Inhaled nitric oxide enhances distal lung growth after exposure to hyperoxia in neonatal rats

Pediatr Res. 2005 Jul;58(1):22-9. doi: 10.1203/01.PDR.0000163378.94837.3E. Epub 2005 May 5.


Exposure of newborn rats to hyperoxia impairs alveolarization and vessel growth, causing abnormal lung structure that persists during infancy. Recent studies have shown that impaired angiogenesis due to inhibition of vascular endothelial growth factor (VEGF) signaling decreases alveolar and vessel growth in the developing lung, and that nitric oxide (NO) mediates VEGF-dependent angiogenesis. The purpose of this study was to determine whether hyperoxia causes sustained reduction of lung VEGF, VEGF receptor, or endothelial NO synthase (eNOS) expression during recovery, and whether inhaled NO improves lung structure in infant rats after neonatal exposure to hyperoxia. Newborn rat pups were randomized to hyperoxia [fraction of inspired oxygen (Fio(2)), 1.00] or room air exposure for 6 d, and then placed in room air with or without inhaled NO (10 ppm) for 2 wk. Rats were then killed for studies, which included measurements of body weight, lung weight, right ventricular hypertrophy (RVH), morphometric analysis of alveolarization (by mean linear intercept (MLI), radial alveolar counts (RAC), and vascular volume (Vv), and immunostaining and Western blot analysis. In comparison with controls, neonatal hyperoxia reduced body weight, increased MLI, and reduced RAC in infant rats. Lung VEGF, VEGFR-2, and eNOS protein expression were reduced after hyperoxia. Inhaled NO treatment after hyperoxia increased body weight and improved distal lung growth, as demonstrated by increased RAC and Vv and decreased MLI. We conclude that neonatal hyperoxia reduced lung VEGF expression, which persisted during recovery in room air, and that inhaled NO restored distal lung growth in infant rats after neonatal hyperoxia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Animals, Newborn
  • Blotting, Western
  • Body Weight
  • Hypertrophy
  • Hypoxia / metabolism
  • Immunohistochemistry
  • Lung / metabolism*
  • Lung / pathology*
  • Lung Injury
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type III
  • Organ Size
  • Oxygen / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism


  • Vascular Endothelial Growth Factor A
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type III
  • Nos3 protein, rat
  • Vascular Endothelial Growth Factor Receptor-2
  • Oxygen