The Role and Mechanisms of Lipid and Lipoprotein Dysregulation in Sepsis

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Program Director/Principal Investigator : Guirgis, Faheem Wagid Sepsis is a dysregulated response to infection that has both fatal and non-fatal morbid consequences. Unfortunately, initial survival does not provide relief from morbidity for most sepsis survivors. Initial clinical trajectories include rapid recovery, early in-hospital death, and progression to chronic critical illness (ICU stay ≥ 14 days with organ dysfunction). Late complications include sepsis readmission and late death, both of which have rates of approximately 40% at 90 days and 6 months, respectively. Circulating lipids play an important role in sepsis and cholesterol levels of both high density lipoproteins (HDL-C) and low density lipoproteins (LDL-C) are dynamically regulated in sepsis. HDL and LDL are both thought to play protective roles in sepsis via several mechanisms (antioxidant/anti-inflammatory function, bacterial toxin clearance, steroid synthesis), but the exact mechanisms by which HDL and LDL protects against sepsis are not known. Lipid and lipoprotein dysregulation occurs in early sepsis, leading to failure to protect against sepsis. We have shown that: 1) HDL becomes dysfunctional (pro-oxidant and pro-inflammatory) in early sepsis (Dys-HDL); 2) elevated Dys-HDL levels positively correlate with and predict organ failure severity and are associated with poor outcomes including 28-day mortality; 3) HDL from older septic patients exhibits impaired cholesterol efflux capacity (required for toxin clearance and steroidogenesis); 4) HDL and LDL levels drop precipitously during sepsis, and the severity of the drop is predictive of death; and 5) low baseline LDL levels are associated with increased long-term community-acquired sepsis risk. Highly biologically active lipid metabolites are also present in the circulation during sepsis that may propagate and promote inflammation resolution and contribute to cholesterol dysfunction. Our data strongly suggest that lipid and lipoprotein dysregulation occurs in sepsis and leads to altered function, oxidation, and reduced levels that may influence clinical outcomes. We hypothesize that specific functional, lipidomic, and genomic changes in lipid and lipoprotein metabolism occur in early sepsis and relate to relevant clinical trajectories (rapid recovery, early death, and chronic critical illness and sepsis recidivism). To test our hypothesis, we will capitalize on an established and experienced sepsis research team and the opportunity provided by an existing bank of samples from a diverse cohort of 80 community-acquired (CA) and 85 hospital-acquired (HA) sepsis patients from two-centers. This approach has several advantages: 1) cost-savings from use of existing samples with isolated mRNA, 2) a recent cohort of sepsis patients (2016-2018) consistently treated with institutional evidence-based management bundles, 3) availability of serial samples over time (enrollment, 48h, 28d, and 90d), sepsis readmission samples, and mRNA for the CA cohort, 4) age/gender matched control samples, 5) available clinical and outcomes data. We also propose two-site prospective enrollment of a small cohort of sepsis readmission patients to study this novel and important outcome. This project satisfies the NIGMS mission of researching biological mechanisms that underlay the foundation for advances in treatment of diseases such as sepsis. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page