Alterations of caspase 9 mRNA gene expression in survivors and nonsurvivors of severe sepsis

Introduction

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 [1]. Specifically apoptosis markers such as caspases 1, 3, 8, 9 and FADD have been shown to be significant in animal models of infection [2]. 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.

Methods

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.

Results

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.

Conclusions

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.