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Protective Effect of Melatonin Against Polymicrobial Sepsis Is Mediated by the Anti-bacterial Effect of Neutrophils.

ABSTRACT: Sepsis is an infection- or toxin-mediated systemic inflammatory syndrome. Previous studies have shown that melatonin, the primary hormone produced by the pineal gland, attenuates the effect of polymicrobial infection-mediated septic shock in animals. However, the mechanism of the anti-septic effect of melatonin during polymicrobial infection has not been well-studied. In this study, we investigated how melatonin protects mice from polymicrobial sepsis. Melatonin treatment inhibited peripheral tissue inflammation and tissue damage in a cecal ligation puncture (CLP)-induced polymicrobial sepsis model, consequently reducing the mortality of the mice. We found that macrophages and neutrophils expressed melatonin receptors. Upon depletion of neutrophils, melatonin-induced protection against polymicrobial infection failed in the mice, but melatonin treatment in macrophage-depleted mice attenuated the mice mortality resulting from polymicrobial sepsis. Moreover, melatonin treatment promoted the development of the neutrophil extracellular trap (NET), which contributed to anti-bacterial activity during polymicrobial infection, whereas the phagocytic activities of neutrophils were inhibited by melatonin. The data from this study support previously unexplained antiseptic effects of melatonin during a polymicrobial infection and could be potentially useful for human patients with sepsis.

SUBMITTER: Xu L

PROVIDER: S-EPMC6593141 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Protective Effect of Melatonin Against Polymicrobial Sepsis Is Mediated by the Anti-bacterial Effect of Neutrophils.

Xu Li L Zhang Wei W Kwak Minseok M Zhang LiJun L Lee Peter C W PCW Jin Jun-O JO

Frontiers in immunology 20190619

Sepsis is an infection- or toxin-mediated systemic inflammatory syndrome. Previous studies have shown that melatonin, the primary hormone produced by the pineal gland, attenuates the effect of polymicrobial infection-mediated septic shock in animals. However, the mechanism of the anti-septic effect of melatonin during polymicrobial infection has not been well-studied. In this study, we investigated how melatonin protects mice from polymicrobial sepsis. Melatonin treatment inhibited peripheral ti ...[more]

PMID: 31275316

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Project description:Background: Acute kidney injury (AKI) portends worse prognosis following sepsis, with limited available interventions. Host iron acquisition by pathogens and systemic inflammatory response are key events in the pathogenesis of sepsis. In sepsis, hepcidin induces iron sequestration to limit iron availability to pathogens. Hepcidin is also known to limit inflammation. Since its role in pathophysiology of sepsis-associated AKI is unknown, we investigated the effect of exogenous hepcidin in endotoxin- and peritonitis-induced pathology and AKI. Methods: C57BL/6 mice were treated with saline or 50-100 µg of hepcidin, pre- and post-LPS injection, or cecal ligation and puncture (CLP, model of peritonitis). Splenectomized mice were challenged with LPS, with and without hepcidin. Mice were euthanized at 24 h after LPS injection and at different time points after CLP. Systemic inflammation and renal injury markers were assessed. Direct effect of hepcidin on renal tubular and endothelial cells was evaluated using endotoxin-induced cytotoxic serum. Role of heavy chain ferritin (H-ferritin) in mediating hepcidin-induced anti-inflammatory effect on LPS stimulated macrophages was evaluated with siRNA studies. Results: Twenty-four hours pretreatment with hepcidin significantly reduced LPS-induced AKI. Hepcidin ameliorated LPS-induced increase in serum TNFα and renal Cox-2, and prevented loss in PGC1α and cytochrome c oxidase activity. This was associated with reduced glomerular injury and preserved mitochondrial structure. Hepcidin did not exert direct protection on the renal parenchymal cells but reduced endotoxin-induced serum cytotoxicity to mitigate renal injury. Splenectomy reduced LPS-induced early inflammation and AKI, independent of hepcidin, indicating the importance of systemic inflammation. Higher splenic H-ferritin in hepcidin-treated animals was associated with reduced splenocytes apoptosis and inflammation. Hepcidin reduced LPS-induced IL-6 secretion in macrophages in H-ferritin dependent manner. Hepcidin significantly reduced CLP-induced AKI, and mortality (20% hepcidin treated vs 80% PBS treated). Importantly hepcidin reduced bacteremia and AKI even when administered after onset of sepsis. Conclusion: We demonstrate a protective role of hepcidin in endotoxin- and peritonitis-induced pathologies and AKI, exerted primarily through its anti-inflammatory effects, and antibacterial property. Macrophage H-ferritin plays an important role in hepcidin-mediated protection against endotoxin-induced inflammation. We uncover a novel prophylactic and therapeutic role of hepcidin in sepsis-associated bacteremia, AKI, and mortality.

Project description:Introductionaccording to the World Health Organization (WHO), COVID-19 is an infectious disease caused by the SARS-CoV-2 virus, responsible for an increasing number of cases and deaths. From a preventive and therapeutic point of view, there are two concerns that affect institutions and healthcare professionals: global immunization (which is still far from being achieved) and the availability of drugs capable of preventing its consequences in the infected patient. In this sense, the role that melatonin can play is has been assessed in the recent literature. Justification and Objectives: the serious health, social and economic consequences of COVID-19 have forced an urgent search for preventive methods, such as vaccines, among others, and therapeutic methods that could be alternatives to the drugs currently used. In this sense, it must be accepted that one of the most recommended has been the administration of melatonin. The present study proposes to carry out a systematic review of its possible role in the treatment and/or prevention of COVID-19. Material and methods: a systematic review of the literature related to the prevention of COVID-19 through the administration of melatonin was carried out, following the sequence proposed by the Prisma Declaration regarding the identification and selection of documents, using the specialized health databases Trip Medical Database, Cochrane Library, PubMed, Medline Plus, BVS, Cuiden and generic databases such as Dialnet, Web of Science and Google Scholar for their retrieval. Appropriate inclusion and exclusion criteria are described for the articles assessed. The main limitation of the study has been the scarcity of works and the lack of defining a specific protocol in terms of dosage and administration schedule. Results: once the selection process was completed, and after an in-depth critical analysis, 197 papers were selected, and 40 of them were finally used. The most relevant results were: (1) melatonin prevents SARS-CoV-2 infection, (2) although much remains to be clarified, at high doses, it seems to have a coadjuvant therapeutic effect in the treatment of SARS-CoV-2 infection and (3) melatonin is effective against SARS-CoV-2 infection. Discussion: until group immunization is achieved in the population, it seems clear that we must continue to treat patients with SARS-CoV-2 infection, and, in the absence of a specific and effective antiviral therapy, it is advisable to continue researching and providing drugs that demonstrate validity based on the scientific evidence. In this regard, we believe that the available studies recommend the administration of melatonin for its anti-inflammatory, antioxidant, immunomodulatory, sleep-inducing, CD147, Mpro, p65 and MMP9 protein suppressing, nephrotoxicity-reducing and highly effective and safe effects. Conclusions: (1) melatonin has anti-inflammatory, antioxidant, immunomodulatory, and Mpro and MMP9 protein-inhibitory activity. (2) It has been shown to have a wide margin of safety. (3) The contributions reviewed make it an effective therapeutic alternative in the treatment of SARS-CoV-2 infection. (4) Further clinical trials are recommended to clearly define the administration protocol.

Project description: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.

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Protective Effect of Melatonin Against Polymicrobial Sepsis Is Mediated by the Anti-bacterial Effect of Neutrophils.

Publications

Protective Effect of Melatonin Against Polymicrobial Sepsis Is Mediated by the Anti-bacterial Effect of Neutrophils.

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