RvE1 Attenuates Polymicrobial Sepsis-Induced Cardiac Dysfunction and Enhances Bacterial Clearance

Frontiers in Immunology, vol. 11, pp. 2080

Abstract

The development of cardiac dysfunction caused by microbial infection predicts high mortality in sepsis patients. Specialized pro-resolving mediators (SPMs) mediate resolution of inflammation in many inflammatory diseases, and are differentially expressed in plasma of sepsis patients. Here, we investigated whether the levels of SPMs are altered in the murine septic heart following polymicrobial sepsis-induced cardiac dysfunction. Ten weeks-old male C57BL/6 mice were subjected to polymicrobial sepsis induced by cecal ligation and puncture (CLP), which is a clinically relevant sepsis model receiving analgesics, antibiotics, and fluid resuscitation. CLP caused a significant systolic dysfunction assessed by echocardiography. The hearts were subjected to LC-MS/MS based lipid mediator profiling. Many SPMs were significantly reduced in septic hearts, among which RvE1 had a ~93-fold reduction. Treatment of CLP mice with synthetic RvE1 (1 μg/mouse i.v.) at 1 h after CLP increased peritoneal macrophages number, particularly MHC II− macrophages. RvE1 reduced pro-inflammatory gene expression (interleukin-1β, interleukin-6, and CCL2) in lipopolysaccharide-stimulated bone marrow-derived macrophages (BMDMs) in vitro. RvE1 attenuated cardiac dysfunction in septic mice and increased cardiac phosphorylated Akt; decreased cardiac phosphorylated IκB kinase α/β, nuclear translocation of the NF-κB subunit p65, extracellular signal–regulated kinase 1/2, and c-Jun amino-terminal kinases 1/2. Most notably, RvE1 treatment reduced peritoneal bacterial load and promoted phagocytosis activity of BMDMs. In conclusion, cardiac SPMs, particularly RvE1, are substantially reduced in mice with polymicrobial sepsis. Delayed therapeutic administration of RvE1 to mice with polymicrobial sepsis attenuates the cardiac dysfunction through modulating immuno-inflammatory responses. In addition to the above effects, the ability to enhance bacterial clearance makes RvE1 an ideal therapeutic to reduce the sequalae of polymicrobial sepsis.

Authors 11

1. Jianmin Chen corresponding

   Queen Mary University of London · William Harvey Research Institute

   Affiliation as printed

   Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom

2. Gareth S. D. Purvis

   University of Oxford

   Affiliation as printed

   Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom

3. Debora Collotta

   University of Turin

   Affiliation as printed

   Department of Drug Science and Technology, University of Turin, Turin, Italy

4. Sura Al Zoubi

   Queen Mary University of London · Al-Balqa Applied University · William Harvey Research Institute

   Affiliation as printed

   Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom

   Department of Basic Medical Sciences, School of Medicine, Al-Balqa Applied University, As-Salt, Jordan

5. Michelle A. Sugimoto

   Queen Mary University of London · William Harvey Research Institute

   Affiliation as printed

   Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom

6. Antonino Cacace

   University College Dublin · Queen Mary University of London · William Harvey Research Institute

   Affiliation as printed

   Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom

   Diabetes Complication Research Centre, School of Medicine, UCD Conway Institute, University College Dublin, Dublin, Ireland

7. Lukas Märtin Aachen Department of Intensive Care and Intermediate Care

   Queen Mary University of London · Universitätsklinikum Aachen · William Harvey Research Institute · RWTH Aachen University

   Affiliation as printed

   Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom

   Department of Intensive Care and Intermediate Care, RWTH University Hospital Aachen, Aachen, Germany

8. Roman A. Colas

   Queen Mary University of London · William Harvey Research Institute

   Affiliation as printed

   Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom

9. Massimo Collino

   University of Turin

   Affiliation as printed

   Department of Drug Science and Technology, University of Turin, Turin, Italy

10. Jesmond Dalli

    Queen Mary University of London · William Harvey Research Institute

    Affiliation as printed

    Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom

11. Christoph Thiemermann corresponding

    Queen Mary University of London · William Harvey Research Institute

    Affiliation as printed

    Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom