Early inhaled nitric oxide at high dose enhances rat lung development after birth

Nitric Oxide. 2014 Apr 30;38:8-16. doi: 10.1016/j.niox.2014.02.004. Epub 2014 Feb 22.


Rational: Inhaled nitric oxide (NO) is frequently administered to full term and preterm newborns in various clinical settings in order to alleviate pulmonary hypertension whilst improving oxygenation. However, the physiological effect of NO on early postnatal lung development has not yet been clearly described. We therefore investigated whether NO administered by inhalation affects lung development at early postnatal life.

Methods: Pregnant rats were placed in a chamber containing 5 ppm (iNO-5 ppm group) and 20 ppm NO (iNO-20 ppm group), started from the last day of their pregnancy in order to keep rat pups under ambient NO from birth to 7 days postnatal. Control animals were kept at room air and all rat pups were sacrificed at postnatal day 7 and day 14.

Results: Lung-to-body weight and wet-to-dry lung weight ratios did not significantly differ among 3 groups at postnatal day 7 and day 14. Vascular volume densities (Vv) in both NO groups (5 and 20 ppm) were higher than controls (P<0.05; P<0.001). Pulmonary vessel number was significantly increased in iNO-20 ppm group. Radial alveolar counts (RAC) and mean linear intercepts (MLI) markedly increased (consistent with increased alveolarization) in iNO-20 ppm group. This was associated with upregulation of VEGF/VEGFR-2, MT1-MMP/MMP2 and HO-1 protein expression in iNO-20 ppm group.

Conclusions: We concluded that inhaled NO at 20 ppm enhanced lung development possibly through increased expression of HO-1, VEGF/VEGFR-2, and MMP2 at early stage of postnatal rat life.

Keywords: Alveolarization; Angiogenesis; Inhaled NO; Lung development; VEGF/VEGFR-2.

MeSH terms

  • Administration, Inhalation
  • Animals
  • Body Weight / drug effects
  • Female
  • Lung / drug effects*
  • Lung / growth & development*
  • Lung / metabolism
  • Nitric Oxide / administration & dosage*
  • Nitric Oxide / pharmacology*
  • Organ Size / drug effects
  • Pregnancy
  • Rats
  • Rats, Sprague-Dawley


  • Nitric Oxide