Sepsis represents a major cause of lethality during intensive care unit (ICU) treatment. Pharmacological treatment strategies for sepsis are still limited and mainly based on the early initiation of antibiotic and supportive treatment. In this context, numerous clinical and serum based markers have been evaluated for the diagnosis, the severity, and the etiology of sepsis. However until now, few of these factors could be translated into clinical use. MicroRNAs (miRNAs) do not encode for proteins but regulate gene expression by inhibiting the translation or transcription of their target mRNAs. Recently it was demonstrated that miRNAs are released into the circulation and that the spectrum of circulating miRNAs might be altered during various pathologic conditions, such as inflammation, infection, and sepsis. By using array- and single PCR-based methods, a variety of deregulated miRNAs, including miR-25, miR-133a, miR-146, miR-150, and miR-223, were described in the context of sepsis. Some of the miRNAs correlated with the disease stage, as well as patients’ short and long term prognosis. Here, we summarize the current findings on the role of circulating miRNAs in the diagnosis and staging of sepsis in critically ill patients. We compare data from patients with findings from animal models and, finally, highlight the challenges and drawbacks that currently prevent the use of circulating miRNAs as biomarkers in clinical routine.
MicroRNA (miRNA) levels in serum have recently emerged as potential novel biomarkers for various diseases. miRNAs are routinely measured by standard quantitative real-time PCR (qPCR); however, the high sensitivity of qPCR demands appropriate normalization to correct for nonbiological variation. Presently, RNU6B (U6) is used for data normalization of circulating miRNAs in many studies. However, it was suggested that serum levels of U6 themselves might differ between individuals. Therefore, no consensus has been reached on the best normalization strategy in ‘circulating miRNA'. We analyzed U6 levels as well as levels of spiked-in SV40-RNA in sera of 44 healthy volunteers, 203 intensive care unit patients and 64 patients with liver fibrosis. Levels of U6 demonstrated a high variability in sera of healthy donors, patients with critical illness and liver fibrosis. This high variability could also be confirmed in sera of mice after the cecal ligation and puncture procedure. Most importantly, levels of circulating U6 were significantly upregulated in sera of patients with critical illness and sepsis compared with controls and correlated with established markers of inflammation. In patients with liver fibrosis, U6 levels were significantly downregulated. In contrast, levels of spiked-in SV40 displayed a significantly higher stability both in human cohorts (healthy, critical illness, liver fibrosis) and in mice. Thus, we conclude that U6 levels in the serum are dysregulated in a disease-specific manner. Therefore, U6 should not be used for data normalization of circulating miRNAs in inflammatory diseases and previous studies using this approach should be interpreted with caution. Further studies are warranted to identify specific regulatory processes of U6 levels in sepsis and liver fibrosis.
miR-133a serum levels were significantly elevated in critical illness and sepsis. High miR-133a levels were associated with the severity of disease and predicted an unfavorable outcome of critically ill patients.
Receptor-interacting protein kinase 1 (RIPK1) represents an essential signaling node in cell death and inflammation. Ablation of Ripk1 in liver parenchymal cells (LPC) did not cause a spontaneous phenotype, but led to tumor necrosis factor (TNF)-dependent hepatocyte apoptosis and liver injury without affecting inducible nuclear factor κB (NF-κB) activation. Loss of Ripk1 induced the TNF-dependent proteasomal degradation of the E3-ligase, TNF receptor-associated factor 2 (TRAF2), in a kinase-independent manner, thereby activating caspase-8. Moreover, loss of both Ripk1 and Traf2 in LPC not only resulted in caspase-8 hyperactivation but also impaired NF-κB activation, promoting the spontaneous development of hepatocellular carcinoma. In line, low RIPK1 and TRAF2 expression in human HCCs was associated with an unfavorable prognosis, suggesting that RIPK1 collaborates with TRAF2 to inhibit murine and human hepatocarcinogenesis.
In mice and humans, miR-122 levels represent an independent and potent marker of ongoing liver injury and hepatic cell death regardless of the underlying disease.
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