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.
Subject(s)
Extracellular Traps/microbiology , Sepsis/therapy , Animals , Bacterial Load/methods , Brazil , Disease Models, Animal , Mice , Mice, Inbred C57BL/blood , Mice, Inbred C57BL/microbiology , Multiple Organ Failure/etiology , Multiple Organ Failure/pathology , Sepsis/mortality , Sepsis/pathologyABSTRACT
BACKGROUND AND PURPOSE: Sepsis-surviving adult individuals commonly develop immunosuppression and increased susceptibility to secondary infections, an outcome mediated by the axis IL-33/ILC2s/M2 macrophages/Tregs. Nonetheless, the long-term immune consequences of paediatric sepsis are indeterminate. We sought to investigate the role of age in the genesis of immunosuppression following sepsis. EXPERIMENTAL APPROACH: Here, we compared the frequency of Tregs, the activation of the IL-33/ILC2s axis in M2 macrophages and the DNA methylation of epithelial lung cells from post-septic infant and adult mice. Likewise, sepsis-surviving mice were inoculated intranasally with Pseudomonas aeruginosa or by subcutaneous inoculation of the B16 melanoma cell line. Finally, blood samples from sepsis-surviving patients were collected and the concentration of IL-33 and Tregs frequency were assessed. KEY RESULTS: In contrast to 6-week-old mice, 2-week-old mice were resistant to secondary infection and did not show impairment in tumour controls upon melanoma challenge. Mechanistically, increased IL-33 levels, Tregs expansion, and activation of ILC2s and M2-macrophages were observed in 6-week-old but not 2-week-old post-septic mice. Moreover, impaired IL-33 production in 2-week-old post-septic mice was associated with increased DNA methylation in lung epithelial cells. Notably, IL-33 treatment boosted the expansion of Tregs and induced immunosuppression in 2-week-old mice. Clinically, adults but not paediatric post-septic patients exhibited higher counts of Tregs and seral IL-33 levels. CONCLUSION AND IMPLICATIONS: These findings demonstrate a crucial and age-dependent role for IL-33 in post-sepsis immunosuppression. Thus, a better understanding of this process may lead to differential treatments for adult and paediatric sepsis.
Subject(s)
Interleukin-33 , Sepsis , Humans , Mice , Animals , Child , Immunity, Innate , Lymphocytes/metabolism , Lymphocytes/pathology , Immunosuppression TherapyABSTRACT
The authors report a case of abdominal compartment syndrome caused by massive pyonephrosis in an infant with primary obstructive megaureter successfully treated with emergency surgical decompression.