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(Chest. 2005;128:613S-614S.)
© 2005 American College of Chest Physicians

Inhaled Nitric Oxide Reverses Hypoxia Induced Lung Hypoplasia in Endothelial Nitric Oxide Synthase-Deficient Mice*

Vivek Balasubramaniam, MD; Anne Maxey, BS and Steven Abman, MD

* From the Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado Health Sciences Center, Denver, CO.

Correspondence to: Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado Health Sciences Center, 4200 E Ninth Ave, C-218, Denver, CO 80262; e-mail: vivek.balasubramaniam{at}uchsc.edu

Inhibition of angiogenesis impairs alveolarization in the developing lung, but mechanisms linking alveolarization and vascular growth are unclear. We have previously shown that exposure to mild hypoxia (fraction of inspired oxygen, 0.16) during early postnatal life decreases alveolarization and reduces vascular density in endothelial nitric oxide synthase (eNOS)-deficient mice. Although these findings support an adaptive role for nitric oxide (NO) in maintaining lung growth during mild hypoxia, the effects of NO on lung growth during recovery after hypoxia are unknown. Therefore, we hypothesize that mice with eNOS deficiency have sustained impairment of lung structure after neonatal hypoxia, and that inhaled NO (iNO) therapy may enhance alveolar and vascular growth during recovery after neonatal hypoxia.

Litters of 1-day-old mouse pups from heterozygote eNOS-deficient matings were placed in a hypobaric chamber at a simulated altitude of 12,300 feet (fraction of inspired oxygen, 0.16). After 10 days, the litters were allowed to recover in room air or in room air plus iNO (10 ppm). At 3 weeks of age, the mice were euthanized and lung tissue was collected. Body weight, size, and lung weight were measured. Lung morphometric analysis of alveolarization included measurements of mean linear intercept (MLI) and by skeletonization, which quantifies nodal points per high-power field.1

At 3 weeks, body and wet lung weights were not different between the eNOS -/- mice recovered in room air or iNO, or in comparison with wild-type littermates. After 10 days of mild hypoxia, MLI of eNOS -/- mice was increased by 25% as compared to wild-type littermates (52 ± 2 µm vs 41 ± 1 µm; p < 0.01) [mean ± SEM]. With recovery in room air, MLI of eNOS -/- mice remained elevated at 42% greater than wild-type control mice (64 ± 2.5 µm vs 44.9 ± 1.3 µm; p < 0.01). iNO therapy during recovery reduced MLI of the eNOS -/- mice (42.5 ± 0.7 µm) to levels seen in wild-type mice. In addition, nodal points in the eNOS -/- mice recovered in room air were decreased by 29% as compared to wild-type littermates (p < 0.01). Recovery in iNO increased the number of nodal points in the eNOS-/- mice as compared to eNOS -/- animals recovered in room air (p < 0.01).

We conclude that eNOS -/- mice have decreased alveolarization after mild hypoxia that persists despite prolonged recovery in room air. Late treatment with iNO enhances the recovery of distal lung growth after hypoxia in eNOS -/- mice. These findings suggest that eNOS activity contributes to lung growth during chronic hypoxia and during recovery after neonatal hypoxia.


   Footnotes
 
Abbreviations: eNOS = endothelial nitric oxide synthase; iNO = inhaled nitric oxide; MLI = mean linear intercept; NO = nitric oxide


   References
TOP
 References
 

  1. Tschanz, SA, Burri, PH (2002) A new approach to detect structural differences in lung parenchyma using digital image analysis. Exp Lung Res 28,457-471[CrossRef][ISI][Medline]




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