Document Detail

Glucocorticoid responsiveness in developing human intestine: possible role in prevention of necrotizing enterocolitis.
MedLine Citation:
PMID:  15591589     Owner:  NLM     Status:  MEDLINE    
Necrotizing enterocolitis (NEC) is a major inflammatory disease of the premature human intestine that can be prevented by glucocorticoids if given prenatally before the 34th wk of gestation. This observation suggests that a finite period of steroid responsiveness exists as has been demonstrated in animal models. Human intestinal xenografts were used to determine whether a glucocorticoid responsive period exists in the developing human intestine. Developmental responsiveness was measured by lactase activity and inflammatory responsiveness by IL-8, IL-6, and monocyte chemotactic protein-1 (MCP-1) induction after an endogenous (IL-1 beta) or exogenous (LPS) proinflammatory stimulus, respectively. Functional development of ileal xenografts were monitored for 30 wk posttransplantation, and the lactase activity recapitulated that predicted by in utero development. Cortisone acetate accelerated the ontogeny of lactase at 20 wk (immature) but the effect was lost by 30 wk (mature) posttransplant. Concomitant with accelerated maturation, the IL-8 response to both IL-1 beta and LPS was significantly dampened (from 6- to 3-fold) by glucocorticoid pretreatment in the immature but not mature xenografts. The induction of IL-8 was reflected at the level of IL-8 mRNA, suggesting transcriptional regulation. The excessive activation of IL-8 in the immature gut was mediated by a prolonged activation of ERK and p38 kinases and nuclear translocation of NF-kappa B due to low levels of I kappa B. Steroid pretreatment in immature intestine dampens activation of all three signaling pathways in response to proinflammatory stimuli. Therefore, accelerating intestinal maturation by glucocorticoids within the responsive period by accelerating functional and inflammatory maturation may provide an effective preventive therapy for NEC.
N Nanda Nanthakumar; Cheryl Young; Jae Sung Ko; Di Meng; Ji Chen; Timothy Buie; W Allan Walker
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  American journal of physiology. Gastrointestinal and liver physiology     Volume:  288     ISSN:  0193-1857     ISO Abbreviation:  Am. J. Physiol. Gastrointest. Liver Physiol.     Publication Date:  2005 Jan 
Date Detail:
Created Date:  2004-12-13     Completed Date:  2005-03-08     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  100901227     Medline TA:  Am J Physiol Gastrointest Liver Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  G85-92     Citation Subset:  IM    
Developmental Gastroenterology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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MeSH Terms
Child, Preschool
Cortisone / analogs & derivatives*,  pharmacology
Enterocolitis, Necrotizing / physiopathology*,  prevention & control*
Glucocorticoids / pharmacology*
Ileum / embryology*,  growth & development*,  pathology
Infant, Newborn
Interleukin-8 / biosynthesis,  pharmacology
Mice, SCID
Signal Transduction
Transcription, Genetic
Transplantation, Heterologous
Grant Support
Reg. No./Substance:
0/Glucocorticoids; 0/Interleukin-8; 50-04-4/cortisone acetate; 53-06-5/Cortisone

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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