Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Critical Care
Published in: Critical Care 1/2018

Open Access 01-12-2018 | Research

Exosomes from patients with septic shock convey miRNAs related to inflammation and cell cycle regulation: new signaling pathways in sepsis?

Authors: Juliana Monte Real, Ludmila Rodrigues Pinto Ferreira, Gustavo Henrique Esteves, Fernanda Christtanini Koyama, Marcos Vinícius Salles Dias, João Evangelista Bezerra-Neto, Edécio Cunha-Neto, Flavia Ribeiro Machado, Reinaldo Salomão, Luciano Cesar Pontes Azevedo

Published in: Critical Care | Issue 1/2018

Login to get access

Abstract

Background

Exosomes isolated from plasma of patients with sepsis may induce vascular apoptosis and myocardial dysfunction by mechanisms related to inflammation and oxidative stress. Despite previous studies demonstrating that these vesicles contain genetic material related to cellular communication, their molecular cargo during sepsis is relatively unknown. In this study, we evaluated the presence of microRNAs (miRNAs) and messenger RNAs (mRNAs) related to inflammatory response and redox metabolism in exosomes of patients with septic shock.

Methods

Blood samples were collected from 24 patients with septic shock at ICU admission and after 7 days of treatment. Twelve healthy volunteers were used as control subjects. Exosomes were isolated by ultracentrifugation, and their miRNA and mRNA content was evaluated by qRT-PCR array.

Results

As compared with healthy volunteers, exosomes from patients with sepsis had significant changes in 65 exosomal miRNAs. Twenty-eight miRNAs were differentially expressed, both at enrollment and after 7 days, with similar kinetics (18 miRNAs upregulated and 10 downregulated). At enrollment, 35 differentially expressed miRNAs clustered patients with sepsis according to survival. The pathways enriched by the miRNAs of patients with sepsis compared with control subjects were related mostly to inflammatory response. The comparison of miRNAs from patients with sepsis according to hospital survival demonstrated pathways related mostly to cell cycle regulation. At enrollment, sepsis was associated with significant increases in the expression of mRNAs related to redox metabolism (myeloperoxidase, 64-fold; PRDX3, 2.6-fold; SOD2, 2.2-fold) and redox-responsive genes (FOXM1, 21-fold; SELS, 16-fold; GLRX2, 3.4-fold). The expression of myeloperoxidase mRNA remained elevated after 7 days (65-fold).

Conclusions

Exosomes from patients with septic shock convey miRNAs and mRNAs related to pathogenic pathways, including inflammatory response, oxidative stress, and cell cycle regulation. Exosomes may represent a novel mechanism for intercellular communication during sepsis.
Appendix
Available only for authorised users
Literature
1.
Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29(7):1303–10.CrossRefPubMed
2.
Angus DC, Pereira CA, Silva E. Epidemiology of severe sepsis around the world. Endocr Metab Immune Disord Drug Targets. 2006;6(2):207–12.CrossRefPubMed
3.
Conde KA, Silva E, Silva CO, Ferreira E, Freitas FG, Castro I, Rea-Neto A, Grion CM, Moura AD, Lobo SM, et al. Differences in sepsis treatment and outcomes between public and private hospitals in Brazil: a multicenter observational study. PLoS One. 2013;8(6):e64790.CrossRefPubMedPubMedCentral
4.
Taniguchi LU, Bierrenbach AL, Toscano CM, Schettino GP, Azevedo LC. Sepsis-related deaths in Brazil: an analysis of the national mortality registry from 2002 to 2010. Crit Care. 2014;18(6):608.CrossRefPubMedPubMedCentral
5.
Salomao R, Brunialti MK, Rapozo MM, Baggio-Zappia GL, Galanos C, Freudenberg M. Bacterial sensing, cell signaling, and modulation of the immune response during sepsis. Shock. 2012;38(3):227–42.CrossRefPubMed
6.
Azevedo LC, Janiszewski M, Soriano FG, Laurindo FR. Redox mechanisms of vascular cell dysfunction in sepsis. Endocr Metab Immune Disord Drug Targets. 2006;6(2):159–64.CrossRefPubMed
7.
Azevedo LC, Pedro MA, Laurindo FR. Circulating microparticles as therapeutic targets in cardiovascular diseases. Recent Pat Cardiovasc Drug Discov. 2007;2(1):41–51.CrossRefPubMed
8.
9.
10.
Gambim MH, de Oliveira do Carmo A, Marti L, Veríssimo-Filho S, Lopes LR, Janiszewski M. Platelet-derived exosomes induce endothelial cell apoptosis through peroxynitrite generation: experimental evidence for a novel mechanism of septic vascular dysfunction. Crit Care. 2007;11(5):R107.CrossRefPubMedPubMedCentral
11.
Janiszewski M, do Carmo AO, Pedro MA, Silva E, Knobel E, Laurindo FR. Platelet-derived exosomes of septic individuals possess proapoptotic NAD(P)H oxidase activity: A novel vascular redox pathway. Crit Care Med. 2004;32(3):818–25.CrossRefPubMed
12.
Azevedo LC, Janiszewski M, Pontieri V, Pedro de Almeida Pedro M, Bassi E, Tucci PJ, Laurindo FR. Platelet-derived exosomes from septic shock patients induce myocardial dysfunction. Crit Care. 2007;11(6):R120.CrossRefPubMedPubMedCentral
13.
Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654–9.CrossRefPubMed
14.
Hunter MP, Ismail N, Zhang X, Aguda BD, Lee EJ, Yu L, Xiao T, Schafer J, Lee ML, Schmittgen TD, et al. Detection of microRNA expression in human peripheral blood microvesicles. PLoS One. 2008;3(11):e3694.CrossRefPubMedPubMedCentral
15.
Lv LL, Cao YH, Ni HF, Xu M, Liu D, Liu H, Chen PS, Liu BC. MicroRNA-29c in urinary exosome/microvesicle as a biomarker of renal fibrosis. Am J Phys Renal Phys. 2013;305(8):F1220–7.
16.
Benz F, Tacke F, Luedde M, Trautwein C, Luedde T, Koch A, Roderburg C. Circulating microRNA-223 serum levels do not predict sepsis or survival in patients with critical illness. Dis Markers. 2015;2015:384208.CrossRefPubMedPubMedCentral
17.
Roderburg C, Luedde M, Vargas Cardenas D, Vucur M, Scholten D, Frey N, Koch A, Trautwein C, Tacke F, Luedde T. Circulating microRNA-150 serum levels predict survival in patients with critical illness and sepsis. PLoS One. 2013;8(1):e54612.CrossRefPubMedPubMedCentral
18.
Goodwin AJ, Guo C, Cook JA, Wolf B, Halushka PV, Fan H. Plasma levels of microRNA are altered with the development of shock in human sepsis: an observational study. Crit Care. 2015;19:440.CrossRefPubMedPubMedCentral
19.
Fan H, Goodwin AJ, Chang E, Zingarelli B, Borg K, Guan S, Halushka PV, Cook JA. Endothelial progenitor cells and a stromal cell-derived factor-1α analogue synergistically improve survival in sepsis. Am J Respir Crit Care Med. 2014;189(12):1509–19.CrossRefPubMedPubMedCentral
20.
Reithmair M, Buschmann D, Märte M, Kirchner B, Hagl D, Kaufmann I, Pfob M, Chouker A, Steinlein OK, Pfaffl MW, et al. Cellular and extracellular miRNAs are blood-compartment-specific diagnostic targets in sepsis. J Cell Mol Med. 2017;21(10):2403–11.CrossRefPubMedPubMedCentral
21.
Bone RC, Sibbald WJ, Sprung CL. The ACCP-SCCM Consensus Conference on Sepsis and Organ Failure. Chest. 1992;101(6):1481–3.CrossRefPubMed
22.
Huang X, Yuan T, Tschannen M, Sun Z, Jacob H, Du M, Liang M, Dittmar RL, Liu Y, Liang M, et al. Characterization of human plasma-derived exosomal RNAs by deep sequencing. BMC Genomics. 2013;14:319.CrossRefPubMedPubMedCentral
23.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔC T method. Methods. 2001;25(4):402–8.CrossRefPubMed
24.
Navarro IC, Ferreira FM, Nakaya HI, Baron MA, Vilar-Pereira G, Pereira IR, Silva AM, Real JM, De Brito T, Chevillard C, et al. MicroRNA transcriptome profiling in heart of Trypanosoma cruzi-infected mice: parasitological and cardiological outcomes. PLoS Negl Trop Dis. 2015;9(6):e0003828.CrossRefPubMedPubMedCentral
25.
Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, Schwille P, Brugger B, Simons M. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science. 2008;319(5867):1244–7.CrossRefPubMed
26.
Yende S, D’Angelo G, Kellum JA, Weissfeld L, Fine J, Welch RD, Kong L, Carter M, Angus DC, GenIMS Investigators. Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis. Am J Respir Crit Care Med. 2008;177(11):1242–7.CrossRefPubMedPubMedCentral
27.
28.
Uhlich RM, Konie JA, Davis JW, Misfeldt ML, Nelson C, Calaluce R, Barnes SL. Novel microRNA correlations in the severely injured. Surgery. 2014;156(4):834–40.CrossRefPubMed
29.
Khalid U, Bowen T, Fraser DJ, Jenkins RH. Acute kidney injury: a paradigm for miRNA regulation of the cell cycle. Biochem Soc Trans. 2014;42(4):1219–23.CrossRefPubMed
30.
Price PM, Megyesi J, Safirstein RL. Cell cycle regulation: repair and regeneration in acute renal failure. Semin Nephrol. 2003;23(5):449–59.CrossRefPubMed
31.
Kashani K, Al-Khafaji A, Ardiles T, Artigas A, Bagshaw SM, Bell M, Bihorac A, Birkhahn R, Cely CM, Chawla LS, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care. 2013;17(1):R25.CrossRefPubMedPubMedCentral
32.
33.
Bowen T, Jenkins RH, Fraser DJ. MicroRNAs, transforming growth factor beta-1, and tissue fibrosis. J Pathol. 2013;229(2):274–85.CrossRefPubMed
34.
Yang QH, Liu DW, Long Y, Liu HZ, Chai WZ, Wang XT. Acute renal failure during sepsis: potential role of cell cycle regulation. J Inf Secur. 2009;58(6):459–64.
35.
Yang QH, Liu DW, Wang XT, Yang RL, Shi Y, Long Y, Liu HZ, He HW, Zhou X, Tang B. G1 cell cycle arrest signaling in hepatic injury after intraperitoneal sepsis in rats. Inflamm Res. 2011;60(8):783–9.CrossRefPubMed
36.
Ximenes VF, Silva SO, Rodrigues MR, Catalani LH, Maghzal GJ, Kettle AJ, Campa A. Superoxide-dependent oxidation of melatonin by myeloperoxidase. J Biol Chem. 2005;280(46):38160–9.CrossRefPubMed
37.
Ferry G, Ubeaud C, Lambert PH, Bertin S, Coge F, Chomarat P, Delagrange P, Serkiz B, Bouchet JP, Truscott RJ, et al. Molecular evidence that melatonin is enzymatically oxidized in a different manner than tryptophan: investigations with both indoleamine 2,3-dioxygenase and myeloperoxidase. Biochem J. 2005;388(Pt 1):205–15.CrossRefPubMedPubMedCentral
38.
Srinivasan V, Pandi-Perumal SR, Spence DW, Kato H, Cardinali DP. Melatonin in septic shock: some recent concepts. J Crit Care. 2010;25(4):656.e1–6.CrossRef
39.
Cunniff B, Wozniak AN, Sweeney P, DeCosta K, Heintz NH. Peroxiredoxin 3 levels regulate a mitochondrial redox setpoint in malignant mesothelioma cells. Redox Biol. 2014;3:79–87.CrossRefPubMedPubMedCentral
40.
Huang X, Zhao YY. Transgenic expression of FoxM1 promotes endothelial repair following lung injury induced by polymicrobial sepsis in mice. PLoS One. 2012;7(11):e50094.CrossRefPubMedPubMedCentral
41.
Zhao YY, Gao XP, Zhao YD, Mirza MK, Frey RS, Kalinichenko VV, Wang IC, Costa RH, Malik AB. Endothelial cell-restricted disruption of FoxM1 impairs endothelial repair following LPS-induced vascular injury. J Clin Invest. 2006;116(9):2333–43.CrossRefPubMedPubMedCentral
42.
Fernandez-Messina L, Gutierrez-Vazquez C, Rivas-Garcia E, Sanchez-Madrid F, de la Fuente H. Immunomodulatory role of microRNAs transferred by extracellular vesicles. Biol Cell. 2015;107(3):61–77.CrossRefPubMedPubMedCentral
Metadata
Title
Exosomes from patients with septic shock convey miRNAs related to inflammation and cell cycle regulation: new signaling pathways in sepsis?
Authors
Juliana Monte Real
Ludmila Rodrigues Pinto Ferreira
Gustavo Henrique Esteves
Fernanda Christtanini Koyama
Marcos Vinícius Salles Dias
João Evangelista Bezerra-Neto
Edécio Cunha-Neto
Flavia Ribeiro Machado
Reinaldo Salomão
Luciano Cesar Pontes Azevedo
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2018
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-018-2003-3

Other articles of this Issue 1/2018

Critical Care 1/2018 Go to the issue

Research

Temporal biomarker profiles and their association with ICU acquired delirium: a cohort study

Letter

Adjuvant vitamin C in cardiac arrest patients undergoing renal replacement therapy: an appeal for a higher high-dose

Research

Multicenter derivation and validation of an early warning score for acute respiratory failure or death in the hospital

Research

Predicting acute kidney injury using urinary liver-type fatty-acid binding protein and serum N-terminal pro-B-type natriuretic peptide levels in patients treated at medical cardiac intensive care units

Research

Neuromuscular blockade is associated with the attenuation of biomarkers of epithelial and endothelial injury in patients with moderate-to-severe acute respiratory distress syndrome

Research

Intrapulmonary autologous transplant of bone marrow-derived mesenchymal stromal cells improves lipopolysaccharide-induced acute respiratory distress syndrome in rabbit