Investigating Lipid-gene Molecular Profiles of Septic ARDS

Sepsis is the most common cause (~75%) of acute respiratory distress syndrome (ARDS), a common condition with over 40% mortality. There are no effective pharmacotherapies for ARDS, likely due to patient heterogeneity. We have shown that HDL, which is usually anti-inflammatory/anti-oxidant, becomes dysfunctional (DysHDL) in sepsis, and becomes a negative regulator of inflammation, lipid oxidation, and chemotaxis. DysHDL harbors an altered proteome and lipidome when compared to normal HDL and has not been studied in septic ARDS. We recently developed a panel of fifteen measurements including lipoproteins, inflammatory molecules, and clinical features and established two new sepsis phenotypes, HYPO and NORMO. We applied our sepsis phenotyping pipeline (preliminary data) to septic ARDS patients and found that HYPO septic ARDS patients had ~70% mortality, lower apoA-I, HDL-C, low density lipoprotein (LDL-C), worse endothelial dysfunction (ICAM-1), and higher organ failure severity when compared to NORMO septic ARDS patients (0% mortality). Moreover, HYPO septic ARDS patient plasma contained significantly elevated lipoxygenase (LOX) pathway oxidized lipids (12- HETE/15-HETE) compared to NORMO septic ARDS. We also identified six upregulated lipid metabolism genes in peripheral blood leukocytes of HYPO vs. NORMO septic ARDS patients, critical for HDL/cholesterol biosynthesis, lipid/drug metabolism, and bacterial toxin clearance. Our central hypothesis is that unique phenotypes based on lipid-gene molecular patterns exist in septic ARDS that can be harnessed to reveal patient molecular heterogeneity. We further hypothesize that HDL metabolism and the LOX pathway play critical roles in septic ARDS, specifically in the HYPO phenotype subset. Our MPI team with unique expertise will address major gaps in ARDS research by i) identifying novel septic ARDS phenotypes, ii) systematically discovering repurposed drugs for septic ARDS treatment. Aim 1 will investigate HYPO/NORMO phenotypes in septic ARDS patients, by measuring fifteen markers and DysHDL in 150 ROSE trial participant samples. We will perform targeted lipidomics to quantify the oxidized lipidome of LOX, COX, and P450 pathways and obtain untargeted transcriptomic signatures via whole blood RNAseq. We will localize expression patterns by cell type using single cell RNAseq in a small subset. Aim 2 will determine novel septic ARDS phenotypes utilizing lipidomic and transcriptomic profiles of septic ARDS patients. We will perform multi-omic, molecular phenotyping using an unsupervised machine learning approach to uncover novel lipidomic/transcriptomic phenotypes and link molecular phenotypes to potential drugs via drug-gene interactions. Project Number: 1R21AI188477-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Faheem Guirgis (+1 co-PI) | Institution: UNIVERSITY OF FLORIDA, GAINESVILLE, FL | Award Amount: $424,223 | Activity Code: R21 | Study Section: Surgery, Anesthesiology and Trauma Study Section[SAT] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI18847701A1