High-dose inhaled nitric oxide and hyperoxia increases lung collagen accumulation in piglets

Nitric oxide (NO), a pro-oxidant gas, is used with hyperoxia (O-2) to treat neonatal pulmonary hypertension and recently bronchopulmonary dysplasia, b ut great concerns remain regarding NO's potential toxicity. Based on report s that exposure to oxidant gases results in pulmonary extracellular matrix injury associated with elevated lavage fluid levels of extracellular matrix components, we hypothesized that inhaled NO with or without hyperoxia will have the same effect. We measured alveolar septal width, lung collagen con tent, lavage fluid hy droxyproline, hyaluronan and laminin levels in neonat al piglets after 5 days' exposure to room air (RA), RA + 50 ppm NO (RA + NO ), O-2 (FiO(2) > 0.96) Or O-2 + NO Matrix metalloproteinase (MMP) activity and MMP-2 mRNA were also measured. In recovery experiments, we measured lun g collagen content in piglets exposed to RA + NO or O-2 + NO and then allow ed to recover for 3 days. The results show that lung collagen increased 4-f old in the RA + NO piglets, the O-2 and O-2 + NO groups had only a 2-fold e levation relative to RA controls. Unlike the RA + NO piglets, the O-2 and O -2 + NO groups had more than 20-fold elevation in lung ravage fluid hydroxy proline compared to the RA group. O-2 and O-2 + NO also had increased lung MMP activity, extravascular water, and lavage fluid proteins. MMP-2 mRNA le vels were unchanged. After 3 days' recovery in room air, the RA + NO groups ' lung collagen had declined from 4-fold to 2-fold above the RA group value s. The O-2 + NO group did not decline. Alveolar septal width increased sign ificantly only in the O-2 and O-2 + NO groups. We conclude that 5 days' exp osure to NO does not result in pulmonary matrix degradation but instead sig nificantly increases lung collagen content. This effect appears potentially reversible. In contrast, hyperoxia exposure with or without NO results in pulmonary matrix degradation and increased lung collagen content. The obser vation that NO increased lung collagen content represents a new finding and suggests NO could potentially induce pulmonary fibrosis. Copyright (C) 200 0 S. Kaiger AG, Basel.