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DOI: 10.1177/0148607106030005400
Glutamine Attenuation of Cell Death and Inducible Nitric Oxide Synthase Expression Following Inflammatory Cytokine-Induced Injury Is Dependent on Heat Shock Factor-1 Expression
From the * Department of Anesthesiology,
University of Colorado Health Science Center, Denver, Colorado; and the Correspondence: Paul Wischmeyer, MD, Director of Nutrition Support Service, Associate Professor of Anesthesiology, University of Colorado Health Sciences Center, Department of Anesthesiology, 4200 E. Ninth Avenue, Campus Box B113, Denver, CO 80262. Electronic mail may be sent to Paul.Wischmeyer{at}UCHSC.edu.
Background: Glutamine (GLN) has been shown to improve outcome
after experimental and clinical models of critical illness. Enhanced
expression of heat shock protein (HSP) has been hypothesized to be responsible
for this protection. The heat shock response has been shown to inhibit
inducible nitric oxide synthase (iNOS) gene expression and nitric oxide (NO)
production. This study tested the hypothesis that GLN-mediated activation of
the HSP pathway is responsible for improved survival and attenuation of iNOS
expression after an inflammatory cytokine–induced injury.
Methods: Heat shock factor-1 (HSF-1) wild-type and knockout mouse
embryonic fibroblasts (HSF-1+/+ and HSF-1–/–) were used in all
experiments. Cells were treated with 0 mmol/L or 8 mmol/L GLN and cytomix
(tumor necrosis factor-
DiscussantUniversity of Texas Southwestern Medical Center
Author's ResponseUniversity of Colorado Health Sciences Center
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, lipopolysaccharide, and interferon-
) in
a concurrent treatment model once they had reached confluence. Cell viability
was assayed with MTS/PMS mixture. Apoptosis and necrosis were assayed
via immunohistochemistry. iNOS and HSP-70 expression were detected
via Western blotting. NO production was measured using the Griess
reagent. Results: GLN treatment significantly attenuated inflammatory
cytokine–induced cell death and apoptosis in HSF-1+/+ cells vs
0 mmol/L GLN treatment; however, GLN's cellular protection was lost in
HSF-1–/– cells. GLN supplementation attenuated cytomix-induced
iNOS expression and NO production only in HSF-1+/+ cells. Further, GLN induced
HSP-70 expression only in HSF-1+/+ cells. Conclusions: This is the
first demonstration that GLN-mediated cellular protection after inflammatory
cytokine injury is due to HSF-1 expression and cellular capacity to activate
an HSP response. 
