A neonatal mouse model of intestinal perforation: Investigating the harmful synergism between glucocorticoids and indomethacin

Phillip V. Gordon, Andrew C. Herman, Marek Marcinkiewicz, Benjamin M. Gaston, Victor E. Laubach, Judy L. Aschner

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

BACKGROUND: Early postnatal steroids and indomethacin in combination have been shown to increase the risk of spontaneous intestinal perforation (SIP) in infants with extremely low birth weight (ELBW), but the mechanism behind this synergistic effect is unknown. MATERIALS AND METHODS: Based on literature in a variety of models suggesting that glucocorticoids and nonsteroidal antiinflammatory agents diminish complementary isoforms of nitric oxide synthase (NOS), we hypothesized that perturbations in NO metabolism contribute to SIP. RESULTS: Our results using newborn wild-type (WT) and endothelial NOS-knockout (eNOS KO) mice treated with dexamethasone and/or indomethacin indicate that indomethacin treatment diminishes ileal eNOS abundance; dexamethasone treatment diminishes ileal inducible NOS and neuronal NOS (nNOS); 100% of dexamethasone-treated eNOS KO mice die after 3 days; eNOS KO mice treated for 2 days with dexamethasone develop acute pyloric stenosis in association with reduced expression of pyloric nNOS; and isolated ileum from eNOS KO mice treated for 2 days with dexamethasone exhibit a significant decrease in spontaneous peristalsis, decreased circumference, and decreased capacitance for forced volume before ileal perforation compared with ileum from untreated controls. CONCLUSIONS: Our findings suggest that eNOS and nNOS display functional overlap in the newborn mouse gastrointestinal tract and that simultaneous reduction in the activity of both NOS isoforms may be a risk factor for neonatal ileal perforation. If this holds true in human infants, then it provides a plausible etiologic explanation for the strong temporal association between SIP and the simultaneous treatment of ELBW infants with glucocorticoids and indomethacin.

Original languageEnglish (US)
Pages (from-to)509-519
Number of pages11
JournalJournal of Pediatric Gastroenterology and Nutrition
Volume45
Issue number5
DOIs
StatePublished - Nov 2007
Externally publishedYes

Fingerprint

Intestinal Perforation
indomethacin
synergism
dexamethasone
glucocorticoids
Indomethacin
Dexamethasone
Glucocorticoids
neonates
Knockout Mice
animal models
Extremely Low Birth Weight Infant
mice
low birth weight
nitric oxide synthase
Ileum
ileum
Nitric Oxide Synthase
Protein Isoforms
Pyloric Stenosis

Keywords

  • Dexamethasone
  • Indomethacin
  • Neonatology
  • Nitric oxide synthetase
  • Spontaneous intestinal perforation
  • Steroid

ASJC Scopus subject areas

  • Gastroenterology
  • Histology
  • Medicine (miscellaneous)
  • Food Science
  • Pediatrics, Perinatology, and Child Health

Cite this

A neonatal mouse model of intestinal perforation : Investigating the harmful synergism between glucocorticoids and indomethacin. / Gordon, Phillip V.; Herman, Andrew C.; Marcinkiewicz, Marek; Gaston, Benjamin M.; Laubach, Victor E.; Aschner, Judy L.

In: Journal of Pediatric Gastroenterology and Nutrition, Vol. 45, No. 5, 11.2007, p. 509-519.

Research output: Contribution to journalArticle

Gordon, Phillip V. ; Herman, Andrew C. ; Marcinkiewicz, Marek ; Gaston, Benjamin M. ; Laubach, Victor E. ; Aschner, Judy L. / A neonatal mouse model of intestinal perforation : Investigating the harmful synergism between glucocorticoids and indomethacin. In: Journal of Pediatric Gastroenterology and Nutrition. 2007 ; Vol. 45, No. 5. pp. 509-519.
@article{9c92d7d8602a4a71b59806228446c184,
title = "A neonatal mouse model of intestinal perforation: Investigating the harmful synergism between glucocorticoids and indomethacin",
abstract = "BACKGROUND: Early postnatal steroids and indomethacin in combination have been shown to increase the risk of spontaneous intestinal perforation (SIP) in infants with extremely low birth weight (ELBW), but the mechanism behind this synergistic effect is unknown. MATERIALS AND METHODS: Based on literature in a variety of models suggesting that glucocorticoids and nonsteroidal antiinflammatory agents diminish complementary isoforms of nitric oxide synthase (NOS), we hypothesized that perturbations in NO metabolism contribute to SIP. RESULTS: Our results using newborn wild-type (WT) and endothelial NOS-knockout (eNOS KO) mice treated with dexamethasone and/or indomethacin indicate that indomethacin treatment diminishes ileal eNOS abundance; dexamethasone treatment diminishes ileal inducible NOS and neuronal NOS (nNOS); 100{\%} of dexamethasone-treated eNOS KO mice die after 3 days; eNOS KO mice treated for 2 days with dexamethasone develop acute pyloric stenosis in association with reduced expression of pyloric nNOS; and isolated ileum from eNOS KO mice treated for 2 days with dexamethasone exhibit a significant decrease in spontaneous peristalsis, decreased circumference, and decreased capacitance for forced volume before ileal perforation compared with ileum from untreated controls. CONCLUSIONS: Our findings suggest that eNOS and nNOS display functional overlap in the newborn mouse gastrointestinal tract and that simultaneous reduction in the activity of both NOS isoforms may be a risk factor for neonatal ileal perforation. If this holds true in human infants, then it provides a plausible etiologic explanation for the strong temporal association between SIP and the simultaneous treatment of ELBW infants with glucocorticoids and indomethacin.",
keywords = "Dexamethasone, Indomethacin, Neonatology, Nitric oxide synthetase, Spontaneous intestinal perforation, Steroid",
author = "Gordon, {Phillip V.} and Herman, {Andrew C.} and Marek Marcinkiewicz and Gaston, {Benjamin M.} and Laubach, {Victor E.} and Aschner, {Judy L.}",
year = "2007",
month = "11",
doi = "10.1097/MPG.0b013e3181558591",
language = "English (US)",
volume = "45",
pages = "509--519",
journal = "Journal of Pediatric Gastroenterology and Nutrition",
issn = "0277-2116",
publisher = "Lippincott Williams and Wilkins",
number = "5",

}

TY - JOUR

T1 - A neonatal mouse model of intestinal perforation

T2 - Investigating the harmful synergism between glucocorticoids and indomethacin

AU - Gordon, Phillip V.

AU - Herman, Andrew C.

AU - Marcinkiewicz, Marek

AU - Gaston, Benjamin M.

AU - Laubach, Victor E.

AU - Aschner, Judy L.

PY - 2007/11

Y1 - 2007/11

N2 - BACKGROUND: Early postnatal steroids and indomethacin in combination have been shown to increase the risk of spontaneous intestinal perforation (SIP) in infants with extremely low birth weight (ELBW), but the mechanism behind this synergistic effect is unknown. MATERIALS AND METHODS: Based on literature in a variety of models suggesting that glucocorticoids and nonsteroidal antiinflammatory agents diminish complementary isoforms of nitric oxide synthase (NOS), we hypothesized that perturbations in NO metabolism contribute to SIP. RESULTS: Our results using newborn wild-type (WT) and endothelial NOS-knockout (eNOS KO) mice treated with dexamethasone and/or indomethacin indicate that indomethacin treatment diminishes ileal eNOS abundance; dexamethasone treatment diminishes ileal inducible NOS and neuronal NOS (nNOS); 100% of dexamethasone-treated eNOS KO mice die after 3 days; eNOS KO mice treated for 2 days with dexamethasone develop acute pyloric stenosis in association with reduced expression of pyloric nNOS; and isolated ileum from eNOS KO mice treated for 2 days with dexamethasone exhibit a significant decrease in spontaneous peristalsis, decreased circumference, and decreased capacitance for forced volume before ileal perforation compared with ileum from untreated controls. CONCLUSIONS: Our findings suggest that eNOS and nNOS display functional overlap in the newborn mouse gastrointestinal tract and that simultaneous reduction in the activity of both NOS isoforms may be a risk factor for neonatal ileal perforation. If this holds true in human infants, then it provides a plausible etiologic explanation for the strong temporal association between SIP and the simultaneous treatment of ELBW infants with glucocorticoids and indomethacin.

AB - BACKGROUND: Early postnatal steroids and indomethacin in combination have been shown to increase the risk of spontaneous intestinal perforation (SIP) in infants with extremely low birth weight (ELBW), but the mechanism behind this synergistic effect is unknown. MATERIALS AND METHODS: Based on literature in a variety of models suggesting that glucocorticoids and nonsteroidal antiinflammatory agents diminish complementary isoforms of nitric oxide synthase (NOS), we hypothesized that perturbations in NO metabolism contribute to SIP. RESULTS: Our results using newborn wild-type (WT) and endothelial NOS-knockout (eNOS KO) mice treated with dexamethasone and/or indomethacin indicate that indomethacin treatment diminishes ileal eNOS abundance; dexamethasone treatment diminishes ileal inducible NOS and neuronal NOS (nNOS); 100% of dexamethasone-treated eNOS KO mice die after 3 days; eNOS KO mice treated for 2 days with dexamethasone develop acute pyloric stenosis in association with reduced expression of pyloric nNOS; and isolated ileum from eNOS KO mice treated for 2 days with dexamethasone exhibit a significant decrease in spontaneous peristalsis, decreased circumference, and decreased capacitance for forced volume before ileal perforation compared with ileum from untreated controls. CONCLUSIONS: Our findings suggest that eNOS and nNOS display functional overlap in the newborn mouse gastrointestinal tract and that simultaneous reduction in the activity of both NOS isoforms may be a risk factor for neonatal ileal perforation. If this holds true in human infants, then it provides a plausible etiologic explanation for the strong temporal association between SIP and the simultaneous treatment of ELBW infants with glucocorticoids and indomethacin.

KW - Dexamethasone

KW - Indomethacin

KW - Neonatology

KW - Nitric oxide synthetase

KW - Spontaneous intestinal perforation

KW - Steroid

UR - http://www.scopus.com/inward/record.url?scp=37349104923&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=37349104923&partnerID=8YFLogxK

U2 - 10.1097/MPG.0b013e3181558591

DO - 10.1097/MPG.0b013e3181558591

M3 - Article

C2 - 18030227

AN - SCOPUS:37349104923

VL - 45

SP - 509

EP - 519

JO - Journal of Pediatric Gastroenterology and Nutrition

JF - Journal of Pediatric Gastroenterology and Nutrition

SN - 0277-2116

IS - 5

ER -