Precious Cargo: Modulation of the Mesenteric Lymph Exosome Payload after Hemorrhagic Shock

Background Trauma/hemorrhagic shock (T/HS) causes a release of pro-inflammatory mediators into the mesenteric lymph (ML) that may trigger a systemic inflammatory response and subsequent organ failure. Recently we showed that exosomes in post-shock ML are biologically active mediators of this inflammation. Because the specific inflammatory mediators in post-shock ML exosomes have yet to be characterized, we hypothesized that T/HS would lead to a distinct ML pro-inflammatory exosome phenotype that could be identified by proteomic analysis. We further hypothesized that their regulation by the neuro-enteric axis via the vagus nerve would modify this pro-inflammatory profile. Methods Male rats underwent an established T/HS model including 60 minutes of HS followed by resuscitation. ML was collected before HS (pre-shock) and after resuscitation (post-shock). A subset of animals underwent cervical vagus nerve electrical stimulation (VNS) after the HS phase. Liquid chromatography with tandem mass spectroscopy (LC-MS/MS) followed by protein identification, label free quantification, and bioinformatic analysis was performed on exosomes from the pre-shock and post-shock phases in the T/HS and T/HS+VNS groups. Biological activity of exosomes was evaluated using a monocyte NF-κB activity assay. Results ML exosomes express a distinct protein profile after T/HS with enrichment in pathways associated with cell signaling, cell death and survival, and the inflammatory response. Stimulation of the vagus nerve following injury attenuated the transition of ML exosomes to this T/HS-induced inflammatory phenotype with protein expression remaining similar to pre-shock. Monocyte NF-κB activity was increased after exposure to ML exosomes harvested after T/HS, while ML exosomes from pre-shock had no effect on monocyte NF-KB expression. Conclusion Post-shock ML exosomes carry a distinct, pro-inflammatory protein cargo. Stimulating the vagus nerve prevents the T/HS-induced changes in ML exosome protein payload, and suggests a novel mechanism by which the neuro-enteric axis may limit the systemic inflammatory response after injury. Level of Evidence This study is a Basic Science paper and therefore does not require a level of evidence. Conflicts of interest: None This paper is scheduled to be presented at the 77th Annual Meeting of the American Association for the Surgery of Trauma, San Diego, CA September 27, 2018. Corresponding Author: Todd W. Costantini, MD, Division of Trauma, Surgical Critical Care, Burns and Acute Care Surgery, Department of Surgery, UC San Diego Health, 200 W. Arbor Drive #8896, San Diego, CA 92103, tcostantini@ucsd.edu © 2018 Lippincott Williams & Wilkins, Inc.

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