Abstract
The most common scoring system for critically ill patients is the Sequential Organ Failure Assessment (SOFA) score. Little is known about specific molecular signaling networks underlying the SOFA criteria. We characterized these networks and identified specific key regulatory molecules. We prospectively studied seven patients with sepsis and six controls with high-throughput RNA sequencing (RNAseq). Quantitative reverse transcription PCR (RT-qPCR) confirmation was performed in a second independent cohort. Differentially and significantly expressed miRNAs and their target mRNA transcripts were filtered for admission SOFA criteria and marker RNAs for the respective criteria identified. We bioinformatically constructed molecular signaling networks specifically reflecting these criteria followed by RT-qPCR confirmation of RNAs with important regulatory functions in the networks in the second cohort. RNAseq identified 82 miRNAs (45% upregulated) and 3254 mRNAs (50% upregulated) differentially expressed between sepsis patients and controls. Bioinformatic analysis characterized 6 miRNAs and 76 mRNA target transcripts specific for the SOFA criteria. RT-qPCR validated miRNA and mRNAs included IGFBP2 (respiratory system); MMP9 and PDE4B (nervous system); PPARG (cardiovascular system); AKR1B1, ANXA1, and LNC2/NGAL (acute kidney injury); GFER/ALR (liver); and miR-30c-3p (coagulopathy). There are specific canonical networks underlying the SOFA score. Key regulatory miRNA and mRNA transcripts support its biologic validity.
Highlights
Since its development in the 1990s, the Sequential Organ Failure Assessment (SOFA) score has become a standard instrument in the ICU to quantify acute morbidity of critically ill patients [1]
We addressed this issue by high-throughput and unbiased sequencing (RNAseq) of small non-coding miRNAs and protein-coding mRNAs from blood cells in patients with sepsis and healthy controls
There were no significant differences in SOFA scores, biometric data, source of infection, or number and type of organ failure between patients from the RNA sequencing (RNAseq) and the RT-qPCR confirmation groups
Summary
Since its development in the 1990s, the Sequential Organ Failure Assessment (SOFA) score has become a standard instrument in the ICU to quantify acute morbidity of critically ill patients [1]. The SOFA score has been used in thousands of clinical investigations. SOFA is based on six different sub scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal, and neurological systems, which span from 0 to 4, and a final summary score is calculated ranging from 0 to 24 points [3]. Increased scores reflect more severe organ dysfunctions [4]. Despite the widespread use and clinical validation of the SOFA score, it merely reflects a numeric simplification of morbidity. There appears to be a missing link between the SOFA criteria (e.g., the PaO2/FiO2 ratio for respiratory system or creatinine plasma concentrations for acute kidney injury) and the specific molecular signaling patterns underlying these criteria
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