Exosomes derived from plasma of septic patients inhibit apoptosis of T lymphocytes by down-regulating bad via hsa-miR-7-5p.

Immunosuppression is currently a vital pathophysiological characteristic and core problem of sepsis. Apoptosis of T lymphocyte contribute to immunosuppression by decreasing immune effector cells. A report has recently revealed the potential regulatory role of exosomal miRNAs derived from plasma of septic patients on immune system, but the underlying mechanism is unclear. We discovered the antiapoptotic effect of circulating exosomes derived from plasma of septic patients (Sepsis-Exos) on T lymphocytes and further investigated the molecular mechanism. Next-generation sequencing (NGS) indicated that sepsis induces prominent change of exosomal miRNA expression profile, including the overexpressed hsa-miR-7-5p. Gene Bad, which is in the cGMP-PKG signaling pathway, was negatively regulated by hsa-miR-7-5p by dual luciferase reporter assay. Sepsis-Exos were demonstrated to downregulate the mRNA and protein levels of proapoptotic gene Bad, active Caspase-3 and Bax, while upregulate that of antiapoptotic gene Bcl-2 via hsa-miR-7-5p, thus inhibited apoptosis of T lymphocytes induced by lipopolysaccharide (LPS) in vitro. Furthermore, Sepsis-Exos was verified to inhibit T lymphocytes apoptosis during sepsis in vivo, reducing mortality rate of septic model mice. In conclusion, we provide evidence that Sepsis-Exos participate in ameliorating apoptosis of T lymphocytes by directly suppressing Bad via hsa-miR-7-5p.

Potential roles of vitamin D binding protein in attenuating liver injury in sepsis.

BACKGROUND: In sepsis, vitamin D binding protein (VDBP) has been shown to be low-expressed. The current study examined the relationship between serum VDBP level and liver injury in sepsis patients, as well as in a mouse model for sepsis and in cultured liver epithelial cell line exposed to lipopolysaccharide (LPS). METHODS: The human study included 78 sepsis patients and 50 healthy volunteers. Sepsis patients were categorized into sepsis survivor group (n = 43) and sepsis non-survivor group (n = 35) based on 28-day mortality for data analysis. Adult male C57BL/6 mice were subjected to cecal ligation and puncture (CLP). Serum samples were collected on day 1, 3, 5 and 7 to determine the levels of VDBP, 25-hydroxyvitamin D [25(OH)D3], 1,25-dihydroxyvitamin D [1,25(OH)2D3], interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). Potential protective effects of VDBP overexpression against LPS-induced liver damage were examined in cultured THLE2 cells. RESULTS: Serum levels of VDBP, 25(OH)D3, and 1,25(OH)2D3 were significantly lower in sepsis patients vs. the healthy control (P < 0.001), as well as in the sepsis non-survivor group vs. the sepsis survivor group (P < 0.001, P = 0.0338, or P = 0.0013, respectively). Lower serum VDBP level was associated with higher Acute Physiology and Chronic Health Evaluation (APACHE) II score (r = - 0.2565, P = 0.0234) and Sequential Organ Failure Assessment score (r = - 0.3522, P = 0.0016), but lower serum albumin (ALB, r = 0.4628, P < 0.001) and total protein (TP, r = 0.263, P = 0.02). In CLP mice, there was a 5-day period of serum VDBP reduction, followed by return towards the baseline on day 7. VDBP was also decreased in LPS-treated THLE2 cells (P < 0.001). VDBP overexpression reduced LPS-induced THLE2 damage. Reduced damage was associated with decreased oxidative stress and inactivation of the c-Jun N-terminal kinase signaling pathway. CONCLUSION: VDBP may be protective against sepsis-induced liver injury.