Plasma 8-Isoprostane Is Increased in Preterm Infants Who Develop Bronchopulmonary Dysplasia or Periventricular Leukomalacia

Abstract

Our aim was to assess the plasma free 8-epi-prostaglandin F 2␣ (8-isoprostane) and ascorbyl radical as risk indicators for oxidative damage in extremely low birth weight infants (ELBWIs) and the effect of N-acetylcysteine (NAC) on these markers. Plasma samples were collected on days 3 and 7 of life from infants who were enrolled in a randomized, controlled trial in which i.v. NAC or placebo was administered to ELBWIs during the first week of life, with the aim of preventing bronchopulmonary dysplasia (BPD). Plasma 8-isoprostane was analyzed in 83 infants using an enzyme immunoassay kit. Ascorbyl radical concentration was measured in 61 infants with electron spin resonance spectroscopy. The 8-isoprostane concentrations were similar in the NAC and placebo groups. In infants who later developed BPD or died (n ϭ 29), the median (range) 8-isoprostane concentration was significantly higher (p ϭ 0.001) on day 3 and day 7 [50.0 pg/mL (19 -360) and 57.0 pg/mL (14 -460), respectively] than in survivors without BPD [n ϭ 54; 34.5 pg/mL (5-240) and 39.5 pg/mL (7-400), respectively]. The 8-isoprostane levels increased significantly more (p Ͻ 0.05) in infants who later developed periventricular leukomalacia. NAC treatment or the later development of BPD was not related to the ascorbyl radical levels. The ascorbyl radical level decreased significantly in all groups from day 3 to day 7, but the difference between the groups was not significant. The mean (SD) ascorbyl radical level on day 3 was significantly higher (p Ͻ 0.01) in infants who later developed periventricular leukomalacia [287 (124) Free radical generation and oxidative injury have been implicated as causal factors in several complications of prematurity, such as bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), and periventricular leukomalacia (PVL) (1). Despite improved perinatal care, BPD remains one of the most important causes of long-term morbidity after preterm birth (2). Oxygen therapy and inflammatory neutrophil activation are considered important in increasing the production of reactive oxygen species (ROS) and the release of proinflammatory cytokines resulting in abnormal lung development. Evidence for increased oxidant production and oxidant-induced macromolecular damage has been demonstrated during the first week of life in infants who develop BPD (2,3). Increased levels of volatile lipid peroxidation products have been shown to correlate with poor respiratory outcome and death in very low birth weight infants (4).Preterm newborn infants are considered vulnerable to oxidative stress because of deficient antioxidant capacity. Even though the enzymatic antioxidant defenses of preterm infants seem relatively well developed, with the exception of catalase (5)

Urinary F2-isoprostanes are poor prognostic indicators for the development of bronchopulmonary dysplasia

“…Our findings are in contrast with those of Ahola et al, 13 who reported that plasma levels of isoprostanes increase in the first week of life in preterm infants who later develop BPD. Several reasons may explain our findings.…”

“…It is possible that the large standard deviation in the levels of 8-iso-PGF 2a excretion along with the small number of patients in our study may have resulted in a Type II error; a larger study with a greater number of patients may reveal statistical differences between the two groups, which would support the hypothesis that lipid peroxidation occurs as part of the pathogenesis of BPD. However, the marked variability of both plasma isoprostane levels 13 and urinary isoprostane excretion (this study) that result in a large overlap in the ranges of the results of infants who do or do not develop BPD limit the utility of isoprostanes as a predictive marker for BPD. …”

“…14 Third, we measured isoprostanes using gas chromatography/mass spectrometry (GC-MS), which is a very sensitive and specific method compared to enzyme immunoassay (EIA) that has been used by other investigators. 13,15 To our knowledge, this is the first study to attempt to measure isoprostanes by GC-MS in the urine of preterm infants with regard to BPD. Differences in methodology (GC-MS vs EIA) may explain differences in results between the study by Ahola et al 13 on plasma isoprostanes and ours on urine isoprostanes.…”

“…13,15 To our knowledge, this is the first study to attempt to measure isoprostanes by GC-MS in the urine of preterm infants with regard to BPD. Differences in methodology (GC-MS vs EIA) may explain differences in results between the study by Ahola et al 13 on plasma isoprostanes and ours on urine isoprostanes. For example, it is possible that the EIA assay recognizes fragments or forms that are not detected by the GC-MS method.…”

Advances in emerging treatment options to prevent bronchopulmonary dysplasia

“…In one study, the plasma concentration of cysteine was lower in the N-acetyl cysteine treated group [95].…”