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Mesenteric nitric oxide and superoxide production in experimental necrotizing enterocolitis. J Surg Res 2010 Jun 01;161(1):1-8 PMID: 19922948 PMCID: PMC3196648

Pubmed ID

19922948

DOI

10.1016/j.jss.2009.07.028

Abstract

BACKGROUND: A proposed mechanism of intestinal injury in necrotizing enterocolitis (NEC) involves vascular dysfunction through altered nitric oxide synthase (NOS) activity. We hypothesize that this dysfunction results in an imbalance in nitric oxide (*NO) and superoxide (O(2)(*-)) production by the intestinal vascular endothelium, which contributes to the intestinal injury seen in NEC.

MATERIALS AND METHODS: Neonatal rat pups were divided into two groups. Control pups were breast fed and housed with their mother. Experimental NEC pups were housed separately and either exposed to formula feeding and 5% to 10% hypoxia alone (FF/H) or with the addition of lipopolysaccharide (FF/H/LPS). Mesenteries from each group were analyzed for *NO and O(2)(*-) production with and without NOS inhibition by N(G)-monomethyl-L-arginine (L-NMMA). Western blot analysis for eNOS, phosphorylated eNOS (phospho-eNOS), and inducible NOS (iNOS) was performed, and each terminal ileum was graded for intestinal injury by histology.

RESULTS: Histology revealed mild intestinal injury (grade 1-2 on a 4-point scale) in the FF/H group and severe injury (grade 3-4) in the FF/H/LPS group. The FF/H cohort had significantly increased *NO and lower O(2)(*-) production, while the FF/H/LPS group shifted to significantly decreased *NO and increased O(2)(*-) production. L-NMMA inhibited >50% of O(2)(*-) production in all three groups but only inhibited *NO production in control and FF/H pups. Western blot analysis revealed increased levels of phospho-eNOS in FF/H pups and increased iNOS in FF/H/LPS pups.

CONCLUSIONS: This study demonstrates in the progression of NEC, intestinal ischemia is associated with a shift from *NO to O(2)(*-) production, which is NOS-dependent. Potentially greater injury results from impaired vasodilatation and over-production of reactive oxygen species.

Author List

Whitehouse JS, Xu H, Shi Y, Noll L, Kaul S, Jones DW, Pritchard KA Jr, Oldham KT, Gourlay DM

Authors

David M. Gourlay MD Chief, Professor in the Surgery department at Medical College of Wisconsin
Keith T. Oldham MD Professor in the Surgery department at Medical College of Wisconsin
Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin




Scopus

2-s2.0-77951621050   28 Citations

MESH terms used to index this publication - Major topics in bold

Animals
Animals, Newborn
Enterocolitis, Necrotizing
Mesentery
Nitric Oxide
Rats
Rats, Sprague-Dawley
Superoxides
jenkins-FCD Prod-310 bff9d975ec7f2d302586822146c2801dd4449aad