Influence of drotrecogin alpha (activated) infusion on the variation of Bax/Bcl-2 and Bax/Bcl-xl ratios in circulating mononuclear cells: A cohort study in septic shock patients

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Abstract

Objective:

Drotrecogin alpha (activated) (DAA), or recombinant human activated protein C, is a new treatment in sepsis-induced multiple organ failure, leading to significant reduction in the mortality rate, thanks to its anticoagulant properties. It has been suggested that DAA has anti-inflammatory and antiapoptotic effects in sepsis animal models. This study investigates the potential actions of DAA on circulating mononuclear cells apoptosis in human septic shock.

Design:

Prospective, cohort study.

Setting:

Two intensive care wards and two research laboratories in a university hospital.

Patients:

Twenty-two septic shock patients with DAA treatment (DAA+), 19 septic shock patients without DAA treatment (DAA−), and 14 healthy controls were successively enrolled, but only 20 DAA+ and 16 DAA− patients fulfilled criteria for statistical analysis.

Interventions:

Blood samples were collected at inclusion and 24 hrs later.

Measurements and Main Results:

Circulating mononuclear cell apoptosis levels were assessed by flow cytometry with annexin V, and variations of the apoptotic rheostats (Bax/Bcl-2 and Bax/Bcl-xl ratios) were analyzed by real-time reverse transcription-polymerase chain reaction. Apoptosis was significantly increased in septic shock patients (DAA+, 12 ± 6.4%; DAA−, 10.4 ± 5%) vs. healthy patients (3.4 ± 2.1%, p < .001). Twenty-four hours after DAA infusion, apoptosis was significantly lower in the DAA+ group compared with DAA− ones (respectively, 11.7 ± 5.3% and 16.2 ± 7.6%, p < .001). At inclusion, DAA+ and DAA− groups showed comparable Bax/Bcl-2 ratio (DAA+, 0.92 ± 0.9; DAA−, 1.32 ± 0.87) and Bax/Bcl-xl ratio (DAA+, 2 ± 1.04; DAA−, 1.31 ± 0.93). In contrast, 24 hrs later we observed a significant decrease in these ratios, indicating an antiapoptotic effect in the DAA+ group (Bax/Bcl-2, 0.39 ± 0.27; Bax/Bcl-xl, 0.68 ± 0.35) compared with the DAA− group (Bax/Bcl-2, 1.81 ± 1.1; Bax/Bcl-xl, 1.22 ± 0.92, p = .001 and p = .039, respectively).

Conclusions:

In vivo, in human septic shock, DAA has antiapoptotic effects on circulating mononuclear cells, assessed by a significant decrease of both the Bax/Bcl-2 and Bax/Bcl-xl ratios.

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