Barker Grant, Leeuwenburgh Christiaan, Brusko Todd, Moldawer Lyle, Reddy Srinivasa T, Guirgis Faheem W
Department of Emergency Medicine, College of Medicine-Jacksonville, University of Florida, 655 West 8th Street, Jacksonville, FL 32209, USA.
Department of Aging and Geriatric Research, College of Medicine, University of Florida, Gainesville, FL 32603, USA.
J Clin Med. 2021 Apr 14;10(8):1693. doi: 10.3390/jcm10081693.
In addition to their well-characterized roles in metabolism, lipids and lipoproteins have pleiotropic effects on the innate immune system. These undergo clinically relevant alterations during sepsis and acute inflammatory responses. High-density lipoprotein (HDL) plays an important role in regulating the immune response by clearing bacterial toxins, supporting corticosteroid release, decreasing platelet aggregation, inhibiting endothelial cell apoptosis, reducing the monocyte inflammatory response, and inhibiting expression of endothelial cell adhesion molecules. It undergoes quantitative as well as qualitative changes which can be measured using the HDL inflammatory index (HII). Pro-inflammatory, or dysfunctional HDL (dysHDL) lacks the ability to perform these functions, and we have also found it to independently predict adverse outcomes and organ failure in sepsis. Another important class of lipids known as specialized pro-resolving mediators (SPMs) positively affect the escalation and resolution of inflammation in a temporal fashion. These undergo phenotypic changes in sepsis and differ significantly between survivors and non-survivors. Certain subsets of sepsis survivors go on to have perilous post-hospitalization courses where this inflammation continues in a low grade fashion. This is associated with immunosuppression in a syndrome of persistent inflammation, immunosuppression, and catabolism syndrome (PICS). The continuous release of tissue damage-related patterns and viral reactivation secondary to immunosuppression feed this chronic cycle of inflammation. Animal data indicate that dysregulation of endogenous lipids and SPMs play important roles in this process. Lipids and their associated pathways have been the target of many clinical trials in recent years which have not shown mortality benefit. These results are limited by patient heterogeneity and poor animal models. Considerations of sepsis phenotypes and novel biomarkers in future trials are important factors to be considered in future research. Further characterization of lipid dysregulation and chronic inflammation during sepsis will aid mortality risk stratification, detection of sepsis, and inform individualized pharmacologic therapies.
除了在新陈代谢中具有明确的作用外，脂质和脂蛋白对先天性免疫系统具有多效性作用。在脓毒症和急性炎症反应期间，这些会发生与临床相关的改变。高密度脂蛋白（HDL）通过清除细菌毒素、支持皮质类固醇释放、减少血小板聚集、抑制内皮细胞凋亡、降低单核细胞炎症反应以及抑制内皮细胞粘附分子的表达，在调节免疫反应中发挥重要作用。它会发生定量和定性变化，可使用HDL炎症指数（HII）进行测量。促炎或功能失调的HDL（dysHDL）缺乏执行这些功能的能力，我们还发现它可独立预测脓毒症的不良结局和器官衰竭。另一类重要的脂质称为特殊促消退介质（SPM），以时间依赖性方式对炎症的升级和消退产生积极影响。这些在脓毒症中会发生表型变化，在幸存者和非幸存者之间有显著差异。某些脓毒症幸存者在出院后会经历危险的病程，炎症会以低度方式持续。这与持续性炎症、免疫抑制和分解代谢综合征（PICS）中的免疫抑制有关。免疫抑制继发的组织损伤相关模式的持续释放和病毒再激活助长了这种慢性炎症循环。动物数据表明内源性脂质和SPM的失调在这一过程中起重要作用。近年来，脂质及其相关途径一直是许多临床试验的靶点，但这些试验并未显示出对死亡率的益处。这些结果受到患者异质性和不良动物模型的限制。在未来试验中考虑脓毒症表型和新型生物标志物是未来研究中要考虑的重要因素。进一步阐明脓毒症期间脂质失调和慢性炎症将有助于死亡率风险分层、脓毒症的检测，并为个体化药物治疗提供依据。
