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

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.

Cardiac Dysfunction in Rheumatoid Arthritis: The Role of Inflammation

“…Indications of beneficial effects of SPM in systemic inflammation-induced cardiac dysfunction is also evident from sepsis studies. FPR2 knockout mice have exacerbated cardiac dysfunction following caecal ligation and puncture in a model of polymicrobial sepsis [ 152 ], and RvE1 successfully attenuated polymicrobial sepsis-induced cardiac dysfunction and enhanced bacterial clearance [ 153 ], whilst maresin conjugates in tissue regeneration 1 (MCTR1) markedly improved cardiac function in a model of lipopolysaccharide (LPS)-induced cardiac dysfunction [ 154 ].…”

A New E-Series Resolvin: RvE4 Stereochemistry and Function in Efferocytosis of Inflammation-Resolution

“…RvE1 has unique actions on platelets by inhibiting adenosine diphosphate (ADP)-activated mobilization of P-selectin to minimize platelet aggregation. In addition, RvE1 has potent actions in the nanogram range in vivo including: organ protection, clearing infections, and stimulating resolution in, e.g., peritonitis ( 11 , 12 , 14 , 37 , 38 ), sepsis ( 45 ), ischemia-reperfusion injury ( 46 ), diabetes ( 47 ), colitis ( 39 , 49 , 50 ), lung inflammation ( 51 ), obesity ( 48 ), atherosclerosis ( 55 ), tumor burden ( 58 ), dermatitis ( 59 ), Candida albicans ( 60 ), and herpes simplex virus infections ( 62 ) as well as in pain ( 61 ). In humans, RvE1 has been identified in the plasma of healthy individuals ( 63 ), plasma and synovial fluid from arthritic patients ( 64 ), plasma of type II diabetes mellitus patients ( 65 ), plasma of peripheral artery disease patients ( 66 ), cord blood ( 67 ), breast milk ( 68 ), and blisters induced by UV-killed E. coli ( 69 ).…”

E-series resolvin metabolome, biosynthesis and critical role of stereochemistry of specialized pro-resolving mediators (SPMs) in inflammation-resolution: Preparing SPMs for long COVID-19, human clinical trials, and targeted precision nutrition

“… Name and Abbreviation Stereochemical name Structure Pro-resolving cellular functions and in vivo actions Organ protection Locations/origins in humans and animal models Resolvin E1 (RvE1) 5 S ,12 R ,18 R -trihydroxy-6 Z ,8 E ,10 E ,14 Z ,16 E -eicosapentaenoic acid Limits PMN [ 21 , 77 , 78 , 80 , 99 ] and reduces dendritic cell further tissue infiltration [ 72 , 100 ]. Peritonitis [ 21 , 72 , 77 , 78 , 80 ], air pouch [ 21 ], CLP/sepsis [ 106 ], bacterial [ 101 ], I/R injury [ 107 ], diabetes [ 108 ], obesity [ 112 ], colitis [ 99 , 109 , 110 ]; lung inflammation [ 111 ], kidney injury [ 199 ], depression Alzheimer’s [ 200 ], atherosclerosis [ 113 , 201 ], bone[ 81 ], reduces tumor growth [ 114 ], Dermatitis [ 115 ], Candida albicans [ 116 ], pain [ 118 ], and reduces herpes [ 117 ]. Plasma [ 119 ] Nano-delivery of RvE1 repairs gastrointestinal injury and activates wound healing [ 110 , 202 ...…”

“…RvE1 has unique actions on platelets by inhibiting adenosine diphosphate (ADP)-activated mobilization of P-selectin to minimize platelet aggregation, which is very useful for prolonged storage of blood that can be useful for needed battlefield transfusions [ 104 ]. In addition, RvE1 and the other SPMs have potent actions in the nanogram range in vivo that include organ protection, clearing infections (by increasing killing [ 105 ]), and stimulating resolution as receptor agonists in, e.g., peritonitis [ 21 , 72 , 77 , 78 , 80 ], sepsis [ 106 ], ischemia-reperfusion injury [ 107 ], diabetes [ 108 ], colitis [ 99 , 109 , 110 ], lung inflammation [ 111 ], obesity [ 112 ], atherosclerosis [ 113 ], tumor burden [ 114 ], dermatitis [ 115 ], Candida albicans [ 116 ], and herpes simplex virus infections [ 117 ] as well as in pain [ 118 ]. In humans, RvE1 has been identified in the plasma of healthy individuals [ 119 ], plasma and synovial fluid from arthritic patients [ 46 ], plasma of type II diabetes mellitus patients [ 54 ], plasma of peripheral artery disease patients [ 120 ], cord blood [ 55 ], breast milk [ 121 ], and blisters induced by UV-killed E. coli [ 122 ].…”