title: Intestinal alkaline phosphatase to treat necrotizing enterocolitis.
abstract: BACKGROUND
  Intestinal alkaline phosphatase (IAP) activity is decreased in necrotizing enterocolitis (NEC), and IAP supplementation prevents NEC development. It is not known if IAP given after NEC onset can reverse the course of the disease. We hypothesized that enteral IAP given after NEC induction would not reverse intestinal injury.
  
  
  METHODS
  NEC was induced in Sprague-Dawley pups by delivery preterm followed by formula feedings with lipopolysaccharide (LPS) and hypoxia exposure and continued up to 4 d. IAP was added to feeds on day 2 until being sacrificed on day 4. NEC severity was scored based on hematoxylin and eosin-stained terminal ileum sections, and AP activity was measured using a colorimetric assay. IAP and interleukin-6 expression were measured using real time polymerase chain reaction.
  
  
  RESULTS
  NEC pups' alkaline phosphatase (AP) activity was decreased to 0.18 U/mg compared with controls of 0.57 U/mg (P < 0.01). Discontinuation of LPS and hypoxia after 2 d increased AP activity to 0.36 U/mg (P < 0.01). IAP supplementation in matched groups did not impact total AP activity or expression. Discontinuing LPS and hypoxia after NEC onset improved intestinal injury scores to 1.14 compared with continued stressors, score 2.25 (P < 0.01). IAP supplementation decreased interleukin-6 expression two-fold (P < 0.05), though did not reverse NEC intestinal damage (P = 0.5).
  
  
  CONCLUSIONS
  This is the first work to demonstrate that removing the source of NEC improves intestinal damage and increases AP activity. When used as a rescue treatment, IAP decreased intestinal inflammation though did not impact injury making it likely that IAP is best used preventatively to those neonates at risk.
authors.affiliation: Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Ben E
authors.initials: BE
authors.lastname: Biesterveld
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, Children's Hospital of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Koehler
authors.affiliation: Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Heinzerling
authors.affiliation: Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Rentea
authors.affiliation: Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Katherine
authors.initials: K
authors.lastname: Fredrich
authors.affiliation: Division of Neonatology, Department of Pediatrics, Children's Hospital of Wisconsin, Milwaukee, Wisconsin; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Welak
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, Children's Hospital of Wisconsin, Milwaukee, Wisconsin; Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin. Electronic address: dgourlay@chw.org.
authors.forename: David M
authors.initials: DM
authors.lastname: Gourlay
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn; D004353:Drug Evaluation, Preclinical; D020345:Enterocolitis, Necrotizing / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D015850:Interleukin-6 / Q000378:metabolism; D007422:Intestines / Q000201:enzymology* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D017207:Rats, Sprague-Dawley
chemical_list: D015850:Interleukin-6; D000469:Alkaline Phosphatase
keywords: Intestinal alkaline phosphatase; Necrotizing enterocolitis
references.citation: Eur J Pediatr Surg. 2013 Feb;23(1):39-47
references.pmid: 23165517
references.citation: J Immunol. 2007 Oct 1;179(7):4808-20
references.pmid: 17878380
references.citation: J Surg Res. 2012 Oct;177(2):228-34
references.pmid: 22687880
references.citation: J Pediatr Surg. 2014 Feb;49(2):273-6
references.pmid: 24528965
references.citation: J Perinatol. 2003 Jun;23(4):278-85
references.pmid: 12774133
references.citation: Dig Dis Sci. 2011 Apr;56(4):1020-7
references.pmid: 20844955
references.citation: Cell Host Microbe. 2007 Dec 13;2(6):371-82
references.pmid: 18078689
references.citation: J Surg Res. 2013 Mar;180(1):21-6
references.pmid: 23158403
references.citation: Am J Physiol Gastrointest Liver Physiol. 2013 Mar 15;304(6):G597-604
references.pmid: 23306083
references.citation: Semin Fetal Neonatal Med. 2011 Jun;16(3):145-50
references.pmid: 21514258
references.citation: Pediatrics. 2012 Feb;129(2):e298-304
references.pmid: 22271701
references.citation: Pharmacol Res. 2012 Aug;66(2):144-53
references.pmid: 22569414
references.citation: J Pediatr Surg. 2012 Jun;47(6):1135-42
references.pmid: 22703783
references.citation: J Med Chem. 2009 Nov 12;52(21):6919-25
references.pmid: 19821572
references.citation: J Surg Res. 2010 Jun 1;161(1):1-8
references.pmid: 19922948
references.citation: Am J Physiol Gastrointest Liver Physiol. 2010 Aug;299(2):G467-75
references.pmid: 20489044
references.citation: J Surg Res. 2010 Sep;163(1):79-85
references.pmid: 20599220
references.citation: Inflamm Bowel Dis. 2011 Feb;17(2):532-42
references.pmid: 20645323
references.citation: J Pediatr Surg. 2013 Jan;48(1):124-8
references.pmid: 23331804