| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114
During physiological stress, the lung increases production of the amino acid glutamine (Gln) using the enzyme Gln synthetase (GS) to maintain Gln homeostasis. Glucocorticoid hormones are considered the principal mediators of GS expression during stress. However, whereas animal studies have shown that glucocorticoids increase lung GS mRNA levels 500-700%, GS activity levels rise only 20-45%. This discrepancy suggests that a posttranscriptional control mechanism(s) ultimately determines GS expression. We hypothesized that the level of GS protein in the lung is governed by the intracellular Gln concentration through a mechanism of protein destabilization, a feedback regulatory mechanism that has been observed in vitro. To test this hypothesis, Sprague-Dawley rats were treated with a Gln-free diet and the GS inhibitor methionine sulfoximine (MSO) to deplete tissue Gln levels and prevent this feedback regulation. Exposure to Gln-free chow and MSO (100 mg/kg body wt) for 6 days decreased plasma Gln levels 50% (P < 0.01) and decreased lung tissue Gln levels by 70% (P < 0.01). Although lung GS mRNA levels were not influenced by Gln depletion, there was a sevenfold (P < 0.01) increase in GS protein. A parenteral Gln infusion (200 mM, 1.5 ml/h) for the last 2 days of MSO treatment replenished lung Gln levels to 65% of control level and blunted the increase in GS protein levels by 33% (P < 0.05) compared with rats receiving an isomolar glycine solution. The acute effects of glucocorticoid and MSO administration on lung GS expression were also measured. Whereas dexamethasone (0.5 mg/kg) and MSO injections individually augmented lung GS protein levels twofold and fourfold (P < 0.05), respectively, the combination of dexamethasone and MSO produced a synergistic, 12-fold induction (P < 0.01) in lung GS protein over 8 h. The data suggest that, whereas glucocorticoids are potent mediators of GS transcriptional activity, protein stability greatly influences the ultimate expression of GS in the lung.
methionine sulfoximine; glutamate ammonia ligase; parenteral infusion
This article has been cited by other articles:
|
|
 |
|
  S. A. McGrath-Morrow and J. Stahl Inhibition of Glutamine Synthetase in A549 Cells During Hyperoxia Am. J. Respir. Cell Mol. Biol., July 1, 2002; 27(1): 99 - 106. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. I. Labow, W. W. Souba, and S. F. Abcouwer Mechanisms Governing the Expression of the Enzymes of Glutamine Metabolism--Glutaminase and Glutamine Synthetase J. Nutr., September 1, 2001; 131(9): 2467S - 2474. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Factor, K. Ridge, J. Alverdy, and J. I. Sznajder Continuous enteral nutrition attenuates pulmonary edema in rats exposed to 100% oxygen J Appl Physiol, November 1, 2000; 89(5): 1759 - 1765. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. OKAMOTO, M. ABE, K. SHIBATA, N. SHIMIZU, N. SAKATA, T. KATSURAGI, and K. TANAKA Evaluating the Role of Inducible Nitric Oxide Synthase Using a Novel and Selective Inducible Nitric Oxide Synthase Inhibitor in Septic Lung Injury Produced by Cecal Ligation and Puncture Am. J. Respir. Crit. Care Med., August 1, 2000; 162(2): 716 - 722. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. I. Labow, W. W. Souba, and S. F. Abcouwer Glutamine synthetase expression in muscle is regulated by transcriptional and posttranscriptional mechanisms Am J Physiol Endocrinol Metab, June 1, 1999; 276(6): E1136 - E1145. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
