Functional Significance of Exosome Therapy Improve the Outcome of a Murine Model of Sepsis: Potential role of Thioredoxin-1
*Sean Burgwardt DO1, *Andrew Kemerley DO2, *Santosh Swaminathan 1, *Mahesh Thirunavukkarasu 2, *Shayan Ahmed MD1, Alexander Palesty 1, *Nilanjana Maulik 2
1Surgery, Saint Mary's Hospital/UConn School of Medicine, Waterbury , CT; 2Surgery, UConn School of Medicine, Farmington, CT
Introduction: Sepsis-induced multiple organ failure remains the major cause of morbidity and mortality in the health care system. Previously, we demonstrated increased survival and improved heart function when thioredoxin-1 overexpressed (Trx-1Tg/+) mice were subjected to Cecal Ligation and Puncture (CLP) compared to corresponding wild-type controls. Based on these observations, this project aims to evaluate and determine the therapeutic efficiency of exosomes collected from Trx-1Tg/+ mice exposed to sepsis (CLP.ExoTrx-1Tg/+) and apply this treatment to septic mice. Method(s): The CD-1 (8-12 weeks old) mice were divided into 4 groups as follows: CLP surgery +PBS but without GW4869 (CLP + PBS) (Group 1); CLP surgery + PBS with GW4869 (CLP + PBS + GW4869) (Group 2); CLP surgery and ExoWT with GW4869 (CLP + GW + ExoWT) (Group 3); and CLP surgery and ExoTrx-1Tg/+ with GW4869 (CLP + GW + ExoTrx-1Tg/+) (Group 4). All animals were subjected to cecal ligation and puncture surgery followed by administration of phosphate buffered saline or GW4869 or ExoWT or ExoTrx-1Tg/+. Administration of GW4869, a pharmacological agent will block the release of innate exosomes. We injected mice with GW4869 (2.5mg/g b.wt) 2 hours after CLP surgery to inhibit the release of innate exosomes. After 4 hours of CLP surgery, we injected either CLP.ExoWT or CLP.ExoTrx-1Tg/+, as appropriate to the group. GW4869 was also injected every 12 hours post-surgery into the mice till the end of the experiment. Mouse survivability (Kaplain-Meier Survival Curve) and heart function (echocardiographic analysis) were performed 1-7 days post-surgery. Results: Kaplan-Meier survival curve analysis showed improved survival probability (%) [(Median Survival) (Log-rank test)] in the CLP+GW+ExoTrx-1Tg/+ [60%; p=0.0003] treatment group compared to the CLP + GW + ExoWT (33%) group, CLP + PBS + GW4869 group (48%), and CLP + PBS group (24%). The percent survivability rate of mice in the GW4869 treated group alone was better than the PBS group. Echocardiographic analysis revealed there was no significant difference in the cardiac function between CLP + PBS + GW4869 (EF: 49.62%±3.65; FS: 24.59±1.88) and CLP+PBS (EF: 41.31±6.77; FS: 20±4.01) (n=3-7) groups of mice exposed to sepsis. However, sepsis-induced mice treated with ExoTrx-1Tg/+ (CLP+ GW + ExoTrx-1Tg/+ group) showed preserved left ventricular ejection fraction (EF: 68.05±1.87 vs. 40.82±5.50) and fractional shortening (FS:37.18±1.24 vs. 19.88±2.91) compared to CLP.ExoWT group (CLP+GW+ExoWT) respectively. Conclusion(s): The results obtained from this study will help us to design synthetic or custom-made exosomes with desired cargos for therapy in sepsis subjects.
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