HIF-1α-ROS-NF-κB信号通路介导心理应激加重牙周炎病变的作用机制研究

Periodontitis is the leading cause resulting into tooth loss in adult. In recent years, the influence of psychological factor on periodontitis is catching more and more attentions. We have confirmed that psychological stress could aggravate the periodontitis via further deteriorating the physical structure of periodontal tissue and delaying the elimination of local inflammation. However, the underling mechanism is still unclear. Hypoxia-inducible factor -1α (HIF-1α) which could affect the metabolism of active oxygen species (ROS) is considered to be the key factor response to hypoxia, while nuclear transcription factor-κB (NF-κB) is redox-sensitive and active in the inflammatory process. The hypoxia and oxidative damage in masticatory muscle in rats after psychological stress have been reported in our precious studies. With the fact that periodontitis is also often accompanied by local oxidative damage, we speculate that local HIF-1α-ROS-NF-κB signaling pathway is likely to play an important role in the aggravating process of periodontitis induced by psychological stress. For verifying the hypothesis, we will establish the rodent psychological stress model and experimental periodontitis model. Based on the systematic observation of the adverse influences of psychological stress on the periodontal tissue during periodontitis process, the local oxygen metabolism, redox state and inflammation of periodontal tissue will be clarified with the methods of tissue morphology and molecular biology. Additionally, the potential regulatory mechanism of HIF-1α-ROS-NF-κB signaling pathway during the aggravating process of periodontitis induced by psychological stress will be investigated in vivo and in vitro. The whole project is expected to provide new experimental basis for understanding the role of psychology in the etiology of periodontitis as well as related preventive measures in the future.

牙周炎是导致成年人牙齿丧失的首要原因。近年，其病因学中的心理因素逐渐受到人们关注。我们前期研究发现心理应激可以加重牙周炎组织病变，但调控机制尚不清楚。缺氧诱导因子-lα(HIF-1α)是缺氧应答关键因子，能够影响活性氧(ROS)代谢水平，而参与炎性反应的核转录因子-κB(NF-κB)对氧化还原失稳态敏感。我们早期针对口颌肌实验曾证实组织缺氧和氧化还原反应异常可由心理应激诱导发生。牙周炎过程中也常伴有局部氧化损伤，因此，HIF-1α-ROS-NF-κB信号通路很可能在心理应激加重牙周炎病变中扮演重要角色。本项目拟建立动物心理应激模型和牙周炎模型，观察并明确心理应激时牙周炎组织的氧代谢和氧化还原状态以及炎性反应程度，并通过体内、体外实验探讨HIF-1α-ROS-NF-κB信号通路在心理应激加重牙周炎局部病变过程中的可能作用机制，为研究牙周炎的心理病因学发病机制及有效防治提供新的实验依据和策略。

牙周炎是导致成年人牙齿丧失的首要原因。尽管医学界已经公认牙菌斑微生物及其代谢产物是导致牙周炎发生的始动因素，但临床上牙周组织破坏与菌斑的严重程度常常出现不完全一致的现象，因此单纯的细菌因素尚不足以解释慢性牙周炎的严重性和复杂性。近年来，心理应激因素在牙周炎发生发展过程中发挥的重要作用逐渐引起学者们的关注；甚至有研究指出，宿主的不良心理因素比致病菌的数量和毒性更能决定牙周炎症的严重和进展程度。但到目前为止，心理应激与牙周炎的关系还不甚明确，心理应激状态对牙周炎发生发展过程的影响也亟待探索。本课题针对军人这一特殊群体常因军事生活和军事任务的复杂多样而处于心理应激环境中的实际情况，对空军飞行学员的口腔健康包括牙周健康情况进行了流行病学调查，并将其与心理状态进行相关性分析，明确了不良心理因素与口颌系统疾病密切相关，其中飞行学员的牙龈炎、牙结石和牙周病与焦虑或抑郁状态存在着高度相关性。随后，本研究在对大鼠施加禁食（24h）、禁水（24h）、45℃强迫浸水（5min）、4℃强迫浸水（5min）、潮湿垫料（24h）、昼夜颠倒（24h）、束缚（1h）7种应激因子，建立慢性不可预知性应激模型（CUMS），发现CUMS可以引起动物行为学、血清学的改变，导致心理应激，更好的模拟了人们在现代社会生活中经历多种应激后产生的负性情绪。本研究又通过磨牙结扎丝线的方法建立了大鼠牙周炎模型, 观察到心理应激明显增加了IL-1β、IL-6、TNF-α、INF-γ等炎性因子的表达量，从而延缓牙周炎组织的愈合，而拮抗心理应激可有效逆转其对牙周炎病程的影响。这一发现为丰富牙周炎的心理病因学理论提供实验依据，也能为牙周炎心理病因学的临床防治提供新的治疗治疗思路。