高盐饮食诱发脑缺血损伤加重的机制研究

Nowadays people pay increasing attentions on the relationship between bad life style and diseases. Poor diet habit may induce many lifestyle related diseases. Excessive intake of salt has a direct relationship with high blood pressure, heart diseases and other diseases. High salt diet which is one of the most possibly factors causing the formation of cerebral infarction according to the epidemiologic surveys in recent years, and may be associated with ischemic cerebrovascular disease (ICVD) pathogenesis. However, no direct experimental data have clarified the explicit mechanism. Our previous work found that: High salt diet induced cerebral ischemic injury aggravation, and this result may have a connection with blood-brain barrier damage, endogenous microglial activation and inflammatory cell infiltration which has not been reported or mentioned. We use experimental animals combined with clinical data for this study, and also use cellular, molecular, protein methods to confirm the influence of high salt diet on cerebral ischemic injury; to clarify the process of high salt diet aggravating cerebral ischemia BBB mechanism; to clarify the participatory mechanisms of inflammatory cells during the process of high salt diet induced cerebral ischemia; explore the mechanisms vascular remodeling after high salt diet cerebral ischemic. To solve these problems, not only would enrich the theory of cerebral ischemia pathogenesis, but also provide a theoretical basis for the prevention and treatment of cerebral ischemia, and scientific guidance for people's health and diet.

目前人们越来越重视不良的生活习惯与疾病的关系。不良的饮食习惯可诱发许多生活方式疾病。其中，摄入过多盐与高血压、心脏病等疾病的发生有直接关系，近年来，流病调查显示，高盐饮食可能与缺血性脑血管疾病（ICVD）的发病有关，但是，国内外尚无直接实验数据表明高盐饮食与ICVD的关系，此外，其机制尚无人探讨。我们前期工作发现：高盐饮食诱发脑缺血损伤加重，可能与高盐饮食加重血脑屏障破坏、内源性小胶质细胞活化和外源性炎性细胞浸润增多有关，相关研究未见报道。本课题以实验动物为研究对象，结合临床资料，通过细胞、分子、蛋白水平，证实高盐饮食对脑缺血损伤的影响；阐明高盐饮食加重脑缺血损伤过程中血脑屏障破坏机制；明确高盐饮食脑缺血损伤过程中炎性细胞参与机制；探讨高盐饮食抑制脑缺血后血管重塑机制。阐明这些问题，将不仅丰富脑缺血发病机制的理论，而且为脑缺血的防治提供理论依据，为人们健康饮食提供科学指导。

经过四年的科研工作，我们如期完成课题的研究内容。首先，我们证实缺血性卒中患者脑损伤面积与钠的摄入密切相关。其次，我们将小鼠HSD喂养7d、14d、21d和28d，成功建立血压不相关高盐饮食（HSD）模型，在此基础上建立pMCAL模型2d，发现HSD脑缺血后小鼠缺血脑组织中外周巨噬细胞、CD4+T细胞等炎性细胞浸润增多，脑缺血损伤体积明显增大，说明HSD能够加重脑缺血损伤。并且，阐明HSD和体外高盐环境加重脑缺血后血脑屏障破坏，其机制是由于高盐通过p38/MAPK-SGK1信号通路下调脑微血管内皮细胞紧密连结蛋白ZO-1和Occludin的表达，进而导致血脑屏障通透性增加。另外，我们将小鼠HSD喂养21d，建立pMCAL模型12h、1d、3d和5d，发现HSD和体外高盐环境中的Na离子，通过p38/MAPK-AR信号通路促进脑缺血过程中小胶质细胞AR的表达，进而促进小胶质细胞向M1型细胞极化；此外，我们发现HSD和体外高盐环境通过Notch1信号通路上调脑缺血过程中小胶质细胞MIP-1α的表达，进而促进脑缺血后巨噬细胞的浸润，并且，HSD通过Notch1促进脑缺血后脑内IFN-γ、IL-1β及TNF-α等炎性因子的表达。通过本课题的研究，我们证实HSD加重脑缺血损伤；阐明了HSD加重脑缺血过程中血脑屏障破坏机制；揭示了HSD促进脑缺血过程中小胶质细胞向M1型细胞极化机制；明确了HSD加重脑缺血过程中巨噬细胞等炎性细胞浸润机制。阐明这些问题，丰富了脑缺血的发病机制，为脑缺血的防治提供理论依据，为人们健康饮食提供科学指导。课题完成过程中，发表SCI收录论文11篇，核心期刊4篇；获得黑龙江省政府自然科学二等奖1项；培养硕士研究生8名，圆满完成了科研课题。