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 recidivism 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 protect against sepsis are not known. Lipid and lipoprotein dysregulation occurs in early sepsis, leading to failure to protect against sepsis. Our published work has shown that in sepsis patients: 1) HDL is oxidized, becomes proinflammatory and dysfunctional; 2) dysfunctional HDL correlates with and predicts organ failure severity; 3) HDL cholesterol efflux (required for toxin clearance and steroid synthesis) is impaired in older septic patients compared to healthy older controls; 4) HDL-C and LDL-C levels drop precipitously, and drop-severity predicts organ failure and death; and 5) low LDL-C levels are associated with increased long-term sepsis risk. New preliminary data in this grant revision also suggests that PON1, an HDL associated antioxidant protein, may play a critical protective role in sepsis. A large gap in our knowledge of lipid and lipoprotein dysregulation in sepsis exists that prevents complete understanding of previously observed lipid changes. We hypothesize that inflammatory, lipidomic, and genomic changes in early sepsis result in dysregulated lipid and lipoprotein metabolism & altered lipid function, oxidation and reduced levels that play a central role in sepsis pathobiology. This new investigator R01 application will allow Dr. Guirgis to further establish his laboratory and will capitalize on biobanked samples from a diverse cohort of 165 sepsis patients (UF Jacksonville and UF Gainesville) and will confirm findings in a small prospective cohort. This approach has several advantages: 1) recent cohort of sepsis patients (2016-2018) treated with evidence-based management bundles, 2) availability of serial samples (enrollment, 48-72h, 28d, and 90d) & stored leukocyte mRNA, 3) samples from matched healthy control subjects, 4) detailed clinical and outcomes data, and 5) prospective enrollment of a small cohort of sepsis patients for validation of findings. 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