Intestinal alkaline phosphatase administration in newborns is protective of gut barrier function in a neonatal necrotizing enterocolitis rat model.
BACKGROUND
Previously, we have shown that supplementation of intestinal alkaline phosphatase (IAP) decreased severity of necrotizing enterocolitis (NEC)-associated intestinal injury. We hypothesized that IAP administration is protective of intestinal epithelial barrier function in a dose-dependent manner.


METHODS
Control rat pups were vaginally delivered and breast-fed. Premature rats were divided into 4 groups: formula fed with lipopolysaccharide and hypoxia (NEC) or additional daily bovine IAP 40, 4, or 0.4 U/kg (NEC + IAP 40 U, IAP 4 U, or IAP 0.4 U).


RESULTS
Necrotizing enterocolitis is associated with decreased IAP protein expression and activity. Supplemental IAP increases IAP activity in intestinal homogenates and decreased NEC injury score in a dose-dependent manner. Intestinal injury as measured by fluorescein isothiocyanate-dextran flux from ileal loops showed increased permeability vs control, but supplemental IAP reversed this. Tight junction proteins claudin-1, claudin-3, occludin, and zonula occludin 1 were elevated in the NEC and IAP-treated groups with differences in expression patterns. No differences in messenger RNA levels were observed on postinjury day 3. Intestinal alkaline phosphatase administration decreases intestinal NEC injury in a dose-dependent manner.


CONCLUSIONS
Early enteral supplemental IAP may reduce NEC-related injury and may be useful for preserving the intestinal epithelial barrier function.
Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Rebecca M
RM
Rentea
Jennifer L
JL
Liedel
Scott R
SR
Welak
Laura D
LD
Cassidy
Alan N
AN
Mayer
Kirkwood A
KA
Pritchard
Keith T
KT
Oldham
David M
DM
Gourlay
D000284:Administration, Oral; D000469:Alkaline Phosphatase / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn; D062445:Claudin-1; D062465:Claudin-3; D057167:Claudins / Q000096:biosynthesis / Q000235:genetics; D003911:Dextrans / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D020345:Enterocolitis, Necrotizing / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005786:Gene Expression Regulation / Q000187:drug effects; D007082:Ileum / Q000187:drug effects* / Q000473:pathology; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D023421:Models, Animal; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D019108:Tight Junctions / Q000187:drug effects
D062445:Claudin-1; D062465:Claudin-3; D057167:Claudins; C568114:Cldn1 protein, rat; C568124:Cldn3 protein, rat; D003911:Dextrans; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C015219:fluorescein isothiocyanate dextran; D000469:Alkaline Phosphatase; D016650:Fluorescein-5-isothiocyanate