PMID- 14764921
OWN - NLM
STAT- MEDLINE
DCOM- 20041116
LR  - 20220330
IS  - 0031-3998 (Print)
IS  - 0031-3998 (Linking)
VI  - 55
IP  - 4
DP  - 2004 Apr
TI  - Intestinal epithelial apoptosis initiates gross bowel necrosis in an experimental 
      rat model of neonatal necrotizing enterocolitis.
PG  - 622-9
AB  - The histopathology of necrotizing enterocolitis (NEC) is characterized by 
      destruction of the mucosal layer in initial stages and by transmural necrosis of 
      the intestinal wall in advanced stages of the disease. To test the hypothesis 
      that enhanced epithelial apoptosis is an initial event underlying the gross 
      histologic changes, we analyzed epithelial apoptosis and tissue morphology in an 
      animal model of NEC and evaluated the effect of caspase inhibition on the 
      incidence of experimental NEC in this model. Apoptosis was analyzed with terminal 
      deoxynucleotidyltransferase-mediated dUTP-FITC nick end labeling (TUNEL) staining 
      in intestinal sections and by measuring caspase 3 activity from intestinal 
      lysates of neonatal rats subjected to formula feeding and cold/asphyxia stress 
      (FFCAS) and from mother-fed (MF) controls. Morphologic evaluation was based on 
      hematoxylin and eosin staining of intestinal sections. FFCAS resulted in 
      histologic changes consistent with NEC, which were absent from MF animals. FFCAS 
      was also associated with a significantly increased rate of nuclear DNA 
      fragmentation in the small intestinal epithelium compared with MF. Elevated 
      tissue caspase 3 activity confirmed the presence of apoptosis in samples with 
      increased DNA fragmentation. Analysis of the coincidence of morphologic damage 
      and apoptosis in corresponding tissue sections indicated that apoptosis precedes 
      gross morphologic changes in this model. Furthermore, supplementation of formula 
      with 8 boc-aspartyl(OMe)-fluoromethylketone, a pan-caspase inhibitor, 
      significantly reduced the incidences of apoptosis and experimental NEC. These 
      findings indicate that in neonatal rats FFCAS induces epithelial apoptosis that 
      serves as an underlying cause for subsequent gross tissue necrosis.
FAU - Jilling, Tamas
AU  - Jilling T
AD  - Department of Pediatrics, Evanston Northwestern Healthcare Research Institute, 
      and Northwestern University, Feinberg School of Medicine, Evanston, IL 60201, 
      USA. tjilling@northwestern.edu
FAU - Lu, Jing
AU  - Lu J
FAU - Jackson, Michele
AU  - Jackson M
FAU - Caplan, Michael S
AU  - Caplan MS
LA  - eng
GR  - HD37581-01A1/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20040205
PL  - United States
TA  - Pediatr Res
JT  - Pediatric research
JID - 0100714
RN  - 0 (Caspase Inhibitors)
RN  - EC 3.4.22.- (CASP3 protein, human)
RN  - EC 3.4.22.- (Casp3 protein, rat)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - Animal Nutritional Physiological Phenomena
MH  - Animals
MH  - Animals, Newborn
MH  - Apoptosis/*physiology
MH  - Caspase 3
MH  - Caspase Inhibitors
MH  - Caspases/metabolism
MH  - Cold Temperature
MH  - DNA Fragmentation
MH  - *Disease Models, Animal
MH  - Enterocolitis, Necrotizing/*pathology
MH  - Female
MH  - Humans
MH  - In Situ Nick-End Labeling
MH  - Infant Formula/administration & dosage
MH  - Intestinal Mucosa/cytology/*pathology/physiology
MH  - *Necrosis
MH  - Pregnancy
MH  - Rats
EDAT- 2004/02/07 05:00
MHDA- 2004/11/17 09:00
CRDT- 2004/02/07 05:00
PHST- 2004/02/07 05:00 [pubmed]
PHST- 2004/11/17 09:00 [medline]
PHST- 2004/02/07 05:00 [entrez]
AID - 01.PDR.0000113463.70435.74 [pii]
AID - 10.1203/01.PDR.0000113463.70435.74 [doi]
PST - ppublish
SO  - Pediatr Res. 2004 Apr;55(4):622-9. doi: 10.1203/01.PDR.0000113463.70435.74. Epub 
      2004 Feb 5.