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Research Progress on the Role of NLRP3 Inflammasome and Microglia in Cognitive Impairment
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摘要: 认知功能障碍作为一种常见的神经系统疾病，以认知减退、记忆力和注意力障碍为主要临床表现，严重影响患者的生存质量，是当前医学研究的热点和难点。认知功能障碍的病因及发病机制复杂多样，研究表明慢性持续性神经炎症在其发生发展中发挥关键作用。小胶质细胞、核苷酸结合寡聚化结构域样受体蛋白3(nucleotide-binding oligomerization domain-like receptor protein 3，NLRP3)炎症小体与神经炎症、认知功能障碍密切相关，调控小胶质细胞、NLRP3炎症小体可减少炎症因子、减少β淀粉样蛋白沉积、调控自噬、维持突触稳态，达到减轻神经炎症，进而防治认知功能障碍的作用。因此，阐明小胶质细胞、NLRP3炎症小体及二者共同在认知功能障碍中的作用机制，可为认知功能障碍相关机制的深入研究及临床防治、药物研发提供参考和依据。Abstract: As a common neurological disease, cognitive impairment is characterized by cognitive decline, memory and attention impairment, which seriously affects the patients' quality of life. The etiology and pathogenesis of cognitive impairment are complex and diverse. Studies have shown that chronic persistent neuroinflammation plays a key role in its development. Microglia and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome are closely related to neuroinflammation and cognitive impairment. Regulation of microglia and NLRP3 inflammasome can reduce inflammatory factors, reduce amyloid β-protein(Aβ) deposition, regulate autophagy, maintain synaptic homeostasis, thus reducing neuroinflammation and further preventing and treating cognitive impairment. Therefore, exploring the mechanism of microglia and NLRP3 inflammasome as well as their interaction in cognitive impairment can provide some reference and basis for the in-depth study of the mechanism and clinical prevention and treatment of cognitive impairment, and the subsequent development of more efficient drugs.
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Keywords:
- microglia /
- NLRP3 inflammasome /
- cognitive dysfunction /
- neuroinflammation /
- research progress
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人们对缓和医疗的概念可能并不生疏，但对其认识尚且不够，对其理解抑或存在较大偏颇。无论是医生还是公众，都需要加深对缓和医疗重要性的认识，同时更深入地践行这一理念。
1. 人文理念是缓和医疗的本源
所谓缓和医疗，是指对慢性疾病、不可自愈/难以治愈之症、疾病晚期患者或年迈体弱者，医疗不力或救治无方，为尊重病患及其家人的意愿，为减轻其痛苦和症状，改善生命或生活质量的一种医疗对策[1]。
事实上，疾病晚期患者临近死亡(或称濒死)，是正常的生命过程。缓和医疗也是医疗过程，包含心理调适、营养支持、症状缓解、康复保健、改善预后、慰藉家人等，与延长生命并不矛盾。这些对策和措施，正是人文理念和人文关怀的体现，亦是医学及缓和医疗的本源[2]。正如特鲁多的墓志铭所阐述的，“有时是治愈，常常是帮助，而总是慰籍”。
“和缓是悉”，由来久矣。早在我国南朝，谢灵运的《山居赋》中即写道: “雷桐是别，和缓是悉”。雷、桐是古代的两位药学先祖，和、缓是古代两位名医，药神辨识草药之别，医圣明确病患之悉。尽管如此，面对诸多疾病，往往神药亦无力，圣医亦无方。此时，或者“古方治今病，和缓技亦穷”，或者人们还在留恋是否“如彼久病者，不敢忘和缓”还是“疏淪(音同药)费虽多，尺寸皆有功”呢？
于是，我们必须承认，此时最好的医疗是人文关怀，即“和缓是悉”。这就是医圣和、缓留给我们的无价财富与医疗真谛！
2. 缓和医疗是终极关怀的实施
缓和医疗涉及两个重要概念: 临终关怀(terminal care or hospice care)和终极关怀(ultimate concern)[3]。二者是不同的，临终关怀更侧重于具体的医疗措施，“临终”二字又显得狭隘、刺耳和难耐。而终极关怀则是对于生命的终极认识，比如生老病死、苦难痛殇。终极关怀其实是个哲学问题，亦是我们现今惯常的所谓“三观”(世界观、人生观、价值观)，这里侧重于对生命、身体、生活、健康、疾病与死亡的认识、理解和态度。这是每个人都必须面对，且必然要经历和选择的。
诞生或者死亡，发育或者缺陷，健康或者罹病，是科学的、生物学的、哲学的，也是自然的、宗教的、神秘的。医学当然要遵循自然规律和生命规律，但也有可能打破生死的自然轨迹，从而误导人类抗拒必然的生命过程。问题是作为医者，我们需要真正理解什么是生命的意义，以及什么是死亡的意义。现实中，我们确实在寻找消除病痛、延长生命的药物和方法，但也应该避免无意义的，甚至善意的扰乱。我们应该清楚地认识到，长生不老、无疾而终、健康长寿、万寿无疆，只不过是敬语和神话。
有了对于终极关怀的认识和理解，有了对于临终关怀的具体办法，我们对于缓和医疗就有了更深层次的认识和领会，也有助于更好地开展缓和医疗工作。可以认为，终极关怀是临终关怀或缓和医疗的目标和升华，临终关怀或缓和医疗是终极关怀的体现和实施。
3. 科学的认识论与医学的发展观
医学是一个复杂的认知系统，是自然科学与社会科学或人文科学的结合。其关乎国家、民族、社会、家庭、个人健康及幸福。所谓“天地神圣，生命至上”。为此，我们要实施全生命周期的健康管理。所谓全生命周期，就是从生到死的人生各个阶段。现阶段，缓和医疗可能更多实施于年长者，但在生命的各个阶段我们都会遇到不同的健康问题，缓和医疗理念在这些阶段具有同样重要的意义。
医学的认识和实践有两个明显的特征：一是局限性，二是风险性。所谓局限性，就是认知的局限，由于人体的复杂性以及人与环境(自然与社会)的交叉性，形成了诸多影响和变数。因此，我们对于疾病的认识和处理可能是局限的、片面的，甚至是错误的。二是风险性，因为医疗的对象是活的人体，诊断、治疗、药物、手术等都会有风险，是“危险的丛林”。先哲们告诫我们，临床工作“如临深渊，如履薄冰”，要“戒慎恐惧”。
近二三十年，医学在其他各个学科，特别是在遗传学、分子生物学、机械工艺学等技术的推动下，于颠簸中快速发展。诚然，技术的进步给医疗领域带来了巨大推动力，但也带来了诸多问题。过度诊断、过度治疗，过分相信和依赖机器检查及化验报告，脱离临床、脱离实际等的倾向日趋严重。数字化冲淡了医学的人文观念, 隔离了医生与患者，这给临床医学带来了巨大影响，却也进一步凸显了缓和医疗的重要性。
4. 小结
缓和医疗方兴未艾，可以说其是个幸运者，同时又是个逆行者。未来，缓和医疗必须紧密联系临床，既要走到患者床边去做面对面的具体工作，更要进行多学科协作，共同管理患者全生命周期各个阶段的各种问题。无论是大医院还是小诊所，缓和医疗都同样重要，都要践行和发展这一理念。北京协和医院是全国疑难重症诊疗中心，是医疗、教学和科研的结合与转化基地，应该在推动缓和医疗发展中发挥引领和示范作用，因此任重而道远。
缓和医疗不是一枝奇葩的花朵，而是一片关爱的森林。
作者贡献：王彩红、薛建军、魏晓涛负责查阅文献及撰写论文；刘荣鑫、汤峰、徐紫清、候怀晶、张杰负责修订论文；王彩红、薛建军、赵永强负责设计选题和审校论文。利益冲突：所有作者均声明不存在利益冲突 -
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