Glutamine reduces cytokine release, organ damage, and mortality in a rat model of endotoxemia.

Clinical trials have demonstrated that glutamine (GLN) supplementation can decrease infectious morbidity and improve survival in a number of settings of critical illness. The mechanism of this protection remains unclear. The objective of this study was to evaluate the effect of GLN on cytokine release, organ injury, and survival from endotoxin-induced septic shock. Endotoxemia was induced in Male Sprague-Dawley rats by intravenous administration of 5 mg/kg Escherichia coli lipopolysaccharide (LPS). Concomitantly, animals were fluid resuscitated with a lactated ringers (LR) solution and given GLN (0.75 g/kg i.v.) or LR alone. Blood samples were obtained at multiple time points post-LPS injury for cytokine analysis. Survival rates were monitored for 72 h. Organ injury was evaluated in a separate set of animals via pathologic exam of tissues harvested 6 h post-LPS injury. A single dose of GLN significantly attenuated the release of TNF-alpha at 2 h (P < 0.005) and IL-1 beta at 4 h (P < 0.0001). This attenuation of cytokine release was associated with a significant decrease in mortality (P < 0.003). Pathologic exam demonstrated significant protection of both lung and small bowel tissue by GLN. Blood gas values 6-h post-LPS injury showed increased PaO2 and bicarbonate concentration in GLN treated animals. These data indicate that GLN can significantly attenuate pro-inflammatory cytokine release, protect against end-organ damage, and decrease mortality from endotoxemia. GLN confers protection even when administered at the onset of endotoxemia, rather then as pre-treatment. Thus, one explanation for the clinical benefits observed from GLN-supplementation may be related to the attenuation of pro-inflammatory cytokines.

Glutamine induces heat shock protein and protects against endotoxin shock in the rat.

Enhanced expression of heat shock protein (HSP) has been shown to be protective against laboratory models of septic shock. Induction of HSPs to improve outcome in human disease has not been exploited because laboratory induction agents are themselves toxic and not clinically relevant. In this study, we demonstrate that a single dose of intravenous glutamine causes a rapid and significant increase in HSP25 and HSP72 expression in multiple organs of the unstressed Sprague-Dawley rat. With the utilization of a fluid-resuscitated rat model of endotoxemia, mortality was dramatically reduced by glutamine administration concomitant with the endotoxin injury. Endotoxin-treated animals given glutamine exhibited dramatic increases in tissue HSP expression and marked reduction of end-organ damage. These data suggest glutamine may protect against mortality and attenuate end-organ injury in endotoxemic shock via enhanced HSP expression. Furthermore, glutamine confers protection when administered at the initiation of sepsis, rather than as pretreatment. Thus glutamine appears to be a clinically viable enhancer of HSP expression and may prove beneficial in the therapy of sepsis and sepsis-induced organ injury.