title: Glutamine attenuates lung injury and improves survival after sepsis: role of enhanced heat shock protein expression.
abstract: OBJECTIVE
  Heat shock protein (HSP) expression is vital to cellular and tissue protection after stress or injury. However, application of this powerful tool in human disease has been limited, as known enhancers of HSPs are toxic and not clinically relevant. Glutamine (GLN) can enhance HSP expression in non-clinically relevant animal injury models. The aim of this study was to assess the ability of GLN to enhance pulmonary HSP expression, attenuate lung injury, and improve survival after sepsis in the rat.
  
  
  METHODS
  Prospective, randomized, controlled animal trial.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  Male Sprague-Dawley rats.
  
  
  METHODS
  We utilized a rat model of cecal ligation and puncture to induce sepsis. GLN or saline was administered 1 hr after initiation of sepsis via single tail-vein injection. We analyzed heat shock factor-1 phosphorylation, HSP-70, and HSP-25 via Western blot. Tissue metabolism was assayed by magnetic resonance spectroscopy. Occurrence of lung injury was determined via histopathologic examination. An inhibitor of HSP expression, quercetin, was utilized to assess role of HSP expression in prevention of sepsis-related mortality.
  
  
  RESULTS
  GLN, given after initiation of sepsis, enhanced pulmonary heat shock factor-1 phosphorylation, HSP-70, HSP-25, and attenuated lung injury after sepsis. Further, GLN improved indices of lung tissue metabolic function (adenosine 5-triphosphate/adenosine 5-diphosphate ratio, nicotinamide adenine dinucleotide) after sepsis. No significant effect of GLN on lung tissue-reduced glutathione was observed. GLN treatment led to a significant decrease in mortality (33% [6 of 18] GLN-treated rats vs. 78% [14 of 17] saline-treated rats). Administration of the HSP inhibitor quercetin blocked GLN-mediated enhancement of HSP expression and abrogated GLN's survival benefit.
  
  
  CONCLUSIONS
  GLN has been safely administered to critically ill patients and shown to improve outcome without clear understanding of the protective mechanism. Our results indicate GLN may prevent the occurrence of lung injury, lung tissue metabolic dysfunction, and mortality after sepsis via enhancement of deficient lung heat shock factor-1 phosphorylation/activation and HSP expression.
authors.affiliation: Department of Anesthesiology, University of Colorado Health Sciences Center, Denver, CO, USA.
authors.forename: Kristen D
authors.initials: KD
authors.lastname: Singleton
authors.forename: Natalie
authors.initials: N
authors.lastname: Serkova
authors.forename: Virgina E
authors.initials: VE
authors.lastname: Beckey
authors.forename: Paul E
authors.initials: PE
authors.lastname: Wischmeyer
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D005973:Glutamine / Q000494:pharmacology / Q000627:therapeutic use*; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000819:agonists; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000819:agonists*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D009363:Neoplasm Proteins / Q000819:agonists; D010085:Oxidative Phosphorylation / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000188:drug therapy / Q000401:mortality / Q000517:prevention & control*; D018805:Sepsis / Q000188:drug therapy* / Q000401:mortality; D016019:Survival Analysis; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C486114:Hspb1 protein, rat; D009363:Neoplasm Proteins; D014157:Transcription Factors; D005973:Glutamine; D005978:Glutathione