PMID- 32983159 OWN - NLM STAT- MEDLINE DCOM- 20210422 LR - 20210422 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 11 DP - 2020 TI - RvE1 Attenuates Polymicrobial Sepsis-Induced Cardiac Dysfunction and Enhances Bacterial Clearance. PG - 2080 LID - 10.3389/fimmu.2020.02080 [doi] LID - 2080 AB - 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 mug/mouse i.v.) at 1 h after CLP increased peritoneal macrophages number, particularly MHC II(-) macrophages. RvE1 reduced pro-inflammatory gene expression (interleukin-1beta, 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 IkappaB kinase alpha/beta, nuclear translocation of the NF-kappaB 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. CI - Copyright (c) 2020 Chen, Purvis, Collotta, Al Zoubi, Sugimoto, Cacace, Martin, Colas, Collino, Dalli and Thiemermann. FAU - Chen, Jianmin AU - Chen J AD - Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom. FAU - Purvis, Gareth S D AU - Purvis GSD AD - Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom. FAU - Collotta, Debora AU - Collotta D AD - Department of Drug Science and Technology, University of Turin, Turin, Italy. FAU - Al Zoubi, Sura AU - Al Zoubi S AD - Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom. AD - Department of Basic Medical Sciences, School of Medicine, Al-Balqa Applied University, As-Salt, Jordan. FAU - Sugimoto, Michelle A AU - Sugimoto MA AD - Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom. FAU - Cacace, Antonino AU - Cacace A AD - Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom. AD - Diabetes Complication Research Centre, School of Medicine, UCD Conway Institute, University College Dublin, Dublin, Ireland. FAU - Martin, Lukas AU - Martin L AD - Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom. AD - Department of Intensive Care and Intermediate Care, RWTH University Hospital Aachen, Aachen, Germany. FAU - Colas, Roman A AU - Colas RA AD - Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom. FAU - Collino, Massimo AU - Collino M AD - Department of Drug Science and Technology, University of Turin, Turin, Italy. FAU - Dalli, Jesmond AU - Dalli J AD - Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom. FAU - Thiemermann, Christoph AU - Thiemermann C AD - Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom. LA - eng GR - WT_/Wellcome Trust/United Kingdom GR - 107613/Z/15/Z/WT_/Wellcome Trust/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200902 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Biomarkers) RN - 0 (Inflammation Mediators) RN - AAN7QOV9EA (Eicosapentaenoic Acid) RN - GND3JH08JA (5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid) SB - IM MH - Animals MH - Bacterial Load/drug effects MH - Biomarkers MH - Disease Models, Animal MH - Echocardiography MH - Eicosapentaenoic Acid/*analogs & derivatives/pharmacology MH - Flow Cytometry MH - Gene Expression Regulation/drug effects MH - Heart Diseases/diagnosis/drug therapy/*etiology/metabolism MH - Heart Function Tests MH - Immunity/drug effects MH - Inflammation Mediators/metabolism MH - Lipid Metabolism/drug effects MH - Macrophages/immunology/metabolism MH - Mice MH - Models, Biological MH - Phagocytosis/drug effects/immunology MH - Prognosis MH - Sepsis/*complications/immunology/*microbiology MH - Signal Transduction/drug effects PMC - PMC7492649 OTO - NOTNLM OT - bacterial clearance OT - cardiomyopathy OT - immune response OT - polymicrobial sepsis OT - resolvin E1 EDAT- 2020/09/29 06:00 MHDA- 2021/04/23 06:00 PMCR- 2020/01/01 CRDT- 2020/09/28 05:41 PHST- 2020/06/24 00:00 [received] PHST- 2020/07/30 00:00 [accepted] PHST- 2020/09/28 05:41 [entrez] PHST- 2020/09/29 06:00 [pubmed] PHST- 2021/04/23 06:00 [medline] PHST- 2020/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2020.02080 [doi] PST - epublish SO - Front Immunol. 2020 Sep 2;11:2080. doi: 10.3389/fimmu.2020.02080. eCollection 2020.