实验性牙周炎促血小板CD62P和CD63表达的作用及干预对其表达的影响

Periodontitis are a group of chronic infectious diseases.It is recently reported that periodontitis were associated with increased platelet activation. As in periodontitis, low grade systematic inflammation and bacteremia occur regularly. Such events may contribute to platelet activation. Platelet activation plays significant roles in the formation of artherosclerosis and thrombus, and may explain the epidemiological association between periodontitis and cardiovascular diseases. As the longevity of platelet in blood is only 8 to 10 days, the potential mechanisms and to what extent of the chronic periodontal inflammation increase platelet activation are not clear. This study will establish experimental periodontitis in SD rats, mimesis bacteraemias by applying Porphyromonas gingivalis in gingival crevicular at different time of the periodontal disease progression. The effects of progressing periodontal destruction, bacteremia and elevated interleukin-6, C reactive protein and tumor necrosis factor levels on the expression of platelet activation-dependent granule-external membrane protein (CD62p) and platelet dense granule membrane (CD63) will be analyzed. The activation of platelet could promote systematic inflammation in variou ways, such as by forming platelet-leukocyte aggregates. Then the inhibition of platelet activation may reduce inflammation and interfere the repair of periodontal destruction, while this hypothesis needs to be proved. In this study, periodontal therapy will be given to the SD rat model with experimental periodontitis in combination with or without antiplatelet cyclooxygenase (COX) 1 therapy. The aims of this part are to analyze the effects of periodontal treatment on platelet activation, the inhibition of platelet activation on the repair of periodontal destruction, and the combining effects of the two therapies. The effects of butyric acid, a kind of bacteria metabolic product, on platelet activation will also be analyzed in vitro. The results of this study will give some new evidence on the relationship between periodontal diseases and cardivascular diseases.

牙周炎是慢性感染性疾病，最新研究报道牙周炎患者血小板活化的程度升高，血小板活化后可促进动脉粥样硬化和血栓的形成。血小板寿命较短，长期慢性牙周炎症对其活化的作用程度尚不明确，可能的原因尚需探讨。本研究拟制备大鼠实验性牙周炎模型，在牙周炎进展的不同时间点在龈沟内涂擦一定量的牙龈卟啉单胞菌模拟菌血症。从牙周破坏程度、菌血症、炎症因子水平升高等角度，探讨牙周炎对血小板α颗粒膜糖蛋白(CD62p)和溶酶体膜蛋白(CD63)的表达、血清可溶性P选择素等水平的作用。血小板活化后可增强体内免疫炎症反应，抑制其活化是否对牙周炎症的愈合产生影响尚不明确。本研究拟对实验性牙周炎模型进行牙周治疗和/或抗血小板环氧化酶治疗，探讨牙周治疗对血小板活化、抑制血小板活化对牙周组织愈合的影响，以及两者联合治疗的疗效。研究结果将为牙周疾病与心血管疾病的关系提供新的证据。

牙周炎是一类常见的慢性感染性疾病，是导致成人牙齿丧失的最主要原因。菌斑是牙周疾病的始动因素，宿主的免疫反应决定疾病的严重程度。血小板除了参与止血和血栓形成外，在多种疾病的组织损伤、免疫反应和修复中也发挥重要作用。本研究表明在侵袭性牙周炎患者（aggressive periodontitis, AgP）中，外周血中血小板的数目减少，大血小板分布比率降低，控制牙周炎症后这2项指标升高到与健康对照者基本一致的水平；AgP患者血小板数目、大血小板分布比率，平均血小板体积与牙周临床指标负相关，提示血小板与牙周炎症间存在联系。AgP牙龈组织中白细胞-血小板聚合体的形成增加，血浆中CD62P、binding PAC-1的表达升高，推测AgP患者体内循环系统中血小板的体积减少可能与牙周炎症部位大的活化的血小板被消耗有关，这种消耗可能与血小板和白细胞的结合形成聚合体相关，形成聚合体后有利于粒细胞到达炎症部位发挥抗炎作用，本研究为血小板与粒细胞作用的提供了新可能。体外研究中牙龈卟啉单胞菌促进血小板活化，在浓度为107, 108, 或者109 CFU/mL 时促进血小板活化的能力逐渐增强，炎症介质水平升高，也可能是诱导血小板活化升高的原因。结扎C57小鼠4个象限的第二磨牙制备实验性牙周炎模型，结扎2周后CT和牙龈软硬组织病理学分析均证实造模成功。实验性牙周炎小鼠牙龈组织IL-1β和IL-6 mRNA的表达水平，血浆中IL-1b、IL-6和sCD40L均显著高于健康小鼠。采用生理盐水灌胃的实验性牙周炎小鼠血小板-白细胞聚合体的水平显著高于健康小鼠，但是采用干预血小板活化的阿司匹林或者氯吡格雷溶液灌胃的牙周炎小鼠血小板-白细胞聚合体的形成与健康小鼠间差异无统计学意义，但是干预均不能显著降低血小板膜受体CD62P表达的水平。牙周炎小鼠胸主动脉和腹主动脉中黏附分子(ICAM-1 和VCAM-1) 和细胞因子mRNA表达上调，提示牙周炎可能与心血管疾病的发生相关，而血小板活化可能作为桥梁连接牙周炎与心血管疾病。研究结果已经发表SCI论文4篇，中文核心期刊论文2篇，动物实验部分相关的数据正在整理和投稿中。

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