Changes in peroxisome proliferator-activated receptor-gamma activity in children with septic shock

Abstract

Purpose: To assess changes in peroxisome proliferator-activated receptor-gamma (PPARgamma) in peripheral blood mononuclear cells (PBMC) from critically ill children with sepsis. Additionally, to investigate the effects of sepsis on the endogenous activator of PPARgamma, 15-deoxy-(12,14)-PGJ(2) (15d-PGJ(2)), and the downstream targets of PPARgamma activity, adiponectin and resistin.

Methods: Single-center, prospective case-control study in critically ill children with systemic inflammatory response syndrome, sepsis or septic shock.

Results: PPARgamma nuclear protein expression was decreased but PPARgamma activity was increased in PBMC from children with septic shock compared with controls. PPARgamma activity on day 1 was significantly higher in patients with higher pediatric risk of mortality (PRISM) score compared with controls [mean 0.22 optical density (OD) +/- standard error of the mean (SEM) 0.03 versus 0.12 OD +/- 0.02; p < 0.001]. Patients with resolved sepsis had increased levels of the endogenous PPARgamma ligand, 15d-PGJ(2), compared with patients with systemic inflammatory response syndrome (SIRS) and septic shock (77.7 +/- 21.7 versus 58 +/- 16.5 pg/ml; p = 0.03). Plasma high-molecular-weight adiponectin (HMWA) and resistin levels were increased in patients with septic shock on day 1 and were significantly higher in patients with higher PRISM scores. Nonsurvivors from sepsis had higher resistin levels on the first day of hospitalization compared with survivors from septic shock [660 ng/ml, interquartile range (IQR) 585-833 ng/ml versus 143 ng/ml, IQR 66-342 ng/ml; p < 0.05].

Conclusions: Sepsis is associated with altered PPARgamma expression and activity in PBMC. Plasma adipokines correlate with risk of mortality scores in sepsis and may be useful biomarkers. Further studies are needed to understand the mechanisms underlying changes in PPARgamma in sepsis.

Fig. 1

Nuclear PPARγ protein expression is decreased in PBMC in septic shock. (A) Representative western blot of nuclear PPARγ protein expression in PBMC from two patients with various categories of sepsis on day 1 or 3 and in four control patients. (B) Box and whisker plot of PPARγ nuclear protein levels from PBMC by western blot analysis based on densitometric analysis of the absolute intensity. Patients were grouped according to their sepsis category and therefore multiple samples were obtained from the same patient if they fulfilled the requirement for the diagnostic category on day 1,3, or 7 of their illness. The vertical box represents the 25^th percentile (bottom line), median (middle line), and 75^th percentile (top line) values

Fig. 2

Nuclear PPARγ activity is increased in PBMC in septic shock. Box and whisker plot of nuclear PPARγ activity levels from PBMC. Patients were grouped according to their sepsis category. The vertical box represents the 25th percentile (bottom line), median (middle line), and 75th percentile (top line) values, while the error bars represent the 10th and 90th percentile values. The dots represent values outside the 10th and 90th percentile. *p<0.05 vs control

Fig. 3

Plasma high molecular weight adiponectin (HMWA) and resistin levels are increased in sepsis on the first day of hospitalization. Box and whisker plot of day one plasma resistin levels grouped by sepsis category. The vertical box represents the 25^th percentile (bottom line), median (middle line), and 75^th percentile (top line) values, while the error bars represent the 10^th and 90^th percentile values. The dots represent values outside the 10^th and 90^th percentile. *p<0.05 vs control

Fig. 4

Plasma HMWA and resistin levels are increased in children with an increased pediatric risk of mortality score (PRISM). Box and whisker plot showing levels of plasma HMWA and resistin categorized by severity using the admission PRISM score. The vertical box represents the 25^th percentile (bottom line), median (middle line), and 75^th percentile (top line) values, while the error bars represent the 10^th and 90^th percentile values. The dots represent values outside the 10^th and 90^th percentile. *p< vs PRISM? 10