INHALED NITRIC-OXIDE PREVENTS NEUTROPHIL-MEDIATED, OXYGEN RADICAL-DEPENDENT LEAK IN ISOLATED RAT LUNGS

We found that ventilation with nitric oxide (NO, 50 ppm) significantly (P < 0.05) reduced capillary leak (as reflected by weight gain and Ficoll retention) in isolated rat lungs perfused for 60 min with N-formylmethionyl-leucyl-phenylalanine (fMLP; 10(-7) M) and human neutrophils (1,300/mu l). Perfusion with previously heated neutrophils (48 degrees C for 10 min, which inactivates NADPH oxidase) did not cause weight gain or Ficoll retention, indicating that neutrophil-derived oxidants mediated lung leak. Although perfusion with fMLP and neutrophils increased mean pulmonary artery pressures (($$$) over bar PAP) from 7 to 11.7 +/- 0.5 mmHg at 10 min, lungs perfused with fMLP and neutrophils in which ($$$) over bar PAP was maintained at 7 mmHg by reducing perfusion flow rates also developed significant (P < 0.05) weight gain and Ficoll retention. Furthermore, inhaled NO did not reduce (P > 0.05) ($$$) over bar PAP at 10 min and only modestly reduced ($$$) over bar PAP at 30 and 60 min of perfusion. Our results suggest that-oxidative endothelial damage, and not increased hydrostatic pressure, was the primary cause of the capillary leak, and that the protection provided by inhaled NO was not solely a consequence of vasodilation. We conclude that inhaled NO prevents neutrophil-mediated, oxygen radical-dependent leak in isolated rat lungs, and speculate that inhaled NO has anti-inflammatory properties in addition to its ability to cause pulmonary vasodilation.