Necrotizing Enterocolitis (NEC) & Platelet-Activating Factor (PAF)-Stimulated Protein Translation in Premature Infants

Conditions:Colitis, Gastrointestinal
Therapuetic Areas:Gastroenterology
Age Range:Any
Start Date:October 2003
End Date:December 2019
Contact:Christian C Yost, M.D.

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This is a prospective in vitro cell biology study of polymorphonuclear leukocyte (PMN)
protein synthesis in response to PAF. PMNs from cord blood of premature human infants at risk
for NEC (birth weight between 501 - 1500 grams) and PMNs from cord blood of healthy term
infants will be isolated and stimulated with PAF, a biologically active phospholipid
implicated in the pathogenesis of NEC. NEC, a disease of prematurity with an incidence of
10.1% of infants born weighing between 501 - 1500 grams, is associated with significant
morbidity and mortality. We will compare the protein synthesis of inflammatory modulators,
including Interleukin 6 Receptor alpha (IL-6R alpha) and Retinoic Acid Receptor alpha (RAR
alpha) proteins to protein synthesis responses already observed in PMNs isolated from healthy
adults. Furthermore, we will characterize the expression and activity of the mammalian target
of rapamycin (mTOR) translational protein synthesis control pathway in PMNs isolated from
preterm and term infants and compare those results with previous observations in PMNs
isolated from adults. This pathway is known to regulate IL-6R alpha and RAR alpha protein
expression in PMNs isolated from adults. We will also follow those premature infants at risk
for NEC clinically to determine which infants develop NEC and what risk factors may be
associated with NEC in this population.

Many pediatric diseases including Systemic Inflammatory Response Syndrome (SIRS), sepsis,
Acute Respiratory Distress Syndrome (ARDS) and neonatal Chronic Lung Disease (CLD) have been
associated with dysregulation of the acute inflammatory response [1]. So it is with
necrotizing enterocolitis (NEC). NEC, a disease of premature infants, afflicts 10% of very
low birth weight infants. This disease is often fatal [2]. Less significant but nonetheless
devastating sequelae include intestinal perforation, short gut syndrome, prolonged total
parenteral nutrition with possible concomitant liver failure and a prolonged intensive care
unit stay. The etiology remains unknown, although risk factors of prematurity, enteral feeds,
infection and intestinal ischemia are associated with NEC [3].

The final common pathway for NEC appears, at least in part, to be mediated through the
biologically active phospholipid platelet-activating factor (PAF). Each identified risk
factor for NEC increases the serum levels of PAF in premature infants[4, 5]. Furthermore,
serum levels of PAF-acetylhydrolase (PAF-AH), the enzyme responsible for catabolizing PAF,
are lower in premature infants compared to term infants and lower in term infants compared to
young children and adults [6, 7]. Although no clinical trials of PAF antagonists have been
conducted in premature human infants, various PAF antagonists prevent NEC-like clinical
disease in animal models [8-10].

Other data from animal models suggest a prominent role of the polymorphonuclear leukocyte
(PMN) in the pathogenesis of NEC. Musemeche et al. induced NEC-like disease in rats by
intra-aortic injection of PAF [11]. They used vinblastine, a chemotherapeutic agent with a
side-effect profile significant for induction of neutropenia, to induce neutropenia in rats
four days prior to intra-aortic injection of PAF. The vinblastine-induced neutropenia was
protective for the clinical and pathologic manifestations of NEC-like disease. Other
investigators have demonstrated an increase in PAF levels in the gastrointestinal tracts of
rats subjected to gut ischemia/reperfusion. The elevated levels of intestinal PAF were then
shown to chemo attract and prime PMNs [12].

The role of the human PMN in the acute inflammatory response is well documented. They play a
fundamental role in the non-specific immune response and are rapidly recruited to areas of
injury or inflammation where they participate in bacterial phagocytosis and killing.
Disorders associated with a deficiency or impairment of PMNs (neutropenia, chronic
granulomatous disease, leukocyte adhesion deficiency) predispose to infections with
gram-negative and gram-positive bacteria [13]. However, regulation of this potent component
of the acute inflammatory response is imperative. Disorders such as ARDS,
ischemia/reperfusion injury and rheumatoid arthritis appear to result from the dysregulation
of the PMNs' acute inflammatory response [1].

The molecular mechanisms regulating the PMNs' response in acute inflammation are not fully
understood. In neutrophil priming, the activation of the NADPH oxidase enzyme via
receptor-mediated stimulation with mediators such as fMLP or PAF is an increasingly complex
process involving various cellular secondary messengers and the Rho family GTPase Rac2 [14,
15]. The mechanisms regulating PMN synthesis and release of pro-inflammatory cytokines such
as IL-8 are less well understood. The mechanisms regulating PMN apoptosis are also not well
understood. In vitro and in vivo studies indicate that the pro-inflammatory agents
responsible for the priming of human PMNs also affect the longevity of those cells by
delaying the PMNs in-built capacity to undergo apoptosis. In vitro studies on human PMNs show
that pro-inflammatory mediators like Granulocyte/Macrophage - Colony Stimulating Factor
(GM-CSF), Interleukin-8 (IL-8), Lipopolysaccharide (LPS), Complement 5a (C5a) and
Interleukin-6 (IL-6) inhibit PMN apoptosis, while Tumor Necrosis Factor (TNF) and Fas-ligand
(Fas-L) accelerate the rate of neutrophil apoptosis [16].

Inclusion Criteria:

- Patients hospitalized in the NICU who were less than or equal to 1500 grams or less
than 30 weeks gestational age at birth; Term infants delivered at UUMC without
complication, either via cesarean section or vaginal delivery; Cord blood isolated
within first hour of life; and parents or guardians must have signed informed consent.

Exclusion Criteria:

- Infants with major congenital anomalies will be excluded.
We found this trial at
201 Presidents Circle
Salt Lake City, Utah 84108
801) 581-7200
Principal Investigator: Christian C Yost, M.D.
Phone: 801-581-7052
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