-/-相关的高血压小鼠模型以及牙周炎小鼠疾病模型在体内研究了AngII介导牙槽骨吸收的相关分子机制。.重要结果及关键数据：（1）揭示了在牙周病伴发高血压情况下，AngII促进了病变区域DCs表面TLR4的表达增加，同时上调了牙周炎病变中TLR4基因及其下游通路及炎症因子的表达，导致炎症反应的持续激活，导致破骨细胞介导的骨吸收加重。在牙周病伴发高血压的情况下，牙周区域内B、T淋巴细胞、巨噬细胞数量增多，牙槽骨吸收的程度加重。抑制STAT1的表达，骨吸收程度会降低，同时免疫细胞的数量也会下降。（2）申请人证明了AngII与LPS共刺激可以增加TLR4及体外促炎基因的表达。AngII可以刺激免疫细胞进一步释放炎症因子，同时能对STAT3存在负调节作用。AngII与LPS共同刺激后，炎症因子表达水平较对照组与单刺激组均有明显增高。STAT1磷酸化水平，下游因子CXCL9mRNA，JAK/STAT3抑制因子SOCS3mRNA以及炎性因子表达水平，较对照组与单刺激组均有明显增高，而STAT3磷酸化水平及下游抑炎因子IL10 mRNA表达水平较LPS单纯刺激组显著下降。.科学意义：AngII在高血压介导的牙周炎骨吸收中有着重要作用，其主要通过促进牙周炎牙龈病变区域中的TLR4高表达而加重牙周炎，STAT1可能是潜在的牙周炎治疗靶点。.