Antonio Arciniegas Rubio, MD
Rank
Research Staff
Department
Medicine
Pulmonary and Clinical Care Medicine
Authors
Arciniegas A*, Varon J, Decorte J, Fandino L, Haemmig S, Yang D, Chang SC, Feinberg MW, Baron RM
Principal Investigator
Rebecca Baron, MD
Twitter / Website
Categories
Introduction: Sepsis is a condition with high morbidity and mortality with no targeted treatment options. MicroRNA181b (miR181b) dampens inflammation through limiting NF-kB-mediated vascular endothelial inflammation in endotoxemia. The role of miR181b in bacterial sepsis remains unclear. We hypothesized that miR181b might play a protective role in abdominal sepsis.
Methods and Results: MiR181b KO vs. control mice were exposed to polymicrobial sepsis via cecal ligation and puncture (CLP) vs sham surgery. KO mice experienced increased earlier mortality after CLP vs. controls (cumulative median survival of 35.0 hrs. vs. 95.2 hrs.; hazard ratio: 2.721, 95% CI (1.28,5.79)), and had higher bacteremia than control mice at 6 hrs. To elucidate the mechanism underlying this phenotype, we investigated transcription of various cecum tight junction transcripts by qPCR. All but one transcript was suppressed in the KO vs. control mice (p=0.0012). Peritoneal inflammatory cell phagocytosis was assessed using co-cultured cells with green fluorescent protein (GFP)-labelled E. coli via flow cytometry. There were no differences in phagocytosis between KO and controls. To assess vascular permeability in the GI tract, mice were exposed to sepsis (7 hrs.) and gavaged with fluorescein-isothiocyante-dextran-4 (FD-4) prior to sacrifice. Blood levels of FD-4 were measured. Gut permeability was increased in KO mice at baseline (2-fold) and after sepsis (8-fold) compared controls (p<0.05).
Conclusions: Absence of miR181b leads to increased early mortality and bacteremia in murine sepsis, an effect that appears to be mediated by increased endovascular leak in the GI tract. In contrast to murine endotoxemia, the effect does not appear to be mediated by alterations in the inflammatory response. Future studies will be important to delineate the role of miR181b in mediating vascular integrity during sepsis with the goal of deriving a novel target for therapeutics in this devastating condition.
