Lipid and Lipoprotein Dysregulation in Sepsis: Clinical and Mechanistic Insights into Chronic Critical Illness

Abstract

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.

Keywords: chronic critical illness; lipids; lipoproteins; sepsis.

Figure 1

Functional high density lipoprotein (HDL) exhibits pleiotropic effects during an acute stress response: (1) Supports endogenous corticosteroid stress-response; (2) Decreases platelet aggregation; (3) Binds and clears bacterial toxins (lipopolysaccharide and lipoteichoic acid); (4) Inhibits endothelial cell apoptosis [26,27]; (5) Reduces the monocyte inflammatory response; (6) Inhibits expression of endothelial cell adhesion molecules vascular cellular adhesion molecule(VCAM)/intercellular adhesion molecule (ICAM)/E-selectin.

Figure 2

Dysfunctional HDL (Dys HDL) fails to regulate and actively impairs the innate immune response (see Figure 1). Elevations in triglycerides and fatty acids, which have innate signaling properties contribute to this impairment. This leads to tissue damage, organ failure, and immune cell dysfunction. These factors contribute to complex interactions between sustained inflammasome activation and dysregulated lipid pro-resolving mediators, maintained by low grade endotoxemia and DAMPs, leading to an inappropriate inflammatory response. SPMs, specialized pro-resolving mediators; PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns.