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


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.
Gordon
Phillip V
PV
Division of Neonatology, Department of Pediatrics, University of Virginia Children's Hospital, Charlottesville, VA 22908-0386, USA. pvg4n@virginia.edu
Herman
Andrew C
AC
Marcinkiewicz
Marek
M
Gaston
Benjamin M
BM
Laubach
Victor E
VE
Aschner
Judy L
JL
D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects*; D015153:Blotting, Western; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D020022:Genetic Predisposition to Disease; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects*; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D007213:Indomethacin / Q000008:administration & dosage / Q000009:adverse effects*; D007416:Intestinal Perforation / Q000139:chemically induced* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism; D010528:Peristalsis / Q000187:drug effects; D011707:Pyloric Stenosis / Q000209:etiology; D012307:Risk Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005938:Glucocorticoids; D003907:Dexamethasone; D019001:Nitric Oxide Synthase; D007213:Indomethacin