Inflammatory Mediators in Tracheal Aspirates of Preterm Infants Participating in a Randomized Trial of Inhaled Nitric Oxide

PLoS One. 2017 Jan 3;12(1):e0169352. doi: 10.1371/journal.pone.0169352. eCollection 2017.

Abstract

Background: Ventilated preterm infants frequently develop bronchopulmonary dysplasia (BPD) which is associated with elevated inflammatory mediators in their tracheal aspirates (TA). In animal models of BPD, inhaled nitric oxide (iNO) has been shown to reduce lung inflammation, but data for human preterm infants is missing.

Methods: Within a European multicenter trial of NO inhalation for preterm infants to prevent BPD (EUNO), TA was collected to determine the effects of iNO on pulmonary inflammation. TA was collected from 43 premature infants randomly assigned to receive either iNO or placebo gas (birth weight 530-1230 g, median 800 g, gestational age 24 to 28 2/7 weeks, median 26 weeks). Interleukin (IL)-1β, IL-6, IL-8, transforming growth factor (TGF)-β1, interferon γ-induced protein 10 (IP-10), macrophage inflammatory protein (MIP)-1α, acid sphingomyelinase (ASM), neuropeptide Y and leukotriene B4 were measured in serial TA samples from postnatal day 2 to 14. Furthermore, TA levels of nitrotyrosine and nitrite were determined under iNO therapy.

Results: The TA levels of IP-10, IL-6, IL-8, MIP-1α, IL-1β, ASM and albumin increased with advancing postnatal age in critically ill preterm infants, whereas nitrotyrosine TA levels declined in both, iNO-treated and placebo-treated infants. The iNO treatment generally increased nitrite TA levels, whereas nitrotyrosine TA levels were not affected by iNO treatment. Furthermore, iNO treatment transiently reduced early inflammatory and fibrotic markers associated with BPD development including TGF-β1, IP-10 and IL-8, but induced a delayed increase of ASM TA levels.

Conclusion: Treatment with iNO may have played a role in reducing several inflammatory and fibrotic mediators in TA of preterm infants compared to placebo-treated infants. However, survival without BPD was not affected in the main EUNO trial.

Trial registration: NCT00551642.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Administration, Inhalation
  • Albumins / metabolism
  • Analysis of Variance
  • Case-Control Studies
  • Chemokines / metabolism
  • Demography
  • Female
  • Humans
  • Infant, Newborn
  • Infant, Premature / metabolism*
  • Inflammation Mediators / metabolism*
  • Male
  • Nitric Oxide / administration & dosage*
  • Nitrites / metabolism
  • Sphingomyelin Phosphodiesterase / metabolism
  • Suction
  • Trachea / metabolism*
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism

Substances

  • Albumins
  • Chemokines
  • Inflammation Mediators
  • Nitrites
  • Nitric Oxide
  • 3-nitrotyrosine
  • Tyrosine
  • Sphingomyelin Phosphodiesterase

Associated data

  • ClinicalTrials.gov/NCT00551642

Grants and funding

We acknowledge financial support by iNO Therapeutics. We declare that iNO Therapeutics had no role in the study design, data collection and analysis, their interpretation, in writing of the paper and in the decision to submit the publication. We further acknowledge support from the German Research Foundation (DFG) and Leipzig University within the program of Open Access Publishing. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.