Department of Emergency and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, China.
Department of Pathology, The Second Hospital of Jilin University, Changchun, China.
Neurotox Res. 2021 Apr;39(2):489-503. doi: 10.1007/s12640-020-00270-5. Epub 2020 Sep 2.
Sepsis-associated cerebral dysfunction is complex pathophysiology, generated from primary infections that are developed elsewhere in the body. The neonates, elderly population and chronically ill and long-term hospitalized patients are predominantly vulnerable to sepsis and related cerebral damage. Generally, electrophysiological recordings, severity and sedation scales, computerized imaging and spectroscopy techniques are used for its detection and diagnosis. About the underlying mechanisms, enhanced blood-brain barrier permeability and metalloprotease activity, tight junction protein loss and endothelial cell degeneration promote the influx of inflammatory and toxic mediators into the brain, triggering cerebrovascular damage. An altered neutrophil count and phenotype further dysregulate the normal neuroimmune responses and neuroendocrine stability via modulated activation of protein kinase C-delta, nuclear factor kappa-B and sphingolipid signaling. Glial activation, together with pro-inflammatory cytokines and chemokines and the Toll-like receptor, destabilize the immune system. Moreover, superoxides and hydroperoxides generate oxidative stress and perturb mitochondrial dynamics and ATP synthesis, propagating neuronal injury cycle. Activated mitochondrial apoptotic pathway, characterized by increased caspase-3 and caspase-9 cleavage and Bax/Bcl2 ratio in the hippocampal and cortical neurons, stimulate neurocognitive impairments. Additionally, altered LC3-II/I and P62/SQSTM1, p-mTOR, p-AMPK1 and p-ULK1 levels and dysregulated autophagosome-lysosome fusion decrease neuronal and glial energy homeostasis. The therapies and procedures for attenuating sepsis-induced brain damage include early resuscitation, cerebral blood flow autoregulation, implantable electric vagus nerve stimulation, antioxidants, statins, glucocorticoids, neuroimmune axis modulators and PKCδ inhibitors. The current review enumerates the pathophysiology of sepsis-induced brain damage, its diagnosis, the role of critical inducers and mediators and, ultimately, therapeutic measures attenuating cerebrovascular degeneration.
脓毒症相关性脑功能障碍是一种复杂的病理生理学过程，由身体其他部位发生的原发性感染引起。新生儿、老年人口以及慢性病和长期住院患者是易受脓毒症和相关脑损伤影响的主要人群。通常，使用电生理学记录、严重程度和镇静评分、计算机成像和光谱技术来检测和诊断它。关于潜在机制，增强的血脑屏障通透性和金属蛋白酶活性、紧密连接蛋白丢失和内皮细胞退化促进炎症和毒性介质流入大脑，引发脑血管损伤。中性粒细胞计数和表型的改变进一步通过调节蛋白激酶 C-δ、核因子 kappa-B 和鞘脂信号的激活来失调正常的神经免疫反应和神经内分泌稳定性。神经胶质细胞的激活，以及促炎细胞因子和趋化因子和 Toll 样受体，使免疫系统不稳定。此外，超氧化物和过氧化物产生氧化应激，扰乱线粒体动力学和 ATP 合成，从而促进神经元损伤循环。激活的线粒体凋亡途径，表现为海马和皮质神经元中 caspase-3 和 caspase-9 切割增加以及 Bax/Bcl2 比值增加，刺激神经认知障碍。此外，LC3-II/I 和 P62/SQSTM1、p-mTOR、p-AMPK1 和 p-ULK1 水平的改变以及自噬体-溶酶体融合的失调降低神经元和神经胶质的能量稳态。减轻脓毒症引起的脑损伤的治疗和程序包括早期复苏、脑血流自动调节、可植入电迷走神经刺激、抗氧化剂、他汀类药物、糖皮质激素、神经免疫轴调节剂和 PKCδ 抑制剂。本综述列举了脓毒症引起的脑损伤的病理生理学、诊断、关键诱导剂和介质的作用，以及最终减轻脑血管退化的治疗措施。
