Matt Harmon

Chapter four 87 antagonizing CIRBP mitigates inflammation and improves survival in a mouse model of sepsis. 25 HSPH1 and HSPA6, members of the HSP70 complex, were downregulated in hypothermic septic patients. HSP70 expression is temperature dependent and important for sustaining immune function during sepsis as well as cell protection. 27 Among other things it can upregulate the expression of proinflammatory and pyrogenic cytokines, such as tumor necrosis factor alpha and interleukin-1 beta. 28 HSP70 deficiency can aggravate peritonitis in mice. 29 In the matched analysis, three canonical pathways associated with amino acid and polyamine degradation were significantly upregulated in hypothermic septic patients compared to febrile septic patients. First, the tryptophan degradation X pathway was upregulated. Tryptophan is an essential amino acid and degradation occurs along two different pathways. 30 Metabolites of one, the kynurenine pathway, mainly regulate anti-inflammatory effects of the immune response. 31 Tryptophan degradation to kynurenine is dependent on indoleamine- 2,3-dioxygenase (IDO) enzyme activity. 30 In sepsis, increased degradation from tryptophan to kynurenine is associated with decreased lymphocyte counts. 32 In vitro and in vivo evidence shows that tryptophan metabolites are fatal for T-cell survival. 33 Hypothetically this could provide an explanation the association of prolonged lymphopenia and the occurrence of hypothermia in sepsis in the first 24 hours of ICU admission. 10 Tryptophan is also degraded to serotonin. Interestingly, serotonin deficient mice are extremely susceptible to temperature variations and show a profound hypothermic response when placed in a cold environment. 34 Serotonin also induces permeability of endothelial cells in sepsis. 35 Depending on the mechanisms involved in serotonin and sepsis, future studies could evaluate the effect of interventions on the tryptophan-serotonin axis, such as the use of serotonin receptor antagonists, which has improved survival in experimental settings, but has not been evaluated in humans. 36 Secondly, the putrescine degradation III pathway was upregulated. Putrescine is a polyamine found in almost all living organisms. In humans it has shown the potential to modulate the innate immune response. 37 In a retrospective study in patients with community acquired pneumonia, putrescine levels were associated with disease severity and mortality. 38 In addition, putrescine is essential to the survival of important pathogens such as Streptococcus pneumoniae 39,40 and Escherischia coli . 41 Phenylalanine degradation IV pathway was the third pathway which was significantly upregulated; phenylalanine is a precursor to L-dopa and catecholamines. Increased serum levels of phenylalanine have been shown to be increased in patients after trauma, burns and sepsis 42,43 and predict mortality in patients with a severe infection 44 . Increased serum levels of phenylalanine are related to insufficient tissue perfusion and impaired cellular energy production.