Plasma Protein 3-Nitrotyrosine (PPNT) Levels in Infants with Severe Ventilator Dependent Bronchopulmonary Dysplasia (BPD) Treated with Inhaled Nitric Oxide (iNO)

Abstract 1071 Poster Session I, Saturday, 5/1 (poster 78)

As part of a Phase II trial to examine the safety of iNO therapy for preterm infants with severe ventilator dependent BPD, the levels of plasma protein 3-nitrotyrosine (PPNT) were measured on 11 infants (69 samples) using solid phase, antibody capture, immunoradiochemical techniques. Nitration of tyrosine residues in protein is derived by secondary reactions of nitric oxide with reactive oxygen species. This protein modification has been associated with a number of potentially toxic effects in the lung including damage to surfactant proteins, decreased phosphatidylcholine synthesis by type II cells, and inhibition of epithelial cell ion channels. We have previously reported elevated levels of PPNT during the first month of life in preterm infants who develop BPD (median 0.34 ng/mg protein, range 0.05-1.3) (Pediatrics 101:870-4, 1998). In contrast, term infants treated with iNO for persistent pulmonary hypertension had low (≤0.1 ng/mg protein) or undetectable PPNT before, during, and after iNO (Pediatr Res 41[4]:138A, 1997). Infants, age 1 to 7 months (23-29 wks gestation; birthweight 448-1790g), ventilated and requiring ≥ 0.45 FiO₂, were entered into the current pilot study and treated with iNO at 20ppm for 72 hours (Pediatr Res 41[4]:246A, 1997). Infants who responded to iNO with decreased oxygen requirement were weaned as tolerated every 3 days and received a prolonged treatment course (max 3 months). All infants had detectable levels of PPNT prior to being treated with iNO (median level = 0.4ng/mg protein, range 0.2 to 2.2). No infant had an increase in PPNT during treatment with iNO, and infants who had a reduction in FiO₂ while on iNO had a significant percent reduction in PPNT over time (mean % reduction ± SE = 50 ± 15%, P < 0.01). Three of 4 infants who died had persistently elevated PPNT levels ≥ 0.45 ng/mg protein, while all of the survivors had declining or persistently low PPNT levels during treatment with iNO. We conclude that infants with established severe BPD have detectable or elevated levels of PPNT, suggesting ongoing nitrative stress. Treatment with iNO of 20ppm or less for up to 3 months was not associated with increased levels of PPNT in this population, and decreasing PPNT levels over time were associated with clinical improvement. Funded by NIH RR-00240, HL-54926, and AG-16987.