Bioactive Lipid Mediators and Cholesterol Metabolism in Sepsis
Background: Sepsis, a life-threatening disease that affects 550,000 Europeans per year, causes major changes in plasma lipoprotein profile, called „lipemia of sepsis“. The underlying mechanisms behind this process are not elucidated yet, but recent results point towards a potential influence of arachidonic acid - derived lipid mediators released during inflammation on cholesterol metabolism. This work tries to delineate an overview of spatiotemporal alterations of proteins and genes involved in cholesterol metabolism during sepsis, and to study the kinetics lipoxins and leukotrienes, bioactive lipid mediators previously shown to critically influence whole-body cholesterol homeostasis.
Methods and results: A murine peritonitis / sepsis model with C57BL/6 mice was used with intraperitoneal injection of 500 CFU Salmonella typhimurium. Sepsis development was monitored over 72 hours. Bacterial infiltration in the system, the inflammatory marker interleukin 6 and the accumul ation of immune cells in peritoneum and liver were measured at different time points. In addition, protein and mRNA expression of various cholesterol-metabolizing genes in the liver was examined. The primary infection in the peritoneum appeared to be successfully repressed, shown by regeneration of innate immune cells within the peritoneal cavity, associated with an eventual decline of inflammatory lipid mediators. In the liver, an overwhelming immune reaction with failed resolution was observed, illustrated by continuing influx of neutrophils and exponentially growing CFUnumbers. From 24 hours on, an elevated amount of lipoxins was measured within the circulation, pointing towards the attempt of the immune system to manage the infection and to induce resolution. Increased levels of VLDL- and LDL-cholesterol in the plasma were measured, which could be traced back to increased de-novo cholesterol synthesis in the liver by increased activity of HMG CoA reductase, accompanied by decreased clearance via LDL-receptor and impaired hepatobiliary excretion due to reduced bile acid synthesis. HDL-cholesterol levels were markedly reduced.
Conclusion: Cholesterol metabolism displays distinct changes during sepsis. It has yet to be determined whether the observed changes are due to inflammatory stimuli including inflammatory and pro-resolving bioactive lipid mediators.