Intestinal alkaline phosphatase administration in newborns decreases systemic inflammatory cytokine expression in a neonatal necrotizing enterocolitis rat model.
BACKGROUND
Supplementation of intestinal alkaline phosphatase (IAP), an endogenous protein expressed in the intestines, decreases the severity of necrotizing enterocolitis (NEC)-associated intestinal injury and permeability. We hypothesized that IAP administration is protective in a dose-dependent manner of the inflammatory response in a neonatal rat model.


METHODS
Pre- and full-term newborn Sprague-Dawley rat pups were sacrificed on day of life 3. Control pups were vaginally delivered and dam fed. Preterm pups were delivered via cesarean section and exposed to intermittent hypoxia and formula feeds containing lipopolysaccharide (NEC) with and without IAP. Three different standardized doses were administered to a group of pups treated with 40, 4, and 0.4U/kg of bovine IAP (NEC+IAP40, IAP4, or IAP0.4U). Reverse transcription-real-time polymerase chain reaction (RT-PCR) for inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF)-α on liver and lung tissues and serum cytokine analysis for interleukin (IL)-1β, IL-6, IL-10, and TNF-α were performed. Data were analyzed by Kruskal-Wallis and Mann-Whitney tests, expressed as mean±standard error of the mean and P≤0.05 considered significant.


RESULTS
Levels of cytokines IL-1β, IL-6, and TNF-α increased significantly in NEC versus control, returning to control levels with increasing doses of supplemental enteral IAP. Hepatic and pulmonary TNF-α and iNOS messenger ribonucleic acid expressions increased in NEC, and the remaining elevated despite IAP supplementation.


CONCLUSIONS
Proinflammatory cytokine expression is increased systemically with intestinal NEC injury. Administration of IAP significantly reduces systemic proinflammatory cytokine expression in a dose-dependent manner. Early supplemental enteral IAP may reduce NEC-related injury and be useful for reducing effects caused by a proinflammatory cascade.
Department of Surgery Medical College of Wisconsin, Milwaukee, Wisconsin, USA. rrentea@mcw.edu
Rebecca M
RM
Rentea
Jennifer L
JL
Liedel
Katherine
K
Fredrich
Scott R
SR
Welak
Kirkwood A
KA
Pritchard
Keith T
KT
Oldham
Pippa M
PM
Simpson
David M
DM
Gourlay
D000469:Alkaline Phosphatase / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn; D016207:Cytokines / Q000097:blood*; D004353:Drug Evaluation, Preclinical; D020345:Enterocolitis, Necrotizing / Q000097:blood / Q000150:complications / Q000517:prevention & control*; D005260:Female; D006505:Hepatitis / Q000209:etiology / Q000517:prevention & control; D011014:Pneumonia / Q000209:etiology / Q000517:prevention & control; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D016207:Cytokines; D000469:Alkaline Phosphatase