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DHCR7 Expression Predicts Poor Outcomes and Mortality from Sepsis.

ABSTRACT: Objective: Sepsis patients experience poor outcomes including chronic critical illness (CCI) or early death (within 14 days). We investigated lipid metabolic gene expression differences by outcome to discover therapeutic targets. Design: Secondary analysis of samples from prospectively enrolled sepsis patients and a zebrafish sepsis model for drug discovery. Setting: Emergency department or ICU at an urban teaching hospital. Patients: Sepsis patients presenting within 24 hours. Methods: Enrollment samples from sepsis patients were analyzed. Clinical data and cholesterol levels were recorded. Leukocytes were processed for RNA sequencing (RNA-seq) and reverse transcriptase polymerase chain reaction (RT-qPCR). A lipopolysaccharide (LPS) zebrafish sepsis model was used for confirmation of human transcriptomic findings and drug discovery. Measurements and Main Results: There were 96 samples in the derivation (76 sepsis, 20 controls) and 52 in the validation cohort (sepsis only). The cholesterol metabolism gene 7-Dehydrocholesterol Reductase ( DHCR7) was significantly upregulated in both derivation and validation cohorts in poor outcome sepsis compared to rapid recovery patients and in 90-day non-survivors (validation only) and validated using RT-qPCR analysis. Our zebrafish sepsis model showed upregulation of dhcr7 and several of the same lipid genes upregulated in poor outcome human sepsis (dhcr24, sqlea, cyp51, msmo1 , ldlra) compared to controls. We then tested six lipid-based drugs in the zebrafish sepsis model. Of these, only the Dhcr7 inhibitor AY9944 completely rescued zebrafish from LPS death in a model with 100% lethality. Conclusions: DHCR7, an important cholesterol metabolism gene, was upregulated in poor outcome sepsis patients warranting external validation. This pathway may serve as a potential therapeutic target to improve sepsis outcomes.

SUBMITTER: Guirgis FW

PROVIDER: S-EPMC9915766 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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DHCR7 Expression Predicts Poor Outcomes and Mortality from Sepsis.

Guirgis Faheem W FW Jacob Vinitha V Wu Dongyuan D Henson Morgan M Daly-Crews Kimberly K Hopson Charlotte C Black Lauren Page LP DeVos Elizabeth L EL Sulaiman Dawoud D Labilloy Guillaume G Brusko Todd M TM Shavit Jordan A JA Bertrand Andrew A Feldhammer Matthew M Baskovich Brett B Graim Kiley K Datta Susmita S Reddy Srinivasa T ST

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Objective: Sepsis patients experience poor outcomes including chronic critical illness (CCI) or early death (within 14 days). We investigated lipid metabolic gene expression differences by outcome to discover therapeutic targets. Design: Secondary analysis of samples from prospectively enrolled sepsis patients and a zebrafish sepsis model for drug discovery. Setting: Emergency department or ICU at an urban teaching hospital. Patients: Sepsis patients presenting within ...[more]

PMID: 36778468

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Project description:This is a study of lipid metabolic gene expression patterns to discover precision medicine for sepsis.ObjectivesSepsis patients experience poor outcomes including chronic critical illness (CCI) or early death (within 14 d). We investigated lipid metabolic gene expression differences by outcome to discover therapeutic targets.Design setting and particitpantsSecondary analysis of samples from prospectively enrolled sepsis patients (first 24 hr) and a zebrafish endotoxemia model for drug discovery. Patients were enrolled from the emergency department or ICU at an urban teaching hospital. Enrollment samples from sepsis patients were analyzed. Clinical data and cholesterol levels were recorded. Leukocytes were processed for RNA sequencing and reverse transcriptase polymerase chain reaction. A lipopolysaccharide zebrafish endotoxemia model was used for confirmation of human transcriptomic findings and drug discovery.Main outcomes and measuresThe derivation cohort included 96 patients and controls (12 early death, 13 CCI, 51 rapid recovery, and 20 controls) and the validation cohort had 52 patients (6 early death, 8 CCI, and 38 rapid recovery).ResultsThe cholesterol metabolism gene 7-dehydrocholesterol reductase (DHCR7) was significantly up-regulated in both derivation and validation cohorts in poor outcome sepsis compared with rapid recovery patients and in 90-day nonsurvivors (validation only) and validated using RT-qPCR analysis. Our zebrafish sepsis model showed up-regulation of dhcr7 and several of the same lipid genes up-regulated in poor outcome human sepsis (dhcr24, sqlea, cyp51, msmo1, and ldlra) compared with controls. We then tested six lipid-based drugs in the zebrafish endotoxemia model. Of these, only the Dhcr7 inhibitor AY9944 completely rescued zebrafish from lipopolysaccharide death in a model with 100% lethality.ConclusionsDHCR7, an important cholesterol metabolism gene, was up-regulated in poor outcome sepsis patients warranting external validation. This pathway may serve as a potential therapeutic target to improve sepsis outcomes.

Project description:BackgroundThe incidence of coagulopathy, which was responsible for poor outcomes, was commonly seen among patients with sepsis. In the current study, we aim to determine whether the presence of sepsis-associated coagulopathy (SAC) predicts the clinical outcomes among critically ill patients with postoperative sepsis.MethodsWe conducted a single-center retrospective cohort study by including patients with sepsis admitted to surgical ICU of Chinese PLA General Hospital from January 1, 2014 to December 31, 2018. Baseline characteristics and clinical outcomes were compared with respect to the presence of SAC. Kaplan-Meier analysis was applied to calculate survival rate, and Log-rank test was carried out to compare the differences between two groups. Furthermore, multivariable Cox and logistic and linear regression analysis were performed to assess the relationship between SAC and clinical outcomes, including hospital mortality, development of septic shock, and length of hospital stay (LOS), respectively. Additionally, both sensitivity and subgroup analyses were performed to further testify the robustness of our findings.ResultsA total of 175 patients were included in the current study. Among all included patients, 41.1% (72/175) ICU patients were identified as having SAC. In-hospital mortality rates were significantly higher in the SAC group when compared to that of the No SAC group (37.5% vs. 11.7%; p < 0.001). By performing univariable and multivariable regression analyses, presence of SAC was demonstrated to significantly correlate with an increased in-hospital mortality for patients with sepsis in surgical ICU [Hazard ratio (HR), 3.75; 95% Confidence interval (CI), 1.90-7.40; p < 0.001]. Meanwhile, a complication of SAC was found to be the independent predictor of the development of septic shock [Odds ratio (OR), 4.11; 95% CI, 1.81-9.32; p = 0.001], whereas it was not significantly associated with prolonged hospital LOS (OR, 0.97; 95% CI, 0.83-1.14; p = 0.743).ConclusionThe presence of SAC was significantly associated with increased risk of in-hospital death and septic shock among postoperative patients with sepsis admitted to ICU. Moreover, there was no statistical difference of hospital LOS between the SAC and no SAC groups.

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DHCR7 Expression Predicts Poor Outcomes and Mortality from Sepsis.

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DHCR7 Expression Predicts Poor Outcomes and Mortality from Sepsis.

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