Vars Award Recipient Glutamine-Mediated Attenuation of Cellular Metabolic Dysfunction and Cell Death After Injury Is Dependent on Heat Shock Factor-1 Expression

ABSTRACT. Background: Cellular metabolic dysfunction is associated with occurrence of multiple-organ failure after critical illness. Glutamine (GLN) attenuates cellular meta-bolic dysfunction in critical illness models. The mechanism of this protection is unclear. We previously demonstrated that GLNs benefit in critical illness might be due to enhanced heat shock protein (HSP) expression. We hypothesize that GLNs attenuation of cellular metabolic dysfunction is dependent on presence of heat shock factor-1 (HSF-1). Meth-ods: HSF-1 wild-type and knockout mouse embryonic fibro-blasts (HSF-1/ and HSF-1/) were used in all experi-ments. Cells were not treated, or were treated with 8 mmol/L GLN and immediately exposed to heat stress injury (45°C for 45 minutes). Cells were harvested for metabolic analysis by nuclear magnetic resonance (NMR) at 24 hours postinjury. Cell survival was assessed using the MTS assay. Results:GLN treatment in HSF-1/ cells led to significant attenuation of decreases in adenosine triphosphate (ATP)/adenosine diphosphate (ADP) ratio, phosphomonoester/phosphodiester (PME/PDE) ratio, and cell survival observed in non-GLN-treated HSF-1/ cells. In HSF-1/ cells, the beneficial effect of GLN on preservation of ATP/ADP ratio, PME/PDE proliferation, and cell survival was lost. GLN-treated HSF-1/ cells had a significant increase in extracellular lactate concentrations vs GLN-treated HSF/ cells. Conclusions: GLN treatment attenuated cellular metabolic dysfunction and improved cell membrane recovery only in HSF-1/ cells. Cellular injury, as measured by lactate release and cell survival assay, was improved by GLN treatment in HSF-1/ cells alone. Thus, GLNs beneficial effect on cellular metabolic dysfunction and cell survival appears to be depen-dent on HSF-1 expression. ( Journal of Parenteral and Entera