Background: Mitochondrial transplantation is a promising strategy for the treatment of several diseases. However, the effects of mitochondrial transplantation on the outcome of polymicrobial sepsis remain unclear. Methods: The distribution of transplanted mitochondria in cecal ligation and puncture (CLP)-operated mice was detected at 2 and 12 h after intravenous injection in the tail (n ¼ 3). Then, the effects of mitochondrial transplantation on bacterial clearance (n ¼ 7), systemic inflammation (n ¼ 10), organ injury (n ¼ 8), and mortality (n ¼ 19) during CLP-induced sepsis were explored. Microarray analysis (n ¼ 3) was used to testify the molecular changes associated with decreased systemic inflammation and multiorgan dysfunction in sepsis. Results: The extraneous mitochondria were distributed in the lung, liver, kidney, and brain of CLP-operated mice at 2 and 12 h after intravenous injection in the tail. Mitochondrial transplantation increased the survival rate of septic mice, which was associated with decreased bacterial burden, systemic inflammation, and organ injury. Spleen samples were utilized for microarray analysis. Pathway analysis revealed that in polymicrobial sepsis, gene expression was significantly changed in processes related to inflammatory response, complement and coagulation cascades, and rejection reaction. Conclusions: These data displayed that mitochondrial replenishment reduces systemic inflammation and organ injury, enhances bacterial clearance, and improves the survival rate in sepsis. Thus, extraneous mitochondrial replenishment may be an effective adjunctive treatment to reduce sepsis-related mortality.

Background: Sepsis often accompanies gastrointestinal motility disorder that contributes to the development of sepsis in turn. Propofol and dexmedetomidine, as widely used sedatives in patients with sepsis, are likely to depress gastrointestinal peristalsis. We queried whether propofol or dexmedetomidine, at sedative doses, aggravated sepsisinduced ileus. Methods: Sedative/Anesthetic Scores and vital signs of lipopolysaccharide (LPS)-induced endotoxemic mice were measured during sedation with propofol or dexmedetomidine. Endotoxemic mice were divided into 10% fat emulsion, propofol, saline, and dexmedetomidine group. The gastric emptying, small intestinal transit, tests of colonic motility, gastrointestinal transit and whole gut transit were evaluated at 15 mins and 24 h after intraperitoneal injection of sedatives/vehicles respectively. Results: 40 mg•kg − 1 propofol and 80 μg•kg − 1 dexmedetomidine induced a similar depth of sedation with comparable vital signs except that dexmedetomidine strikingly decreased heart rate in endotoxemic mice. Dexmedetomidine markedly inhibited gastric emptying (P = 0.006), small intestinal transit (P = 0.006), colonic transit (P = 0.0006), gastrointestinal transit (P = 0.0001) and the whole gut transit (P = 0.034) compared with the vehicle, whereas propofol showed no depression on all parts of gastrointestinal motility 15 mins after administration. The inhibitive effects of dexmedetomidine in these tests vanished 24 h after the administration. Conclusions: Deep sedation with dexmedetomidine, but not propofol, significantly inhibited gastrointestinal peristalsis in endotoxemic mice while the inhibitory effect disappeared 24 h after sedation. These data suggested that both propofol and dexmedetomidine could be applied in septic patients while dexmedetomidine should be used cautiously in patients with cardiac disease or ileus.

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Results Bulk flow sorted cell populations (CD45, epithelial) from kidney samples can separate LN from controls based on gene expression. IFN stimulated genes were differentially expressed in renal CD45 LN cells. Analysis of single cells sorted from 4 LN kidney biopsies revealed major differences in infiltrates composition, with 2 samples demonstrating a high percentage of B cells (average of 18% compared to no B cells in the other 2 samples) and CD4 T cells (18% vs 8%), and low percentage of CD8 T cells (9% vs 23%). A high transcriptomic lupus interferon signature was detected in urine CD45 cells. Distinct infiltrates and distinct expression profiles were detected across patients. Conclusions The PEARL-Phase 0 project shows the feasibility of single cell isolation and transcriptomic analysis from LN kidney and urine. Analyses at a bigger scale in the two next phases of the project will accelerate discovery of new therapeutic targets and identification of biomarkers to guide therapeutic decisions in lupus nephritis and integrate the treatment effect.