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Plasmalogens are plasma-borne antioxidant phospholipid species that provide protection as cellular lipid components during cellular oxidative stress. In this study we investigated plasma plasmalogen levels in human sepsis as well as in rodent models of infection. In humans, levels of multiple plasmenylethanolamine molecular species were decreased in septic patient plasma compared to control subject plasma as well as an age-aligned control subject cohort. Additionally, lysoplasmenylcholine levels were significantly decreased in septic patients compared to the control cohorts. In contrast, plasma diacyl phosphatidylethanolamine and phosphatidylcholine levels were elevated in septic patients. Lipid changes were also determined in rats subjected to cecal slurry sepsis. Plasma plasmenylcholine, plasmenylethanolamine, and lysoplasmenylcholine levels were decreased while diacyl phosphatidylethanolamine levels were increased in septic rats compared to control treated rats. Kidney levels of lysoplasmenylcholine as well as plasmenylethanolamine molecular species were decreased in septic rats. Interestingly, liver plasmenylcholine and plasmenylethanolamine levels were increased in septic rats. Since COVID-19 is associated with sepsis-like acute respiratory distress syndrome and oxidative stress, plasmalogen levels were also determined in a mouse model of COVID-19 (intranasal inoculation of K18 mice with SARS-CoV-2). 3 days following infection, lung infection was confirmed as well as cytokine expression in the lung. Multiple molecular species of lung plasmenylcholine and plasmenylethanolamine were decreased in infected mice. In contrast, the predominant lung phospholipid, dipalmitoyl phosphatidylcholine, was not decreased following SARS-CoV-2 infection. Additionally total plasmenylcholine levels were decreased in the plasma of SARS-CoV-2 infected mice. Collectively, these data demonstrate the loss of plasmalogens during both sepsis and SARS-CoV-2 infection. This study also indicates plasma plasmalogens should be considered in future studies as biomarkers of infection and as prognostic indicators for sepsis and COVID-19 outcomes.

Abstract Background Enrichment strategies improve therapeutic targeting and trial efficiency, but enrichment factors for sepsis trials are lacking. We determined whether concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1), interleukin-8 (IL8), and angiopoietin-2 (Ang2) could identify sepsis patients at higher mortality risk and serve as prognostic enrichment factors. Methods In a multicenter prospective cohort study of 400 critically ill septic patients, we derived and validated thresholds for each marker and expressed prognostic enrichment using risk differences (RD) of 30-day mortality as predictive values. We then used decision curve analysis to simulate the prognostic enrichment of each marker and compare different prognostic enrichment strategies. Measurements and main results An admission sTNFR1 concentration > 8861 pg/ml identified patients with increased mortality in both the derivation (RD 21.6%) and validation (RD 17.8%) populations. Among immunocompetent patients, an IL8 concentration > 94 pg/ml identified patients with increased mortality in both the derivation (RD 17.7%) and validation (RD 27.0%) populations. An Ang2 level > 9761 pg/ml identified patients at 21.3% and 12.3% increased risk of mortality in the derivation and validation populations, respectively. Using sTNFR1 or IL8 to select high-risk patients improved clinical trial power and efficiency compared to selecting patients with septic shock. Ang2 did not outperform septic shock as an enrichment factor. Conclusions Thresholds for sTNFR1 and IL8 consistently identified sepsis patients with higher mortality risk and may have utility for prognostic enrichment in sepsis trials.

Abstract Background Necroptosis, a form of programmed cell death mediated by receptor interacting serine/threonine-protein kinase-3 (RIPK3), is implicated in murine models of acute respiratory distress syndrome (ARDS). We hypothesized that plasma RIPK3 concentrations in sepsis and trauma would be associated with ARDS development and that plasma RIPK3 would reflect changes in lung tissue RIPK3 in a murine model of systemic inflammation. Methods We utilized prospective cohort studies of critically ill sepsis (n = 120) and trauma (n = 180) patients and measured plasma RIPK3 at presentation and 48 h. Patients were followed for 6 days for ARDS by the Berlin definition. We used multivariable logistic regression to determine the association of plasma RIPK3 with ARDS in each cohort, adjusting for confounders. In mice, we determined whether plasma and lung tissue RIPK3 levels rise concomitantly 4 h after injection with lipopolysaccharide and ZVAD-FMK, an apoptosis inhibitor. Results The change in plasma RIPK3 from presentation to 48 h (ΔRIPK3) was associated with ARDS in sepsis (OR 1.30, 95% CI 1.03–1.63, per ½ standard deviation) and trauma (OR 1.79, 95% CI 1.33–2.40). This association was not evident for presentation RIPK3 levels. Secondary analyses showed similar findings for the association of ΔRIPK3 with acute kidney injury and 30-day mortality. Mice injected with lipopolysaccharide and ZVAD-FMK had significantly higher plasma (p