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The Vascular Contribution to Necrotizing Enterocolitis

eeding, gastrointestinal bacterial colonization, gut motil- NEC. This is the first study to demonstrate reduced eNOS

F ity, cytokines, vascular factors, and gut blood flow all have
been implicated in the etiology and pathogenesis of nec-
rotizing entercolitis (NEC). Further, neonatal complications
function in human tissue samples from patients with NEC.
Nowicki et al show that eNOS activity and NO pro-
duction are decreased in the arterioles of infants with NEC.1
such as respiratory distress syndrome, respiratory disease, apnea, The lack of function of a vasodilatory regulator certainly adds
infection, hypotension, asphyxia, and patent ductus arteriosus to the description of lack of appropriate flow to the bowel in
increase the risk for development of NEC. Infants with NEC the etiology and pathogenesis of NEC. Increased endothelin
generally present with feeding intolerance, abdominal distension, results in significant vasoconstriction that is not able to be
bilious gastric residuals or vomiting, or bloody stools. Nonspe- reversed in the arterioles of the small intestine with NEC.
cific presenting signs and symptoms include apnea, bradycardia, Nowicki et al2 previously provided evidence that intestinal
tissue from patients with NEC had higher concentrations of
desaturation episodes, cyanosis, lethargy, temperature instability,
endothelin. The bal-
poor peripheral perfusion, hypoglycemia, jaundice, and shock.
ance between vasocon-
Diagnosis of NEC is confirmed by the presence of the classic
striction and vasodila-
finding of pneumatosis intestinalis on abdominal x-ray. Associ-
tation is critical in
ated laboratory abnormalities can include metabolic acidosis, assuring bowel ho- See related article, p 40
leukopenia, thrombocytopenia, anemia, and clotting abnormal- meostasis.
ities of disseminated intravascular coagulation. Treatment con- Perhaps modula- Reprint requests: Dr Rosemary D. Higgins,
sists of supportive medical care and surgical care. tion of eNOS function Program Scientist for the Neonatal Re-
Vascular flow to the gastrointestinal tract plays a signifi- may be one modality to search Network, Pregnancy and Perinatol-
ogy Branch, Center for Developmental
cant role in gut development, integrity, and function. Blood flow target increasing blood Biology and Perinatal Medicine, NICHD,
is balanced between needs of the bowel and needs for blood flow flow in ischemic bowel. NIH, 6100 Executive Blvd., Room 4B03B,
MSC 7510, Bethesda, MD 20892. E-mail:
to other organs. Control of blood flow, specifically the balance Possibly, infants who higginsr@mail.nih.gov.
between vasoconstriction and vasodilatation plays a key role in develop NEC have ge- J Pediatr 2007;150:xxx
maintaining gut integrity. Nowicki et al1 should be commended netic susceptibility fac- 0022-3476/$ - see front matter
for their report, published in this issue of the Journal, in delin- tors that render them Copyright © 2007 Mosby Inc. All rights
reserved.
eating the role of endothelial nitric oxide synthase (eNOS) in vulnerable to NEC,
10.1016/j.jpeds.2006.10.063

5
specifically related to eNOS or endothelin expression. Con-
versely, those infants who do not develop NEC may have genetic
protective factors.
Vascular control of blood vessel diameter is paramount to
appropriate blood flow. Lack of appropriate physiologic evidence
of eNOS function in gut vessels of infants with NEC is a new
finding. It remains to be seen whether or not these are innate
genetic differences in eNOS expression and response, or whether
this lack of eNOS expression and function is induced in the
infant at risk for NEC. Perhaps an environmental trigger in
susceptible infants occurs in the pathway to NEC.
Other factors including tissue oxygen levels, cytokines,
vasoactive agents, and factors that can enhance or reduce blood
flow are likely to play a role in control of vasoconstriction and
vasodilatation in mesenteric circulation. Circulatory responses to
factors that affect mesenteric vascular flow have previously been
implication in neonatal disease.3 Injury and reperfusion are also
likely to be involved in the cascade of events that results in NEC.
NEC remains a dreadful disease in the neonatal intensive
6 Higgins
care unit. A brief lack of blood flow to the bowel or alteration of
mucosal integrity can change an infant’s destiny. The research
direction needed for NEC involves identification of children at
high risk and prevention of this devastating disease. Identifica-
tion may potentially be accomplished by newer methods of
genomic and proteomic identification and risk interactions with
the environment. Prevention of NEC remains a challenge.
Rosemary D. Higgins, MD
National Institutes of Health
Bethesda, MD
REFERENCES
1. Nowicki PT, Caniano DM, Hammond S, Giannone PJ, Besner G, Reber KM, et al.
Endothelial nitric oxide synthase in human intestine resected for necrotizing enterocolitis.
J Pediatr 2006;150:40.
2. Nowicki PT, Dunaway DJ, Nankervis CA, Giannone PJ, Reber KM, Hammond
SB, et al. Endothelin-1 in human intestine resected for necrotizing enterocolitis.
J Pediatr 2005;146:805-10.
3. Cheung PY, Barrington KJ, Bigam DL. Temporal effects of prolonged hypoxaemia and
reoxygenation on systemic, pulmonary and mesenteric perfusions in newborn piglets. Car-
diovasc Res 1998;39:451-8.
The Journal of Pediatrics • January 2007