Maresin 1 attenuates mitochondrial dysfunction through the ALX/cAMP/ROS pathway in the cecal ligation and puncture mouse model and sepsis patients

Abstract

Inflammation always accompanies infection during sepsis. Mitochondrial dysfunction and the role of reactive oxygen species (ROS) produced by mitochondria have been proposed in the pathogenesis of sepsis. Maresins have protective and resolving effects in experimental models of infection. In the present study, we investigated the effects of maresin 1 (MaR1) on mitochondrial function in cecal ligation and puncture (CLP)-induced sepsis and sepsis patients to identify mechanisms underlying maresin 1-mediated stimulation of ROS in mitochondria. We found that treatment with MaR1 significantly inhibited production of cytokines, decreased bacterial load in the peritoneal lavage fluid, reduced the number of neutrophils, decreased lactic acid level and upregulated cyclic AMP (cAMP) concentration, with the outcome of decreased lung injury in CLP-induced sepsis in mice. The effects of MaR1 on downregulation nitric oxide (NOX) activity, improvement CAT and SOD activity to inhibit ROS production in mitochondria was dependent on lipoxin receptor (ALX) and cAMP. Survival rates were significantly increased after the treatment of mice with MaR1. In BMDM stimulated with LPS, MaR1 inhibited the ROS production, downregulated enzyme activity, reduced mtO2 production, increased mitochondrial membrane potential, improved adenosine triphosphate (ATP) content and mitochondrial DNA (mtDNA) copy number. Finally, the effects of MaR1 on ROS production in the blood of healthy volunteers stimulated with LPS or sepsis patients were associated with ALX and cAMP. Taken together, these data suggest that treatment with MaR1 could attenuate mitochondrial dysfunction during sepsis through regulating ROS production.

Maresin 1 attenuates neuroinflammation in a mouse model of perioperative neurocognitive disorders

“… 27 This is consistent with our current findings in BMDMs and previous reports that other SPMs reduced reactive oxygen species production. 21 , 28 , 29 , 30 …”

Phagocytosis–Inflammation Crosstalk in Sepsis: New Avenues for Therapeutic Intervention

“…A key characteristic of sepsis is imbalanced cellular energy metabolism ( 85 , 86 ), which contributes to immune paralysis and vulnerability to secondary infections ( 87 ). Although the involvement of ROS and NO during sepsis is debated, as boosting and inhibiting their activity has opposing effects ( 88 , 89 ), they also have an indirect role in phagocyte metabolic switch during the sepsis ( 90 ). The initial phase of sepsis is characterized by elevated mitochondrial respiration and ATP production ( 91 ).…”

Determining 5HT7R’s involvement in modifying the antihyperalgesic effects of electroacupuncture on rats with recurrent migraine

“…including β-endorphins [73], cannabinoid CB2 receptors [74], and adenosine A1 receptor [75], the 5-HT 7 Rmediated PKA and ERK 1/2 phosphorylation through Gαs-cAMP signaling is likely only one of the key factors involved in EA's maintenance of antihyperalgesic effects. Moreover, cAMP interacts with several other proteins in addition to PKA and ERK 1/2 , including ROS [76], NF-κB [77], and AKAP [78], which might also be involved in the maintenance of the antihyperalgesic effects by EA. Next, we will use naloxone to block opioid receptors, or DPCPX to block A1 receptors, so as to exclude the effect of other factors on EA antihyperalgesia, and then con rm the role of 5-HT 7 R.…”