Study of polymorphisms in the genes for TNF-α in pediatric patients in the ICU of Instituto Fernandes Figueira – Fundação Oswaldo Cruz (original) (raw)
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American Journal of Respiratory and Critical Care Medicine, 2000
The expression of NF-B was studied in freshly isolated peripheral blood mononuclear cells (PBMC) of patients with severe sepsis and major trauma. The expression of p65p50 heterodimer, the active form of NF-B, was significantly reduced for all patients as compared with control subjects. The p50p50 homodimer, an inhibitory form of NF-B, was reduced in the survivors of sepsis and in patients with trauma. Subsequent in vitro stimulation of PBMC with lipopolysaccharide (LPS) did not induce further NF-B nuclear translocation: the survivors of sepsis and trauma patients showed low expression of both p65p50 and p50p50, whereas nonsurvivors of sepsis showed a predominance of the inactive homodimer and a low p65p50/p50p50 ratio when compared with control subjects. In the later group of patients there was a reverse correlation between plasma IL-10 levels and the p65p50/p50p50 ratio after in vitro LPS stimulation (r ϭ Ϫ 0.8, p ϭ 0.04). The reduced expression of nuclear NF-B was not due to its inhibition by I B ␣ , as very low expression of I B ␣ , as well as low levels of p65 and p50 were found in the cytoplasm of PBMC from patients with sepsis and trauma when compared with control subjects. These results demonstrate that upon LPS activation, PBMC of patients with systemic inflammatory response syndrome show patterns of NF-B expression that resemble those reported during LPS tolerance: global down-regulation of NF-B in survivors of sepsis and trauma patients and the presence of large amounts of the inactive homodimer in the nonsurvivors of sepsis.
Shock, 2006
Patient response to acute bacterial infection is highly variable. Differing outcomes in this setting may be related to variations in the immune response to an infectious insult. Using quantitative real-time polymerase chain reaction, we quantified gene expression of the tumor necrosis factor !(TNF!), interferon + (IFN+), and interleukin 10 (IL10), IL12p35, and IL4 genes in 3 patient groups. These groups consisted of an intensive care unit (ICU) cohort who presented with severe sepsis or septic shock, a group of noncritically ill ward patients with documented Gram-negative bacteremia, and a group of healthy controls. Greater interleukin 10 messenger RNA (mRNA) levels were detected in the ICU group in comparison with both the bacteremic and control groups (P G 0.0001). More TNF-! mRNA was detected in the ICU group when compared with the control group (P G 0.0001). However, TNF-! mRNA was most abundant in the bacteremic group (P = 0.0007). Lesser IFN-+ mRNA levels were detected in the ICU group when compared with both the bacteremic and control groups (P G 0.0003). Cytokine mRNA levels were not associated with the occurrence of shock upon admission to ICU. On the seventh day of ICU stay, the presence of shock was associated with lesser IFN-+ mRNA (P = 0.0004) and lesser TNF-! mRNA (P = 0.001). Survivors had greater TNF-! mRNA copy numbers on day 7 of ICU stay than nonsurvivors (P = 0.002). We conclude that a proinflammatory response is the appropriate response in the setting of infection and is associated with lesser requirements for inotropes and lesser mortality. Quantitative real-time polymerase chain reaction can be used to predict infection outcome in clinically relevant situations where enzyme-linked immunosorbent assay testing has proved disappointing.