Abstract |
Background: Sepsis is a maladaptive inflammatory process in response to infectious agents, related
to immune dysfunctions and devastating complications. An interesting scientific field has recently
been uncovered, which might decode the oxidative or antioxidant, and the apoptotic (caspases) or
antiapoptotic processes (survivin protein) during sepsis, and might bring to light attractive
therapeutic interventions for septic intensive care unit (ICU) patients.
Methods: This prospective observational study was performed in a sample of critically ill adult
(n=145) and pediatric patients (n=67) with sepsis (S), compared to patients with non-infectious
inflammation (T) (n=112 and 116 for adult and pediatric patients respectively) and to healthy controls
(H) (n=89 and 38 for adults and children respectively), which were used as the two control groups.
The transcriptional expression of survivin, was quantified through real-time quantitative polymerase
chain reaction for the different survivin splice variants (WT, 2B, 3B and ΔΕx3). The enzyme-linked
immunosorbent assay method (ELISA) was used to quantify the apoptotic tendency based on
caspases-3, -8, -9, Bax (Bcl-2-associated X protein) and Smac/Diablo (Second mitochondria-derived
activator of caspase/Direct inhibitor of apoptosis-binding protein with low pI), along with the
antiapoptotic tendency based on XIAP (X-linked inhibitor of apoptosis protein) and survivin protein
in patient serum samples. Photometric analyses of total products of lipid peroxidation, and of the
enzymatic reaction with a predefined oxidative substance were used for total oxidative stress (TOS)
and for total antioxidant capacity (TAC) quantification respectively.
Results: The ratio of total oxidative stress over total antioxidant capacity (TOS/TAC) was significantly
elevated in septic patients (S), compared to non-infectious critical illness (T) and to healthy controls
(H) (p<0.001). With regard to the apoptotic tendency of adult septic patients, the upregulation of the
induced by the endogenous apoptotic pathway caspase-9 (p=0.014), and of the executioner caspase-
3 (p=0.020), along with downregulation of Bax protein (p=0.040) was recorded for the septic group,
compared to the control groups. The enzymatic serum levels of the antiapoptotic survivin protein
were highly expressed in sepsis (p=0.001), compared to non-infectious critically-ill patients and to
healthy controls, whereas an upregulation of the antiapoptotic XIAP was also recorded for the septic
group (p=0.084). As far as the transcriptional behavior of survivin is concerned, survivin’s isoforms -
2B and -ΔΕx3 were significantly higher in sepsis, compared to the control groups (p<0.001 for adult
septic patients). With regard to septic children, upregulation of survivin protein (p=0.022), along with
isoform survivin-2B (p=0.037) and caspase-9 (p=0.017) were recorded in sepsis, compared with the
two control groups.
Receiver operating characteristic (ROC) analysis revealed that TOS/TAC ratio was an independent
prognostic factor of developing sepsis (area under ROC curve-AUROC=0.977, 95% CI= 0.953-1,
p<0.001). In predicting mortality, TOS/TAC ratio also achieved the best AUROC=0.787 (95% CI=0.695-
0.878, p<0.001).
Conclusions: The upregulation of oxidative stress and repressed antioxidant capacity, accompanied
by the overexpression of the apoptotic caspases -3 and -9, and of the antiapoptotic XIAP and survivin
protein, along with the transcriptional upregulation of survivin’s isoforms, seem to characterize the developing process of sepsis. Certain oxidative, apoptotic and antiapoptotic pathways might
represent attractive targets for future research in the clarification of sepsis pathophysiology.
|