Basic nutritional investigation Glutamine attenuates endotoxin-induced lung metabolic dysfunction: potential role of enhanced heat shock protein 70 Kristen D. Singleton, B.S. a , Natalie Serkova, Ph.D. a , Anirban Banerjee, Ph.D. b , Xianzhong Meng, M.D., Ph.D. b , Fabia Gamboni-Robertson, Ph.D. b , Paul E. Wischmeyer, M.D. a, * a Department of Anesthesiology, University of Colorado Health Sciences Center, Denver, Colorado, USA b Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado, USA Manuscript received March 6, 2004; accepted May 12, 2004. Abstract Objective: Septic shock leads to derangement of cellular metabolism. Enhanced heat shock protein 70 (HSP-70) can preserve cellular metabolism after other forms of cellular stress. Glutamine (GLN) can enhance lung HSP-70 expression after lethal endotoxemia. However, it is unknown whether GLN can enhance HSP-70 expression and attenuate lung metabolic dysfunction after sublethal endotoxemia. Our aim was to determine whether GLN could upregulate HSP-70 and attenuate metabolic dysfunction in lung tissue after sublethal endotoxemia. Methods: Sprague-Dawley rats were assigned to one of five groups. The first two groups were treated with Escherichia coli lipopolysaccharide (LPS; 1 mg/kg intravenously). GLN (0.75 g/kg intravenously) or balanced salt solution as a control was administered 5 min after LPS administra- tion. The next two groups of rats were treated with quercetin (HSP-70 inhibitor; 400 mg/kg intraperitoneally) 6 h before LPS administration. The final group received no treatment. Lung tissue was harvested 24-h after LPS and analyzed with immunofluorescence and western blot for HSP-70. Tissue metabolites were quantified by 1 H and 31 P nuclear magnetic resonance spectroscopy. Results: GLN compared with balanced salt solution (BSS) administration in LPS-treated animals led to significant increases in lung HSP-70. Increased HSP-70 expression was observed in lung epithelial cells and macrophages. GLN significantly improved the ratio of adenosine triphosphate to adenosine diphosphate in the lung after LPS. Quercetin inhibited a GLN-mediated increase in lung HSP-70 and blocked a beneficial effect of GLN on the ratio of adenosine triphosphate to adenosine diphosphate after LPS. Conclusions: A single dose of GLN can enhance HSP-70 in pulmonary epithelial cells and macrophages after sublethal endotoxemia. Further, GLN can attenuate endotoxin-induced lung metabolic dysfunction. GLN’s beneficial effect on lung tissue after metabolic dysfunction caused by sublethal endotoxemia may be mediated in part by enhanced HSP-70. © 2005 Elsevier Inc. All rights reserved. Keywords: Amino acid; Animal model; Lipopolysaccharide; Septic shock; Adenosine triphosphate; Metabolism Introduction Sepsis, ischemia and reperfusion injury, and multiorgan dysfunction syndrome are responsible for significant rates of human morbidity and mortality despite the use of anti- biotics, vasoactive agents, and anticytokine therapies [1– 4]. One of the mechanisms by which these injuries may cause morbidity and mortality is by derangement of cellular and tissue metabolisms [5–10]. Specifically, experimental mod- els have shown that sepsis causes an intrinsic derangement in mitochondrial activity and depletion of adenosine triphosphate (ATP) concentrations in skeletal muscle [7]. ATP depletion and inhibition of mitochondrial function This study was supported by grant K23 RR018379-01 from the Na- tional Institutes of Health. * Corresponding author. Tel.: +1-303-372-6300; fax: +1-303-372- 6315. E-mail address: paul.wischmeyer@uchsc.edu (P.E. Wischmeyer). Nutrition 21 (2005) 214 –223 www.elsevier.com/locate/nut 0899-9007/05/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2004.05.023