NETs: Protection or Harm in Neonatal Inflammation or Infection

May 5, 2023 updated by: Christian Con Yost, University of Utah
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.

Study Overview

Status

Recruiting

Conditions

Detailed Description

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].

Study Type

Observational

Enrollment (Anticipated)

388

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Utah
      • Salt Lake City, Utah, United States, 84112
        • Recruiting
        • University of Utah
        • Contact:
        • Principal Investigator:
          • Christian C Yost, M.D.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 1 hour (Child)

Accepts Healthy Volunteers

Yes

Sampling Method

Non-Probability Sample

Study Population

Patients hospitalized in the NICU who were less than or equal to 1500 grams or less than 30 weeks gestational age at birth

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Other
  • Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
The incidence and survival of premature infants with NEC, defined prospectively as disease meeting criteria for Bell's classification category IIA or greater [See Table 1] as applied by the subject's attending physician.
Time Frame: 2 years
2 years

Secondary Outcome Measures

Outcome Measure
Time Frame
Multiple morbidities and other clinical data will be collected and evaluated with respect to NEC and PMN protein analysis
Time Frame: 2 years
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Utah

Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 1, 2003

Primary Completion (Anticipated)

April 30, 2025

Study Completion (Anticipated)

April 30, 2025

Study Registration Dates

First Submitted

September 3, 2008

First Submitted That Met QC Criteria

September 4, 2008

First Posted (Estimate)

September 5, 2008

Study Record Updates

Last Update Posted (Actual)

May 8, 2023

Last Update Submitted That Met QC Criteria

May 5, 2023

Last Verified

May 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 11919
  • R01HD093826 (U.S. NIH Grant/Contract)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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