HEAT SHOCK PROTEINS AND GLUTAMINE ALTERATIONS RELATED TO HORMONAL, IMMUNOLOGICAL, INFLAMMATORY AND MOLECULAR RESPONSE TO SEPSIS: A COMBINED CLINICAL AND EXPERIMENTAL STUDY

Abstract: 

Background: It is not known whether alterations in heat shock proteins (hsp) expression in severe sepsis are associated with glutamine or antioxidant depletion and with hypothalamic-pituitary-adrenal axis (HPAA) dysfunction, organ failure and outcome. No previous studies have evaluated the impact of high dose IV glutamine at improving HPAA hsp70/90 immunological function in experimental sepsis.

Aim: First to test the hypothesis that in septic patients a significant glutamine, arginine, and glutathione depletion is accompanied by de-regulation of the HPAA response and decreased hsp70 (with or without increased hsp90) expression. Second, to test the hypothesis that in LPS-induced murine sepsis a glutamine-mediated activation of the hsp70 and suppression of the hsp90 pathways is responsible for HPAA axis optimization, balanced pro- and anti-inflammatory cytokine expression, and improvement of apoptosis and outcome.

Workpackages:

  1. Clinical animal model: glutamine, HPAA, heat shock proteins in sepsis;
  2. Clinical cell model: dose-response beneficial glutamine effect on hsp70 expression in human peripheral blood polymorphonuclear cells (PBMC);
  3. Clinical animal model: glutamine inflammatory pathways, apoptosis, and hsp70 polymorphisms.

Expected results: Glutamine alters the HPAA in severe sepsis through an hsp machinery up-regulation and antioxidant anti-inflammatory effect. Hsp polymorphisms may modulate its beneficial effect. In experimental sepsis high dose glutamine improves the HPAA immune response - outcome through hsp70 enhancement - hsp90 depression. There is a dose-response beneficial glutamine effect on hsp70 expression in human PBMC on specific inflammatory markers (IL 17, 18, MIF) and a reduced stimulatory E. coli and S. pneumonia effect on PBMC of septic critically ill patients stratified according to hsp polymorphisms, reduced hsp70/90 expression, glutamine, arginine and glutathione levels, and HPAA level of function.

Project info

Acronym:
Sepsis Immunological Biochemical Hormonal ICU Genetic Animal Model (SIBHIGAM)
Coordinating Institution:
University of Crete
Scientific Coordinator:
Briassoulis George
Research Team 2 Leader:
Nanas Serafim
Research Team 3 Leader:
Petrikkos George

Stats

I.D.:
796
Mis:
377287
Duration (months):
45
Budget:
526.98
Diavgeia:
ΑΔΑ: Β4ΛΔ9-6ΜΑ

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