Neutrophil extracellular traps (NETs) exacerbate severity of infant sepsis

Colón, D. F. et al. (2019) Neutrophil extracellular traps (NETs) exacerbate severity of infant sepsis. Critical Care, 23, 113. (doi: 10.1186/s13054-019-2407-8) (PMID:30961634) (PMCID:PMC6454713)

Abstract

Background: Neutrophil extracellular traps (NETs) are innate defense mechanisms that are also implicated in the pathogenesis of organ dysfunction. However, the role of NETs in pediatric sepsis is unknown. Methods: Infant (2 weeks old) and adult (6 weeks old) mice were submitted to sepsis by intraperitoneal (i.p.) injection of bacteria suspension or lipopolysaccharide (LPS). Neutrophil infiltration, bacteremia, organ injury, and concentrations of cytokine, NETs, and DNase in the plasma were measured. Production of reactive oxygen and nitrogen species and release of NETs by neutrophils were also evaluated. To investigate the functional role of NETs, mice undergoing sepsis were treated with antibiotic plus rhDNase and the survival, organ injury, and levels of inflammatory markers and NETs were determined. Blood samples from pediatric and adult sepsis patients were collected and the concentrations of NETs measured. Results: Infant C57BL/6 mice subjected to sepsis or LPS-induced endotoxemia produced significantly higher levels of NETs than the adult mice. Moreover, compared to that of the adult mice, this outcome was accompanied by increased organ injury and production of inflammatory cytokines. The increased NETs were associated with elevated expression of Padi4 and histone H3 citrullination in the neutrophils. Furthermore, treatment of infant septic mice with rhDNase or a PAD-4 inhibitor markedly attenuated sepsis. Importantly, pediatric septic patients had high levels of NETs, and the severity of pediatric sepsis was positively correlated with the level of NETs. Conclusion: This study reveals a hitherto unrecognized mechanism of pediatric sepsis susceptibility and suggests that NETs represents a potential target to improve clinical outcomes of sepsis.

• Item Type: Articles
• Additional Information: The research leading to these results received funding from the São Paulo Research Foundation (FAPESP) under grant agreement n.° 2013/08216-2, the Center for Research in Inflammatory Disease (CRID) under grant agreement 2011/19670-0, the University of São Paulo NAP-DIN (11.1.21625.01.0), the Conselho Nacional de Pesquisa e Desenvolvimento Tecnológico, CNPq) and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Liew, Prof Foo
• Authors: Colón, D. F., Wanderley, C. W., Franchin, M., Silva, C. M., Hiroki, C. H., Castanheira, F. V. S., Donate, P. B., Lopes, A. H., Volpon, L. C., Kavaguti, S. K., Borges, V. F., Speck-Hernandez, C. A., Ramalho, F., Carlotti, A. P., Carmona, F., Alves-Filho, J. C., Liew, F. Y., and Cunha, F. Q.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Critical Care
• Publisher: BMC
• ISSN: 1364-8535
• ISSN (Online): 1466-609X
• Published Online: 08 April 2019
• Copyright Holders: Copyright © The Authors 2019
• First Published: First published in Critical Care 23:113
• Publisher Policy: Reproduced under a Creative Commons license