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Sepsis-induced lymphocyte apoptosis plays a fundamental role in the pathophysiology of sepsis. Recent animal models of sepsis have identified anomalies in the extrinsic apoptotic pathway, a key pathological occurrence in sepsis . Specifically apoptosis markers such as caspases 1, 3, 8, 9 and FADD have been shown to be significant in animal models of infection . We investigated mRNA transcription of these markers in a human model of severe sepsis. We hypothesized that ICU mortality from severe sepsis is associated with distinctive gene expression of extrinsic apoptosis markers.
A prospective observational study of patients with severe sepsis was performed. Mononuclear cells were isolated from 48 patients with severe sepsis. Total RNA was extracted from samples for day 1 of admission and again on day 7. FADD, caspase 1, 3, 8, and 9 mRNA was quantified with quantitative real-time polymerase chain reaction (qRT-PCR). Standard demographic and outcome data were recorded. Between-group comparisons were performed by Wilcoxon rank sum test. All values are stated as median and interquartile range.
Sixteen of the 48 patients died in the ICU. Caspase 9 mRNA copy numbers were significantly increased on day 7 in the survivor group (5.4 × 106; 7.4 × 106 to 8.9 × 106) compared with death in the ICU group (1.9 × 106; 3.0 × 106 to 1.2 × 106) P = 0.001. FADD, caspase 1, 3 and 8 mRNA copy numbers were not significantly different between patients who died and those discharged from the ICU on either day 1 or day 7 of admission.
Caspase 9 may be an important regulator of apoptotic mechanisms in humans with late sepsis. Pro-apoptotic mechanisms may have a role in the resolution of severe sepsis.
This study is funded by the Association of Anaesthetists of Great Britain and Ireland and the Intensive Care Society Ireland.