Document Detail

Hepatic growth hormone resistance during sepsis is associated with increased suppressors of cytokine signaling expression and impaired growth hormone signaling.
MedLine Citation:
PMID:  16540952     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: During sepsis, a two- to four-fold increase in circulating growth hormone (GH) is seen with 40-50% reductions in plasma insulin-like growth factor (IGF)-I. The suppressors of cytokine signaling (SOCS), inhibitors of cytokine, and growth factor signaling via the janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway have been implicated in the development of hepatic GH resistance. In this study we examine the effects of sepsis on GH-induced IGF-I expression and potential mechanisms for GH resistance.
DESIGN: Prospective experimental study.
SETTING: University research laboratory.
SUBJECTS: Male Sprague-Dawley rats.
INTERVENTIONS: Rats were randomized to laparotomy alone (control) or implantation of fecal agar pellets inoculated with Escherichia coli and Bacteroides fragilis (sepsis). GH was injected intravenously to assess hepatic IGF-I synthesis and GH signaling.
MEASUREMENTS AND MAIN RESULTS: Plasma IGF-I was measured in both groups at baseline (4 hrs postoperatively) and then again at 12 hrs and 24 hrs after GH administration. Basal IGF-I levels were similar in both groups, but controls had a 35% increase in IGF-I at 12 hrs, whereas septic rats demonstrated reductions in circulating IGF-I at 12 and 24 hrs after GH. Hepatic expression of SOCS-1, -2, -3, and cytokine-inducible SH2-containing protein (CIS) were determined at 1, 4, 8, and 24 hrs in septic and control rats by Northern blot. SOCS-1, SOCS-3, and CIS messenger RNA in liver were increased from 4 to 8 hrs after the induction of sepsis (p < .05 for SOCS-1 and -3). Total GH receptor (GHR), JAK2, and STAT5 signaling proteins and the time course of STAT5 activation were also measured in liver after recombinant human GH administration by immunoblot and electrophoretic mobility shift analysis. Levels of total GHR, JAK2, and STAT5 were unaltered in liver from septic rats. However, phosphorylated STAT5 and STAT5 DNA binding were significantly reduced 30 mins after GH administration in liver from septic rats.
CONCLUSIONS: Sepsis diminished STAT5 phosphorylation and activity in liver as well as plasma IGF-I following GH administration. Hepatic messenger RNA expression of SOCS-1, SOCS-3, and CIS was transiently increased during abdominal sepsis and temporally associated with the development of hepatic GH resistance.
Gladys Yumet; Margaret L Shumate; D Patrick Bryant; Charles H Lang; Robert N Cooney
Publication Detail:
Type:  Evaluation Studies; Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Critical care medicine     Volume:  34     ISSN:  0090-3493     ISO Abbreviation:  Crit. Care Med.     Publication Date:  2006 May 
Date Detail:
Created Date:  2006-04-24     Completed Date:  2006-05-17     Revised Date:  2012-06-05    
Medline Journal Info:
Nlm Unique ID:  0355501     Medline TA:  Crit Care Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1420-7     Citation Subset:  AIM; IM    
Departments of Surgery, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA.
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MeSH Terms
Analysis of Variance
Growth Hormone / blood*
Insulin-Like Growth Factor I / metabolism*
Janus Kinase 2
Liver / metabolism*
Protein-Tyrosine Kinases / blood
Proto-Oncogene Proteins / blood
Random Allocation
Rats, Sprague-Dawley
STAT5 Transcription Factor / blood
Sepsis / physiopathology*
Signal Transduction / physiology*
Suppressor of Cytokine Signaling Proteins / metabolism*
Grant Support
Reg. No./Substance:
0/Proto-Oncogene Proteins; 0/STAT5 Transcription Factor; 0/Suppressor of Cytokine Signaling Proteins; 67763-96-6/Insulin-Like Growth Factor I; 9002-72-6/Growth Hormone; EC Kinase 2; EC Kinases; EC protein, human; EC protein, rat

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