An early circulating factor in severe sepsis modulates apoptosis of monocytes and lymphocytes

Abstract

We hypothesized that a factor may circulate in serum early during sepsis, modulating apoptosis of monocytes and lymphocytes. Serum was collected from 20 healthy volunteers and from 48 patients with severe sepsis/shock within 12 h from signs of the first failing organ. PBMCs were isolated from 20 healthy volunteers and incubated with collected sera. Apoptosis and expression of CD95 were determined by flow cytometry; experiments were run in the presence of caspase-8 and caspase-9 inhibitors and of CaCl(2). Activity of caspase-3 was determined in cell lysates by a chromogenic kinetic assay. Incubation with serum of patients induced apoptosis of CD4 lymphocytes and inhibited apoptosis of CD14 monocytes. This was attenuated after diluting serum or mixing with healthy serum. Activity of caspase-3 was consistent with these findings. Induced apoptosis of CD4 lymphocytes was greater among nonsurvivors, and it was inhibited in the presence of caspase inhibitors. Inhibitors did not modify the effect of patients' serum on apoptosis of CD14 monocytes. CaCl(2) reversed the inhibitory effect on apoptosis of CD14 moncytes. The above findings support the hypothesis for the existence of an early circulating factor in severe sepsis/shock, modulating apoptosis of CD4 lymphocytes and of CD14 monocytes by interaction with the two apoptotic pathways.

High Mortality Associated with Hyperglycemia, Neutrophilia, and Lymphopenia in Critically Ill Patients

“…These results are consistent with previous reports showing high glucose levels as a negative prognostic factor in patients of the ICU (Van den Berghe et al 2001Berghe et al , 2006. Some authors mention that high blood glucose levels at admission are predictors of poor outcomes in ICU patients (Brunkhorst et al 2008;Kreutziger et al 2009).…”

“…Our results show that patients with CAP and hyperglycemia worsened their prognosis. However, some authors have mentioned the presence of a blood soluble factor, which is released at an early stage and which may modulate apoptosis of CD4 lymphocytes and CD14 monocytes (Vaki et al 2011).…”

“…The factors that may raise blood glucose include proinflammatory mediators such as interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and several interleukins (Inzucchi 2006;Hirasawa et al 2009). Besides, hyperglycemia is considered a negative prognostic factor for the evolution of patients who are admitted to the ICU (Van den Berghe et al 2001;Inzucchi 2006;Gale et al 2007;Falciglia et al 2009;Hirasawa et al 2009) because of its effects on mortality, morbidity, and also by prolonging hospital stay (Van den Berghe et al 2001Berghe et al , 2006. Current studies have tried to explain the negative effects of elevated blood glucose levels in critically ill patients (Brownle 2001).…”

Severe Lymphopenia Is Associated with Elevated Plasma Interleukin-15 Levels and Increased Mortality During Severe Sepsis

“…Nevertheless, a previous study showed the association between lymphopenia and lymphocyte apoptosis during severe sepsis (8). A study has shown that the mediators in the septic plasma could directly induce lymphocyte apoptosis (28). The results might explain the increased circulating levels of several cytokines in patients with severe lymphopenia, and suggest that increased lymphocyte apoptosis is an important cause of severe lymphopenia.…”

Molecular Mechanisms Underlying Delayed Apoptosis in Neutrophils from Multiple Trauma Patients with and without Sepsis

“…Clinical and experimental observations have suggested that apoptosis may play a role in the pathogenesis of sepsis-associated multiple organ dysfunction syndrome (MODS) (2)(3)(4)(5), but the mechanism by which MODS develops remains unclear. Neutrophils are terminally differentiated cells of the innate immune system playing an important role as a first line of defense against bacterial infections as well as in the modulation of the inflammatory response (6).…”